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Sample records for hybrid virtual screening

  1. Discovery of novel Bruton's tyrosine kinase inhibitors using a hybrid protocol of virtual screening approaches based on SVM model, pharmacophore and molecular docking.

    Science.gov (United States)

    Wan, Hua-Lin; Wang, Ze-Rong; Li, Lin-Li; Cheng, Chuan; Ji, Pan; Liu, Jing-Jing; Zhang, Hui; Zou, Jun; Yang, Sheng-Yong

    2012-09-01

    Bruton's tyrosine kinase has emerged as a potential target for the treatment for B-cell malignancies and autoimmune diseases. Discovery of Bruton's tyrosine kinase inhibitors has thus attracted much attention recently. In this investigation, we introduced a hybrid protocol of virtual screening methods including support vector machine model-based virtual screening, pharmacophore model-based virtual screening and docking-based virtual screening for retrieving new Bruton's tyrosine kinase inhibitors from commercially available chemical databases. Performances of the hybrid virtual screening approach were evaluated against a test set, which results showed that the hybrid virtual screening approach significantly shortened the overall screening time, and considerably increased the hit rate and enrichment factor compared with the individual method (SB-VS, PB-VS and DB-VS) or their combinations by twos. This hybrid virtual screening approach was then applied to screen several chemical databases including Specs (202,408 compounds) and Enamine (980,000 compounds) databases. Thirty-nine compounds were selected from the final hits and have been shifted to experimental studies. © 2012 John Wiley & Sons A/S.

  2. Structure-based virtual screening of the nociceptin receptor: hybrid docking and shape-based approaches for improved hit identification.

    Science.gov (United States)

    Daga, Pankaj R; Polgar, Willma E; Zaveri, Nurulain T

    2014-10-27

    The antagonist-bound crystal structure of the nociceptin receptor (NOP), from the opioid receptor family, was recently reported along with those of the other opioid receptors bound to opioid antagonists. We recently reported the first homology model of the 'active-state' of the NOP receptor, which when docked with 'agonist' ligands showed differences in the TM helices and residues, consistent with GPCR activation after agonist binding. In this study, we explored the use of the active-state NOP homology model for structure-based virtual screening to discover NOP ligands containing new chemical scaffolds. Several NOP agonist and antagonist ligands previously reported are based on a common piperidine scaffold. Given the structure-activity relationships for known NOP ligands, we developed a hybrid method that combines a structure-based and ligand-based approach, utilizing the active-state NOP receptor as well as the pharmacophoric features of known NOP ligands, to identify novel NOP binding scaffolds by virtual screening. Multiple conformations of the NOP active site including the flexible second extracellular loop (EL2) loop were generated by simulated annealing and ranked using enrichment factor (EF) analysis and a ligand-decoy dataset containing known NOP agonist ligands. The enrichment factors were further improved by combining shape-based screening of this ligand-decoy dataset and calculation of consensus scores. This combined structure-based and ligand-based EF analysis yielded higher enrichment factors than the individual methods, suggesting the effectiveness of the hybrid approach. Virtual screening of the CNS Permeable subset of the ZINC database was carried out using the above-mentioned hybrid approach in a tiered fashion utilizing a ligand pharmacophore-based filtering step, followed by structure-based virtual screening using the refined NOP active-state models from the enrichment analysis. Determination of the NOP receptor binding affinity of a selected set

  3. Novel Hybrid Virtual Screening Protocol Based on Molecular Docking and Structure-Based Pharmacophore for Discovery of Methionyl-tRNA Synthetase Inhibitors as Antibacterial Agents

    Directory of Open Access Journals (Sweden)

    Cheng Peng

    2013-07-01

    Full Text Available Methione tRNA synthetase (MetRS is an essential enzyme involved in protein biosynthesis in all living organisms and is a potential antibacterial target. In the current study, the structure-based pharmacophore (SBP-guided method has been suggested to generate a comprehensive pharmacophore of MetRS based on fourteen crystal structures of MetRS-inhibitor complexes. In this investigation, a hybrid protocol of a virtual screening method, comprised of pharmacophore model-based virtual screening (PBVS, rigid and flexible docking-based virtual screenings (DBVS, is used for retrieving new MetRS inhibitors from commercially available chemical databases. This hybrid virtual screening approach was then applied to screen the Specs (202,408 compounds database, a structurally diverse chemical database. Fifteen hit compounds were selected from the final hits and shifted to experimental studies. These results may provide important information for further research of novel MetRS inhibitors as antibacterial agents.

  4. Virtual screening against obesity.

    Science.gov (United States)

    Markt, P; Herdlinger, S; Schuster, D

    2011-01-01

    The development of novel drugs against obesity is one of the top priorities of worldwide drug research. In recent years, it has been facilitated by the application of virtual screening methods. In this review, we give a short introduction into obesity-related protein targets and computer-aided drug design techniques. Furthermore, we highlight the most successful virtual screening studies, outline their results, and provide suggestions for future anti-obesity drug development.

  5. Virtual screening of virtual libraries.

    Science.gov (United States)

    Green, Darren V S

    2003-01-01

    Virtual screening of virtual libraries (VSVL) is a rapidly changing area of research. Great efforts are being made to produce better algorithms, selection methods and infrastructure. Yet, the number of successful examples in the literature is not impressive, although the quality of work certainly is high. Why is this? One reason is that these methods tend to be applied at the lead generation stage and therefore there is a large lead-time before successful examples appear in the literature. However, any computational chemist would confirm that these methods are successful and there exists a glut of start-up companies specialising in virtual screening. Moreover, the scientific community would not be focussing so much attention on this area if it were not yielding results. Even so, the paucity of literature data is certainly a hindrance to the development of better methods. The VSVL process is unique within the discovery process, in that it is the only method that can screen the > 10(30) genuinely novel molecules out there. Already, some VSVL methods are evaluating 10(13) compounds, a capacity that high throughput screening can only dream of. There is a huge potential advantage for the company that develops efficient and effective methods, for lead generation, lead hopping and optimization of both potency and ADME properties. To do this, it requires more than the software, it requires confidence to exploit the methodology, to commit synthesis on the basis of it, and to build this approach into the medicinal chemistry strategy. It is a fact that these tools remain quite daunting for the majority of scientists working at the bench. The routine use of these methods is not simply a matter of education and training. Integration of these methods into accessible and robust end user software, without dilution of the science, must be a priority. We have reached a coincidence, where several technologies have the required level of maturity predictive computational chemistry

  6. Encompassing receptor flexibility in virtual screening using ensemble docking-based hybrid QSAR: discovery of novel phytochemicals for BACE1 inhibition.

    Science.gov (United States)

    Chakraborty, Sandipan; Ramachandran, Balaji; Basu, Soumalee

    2014-10-01

    Mimicking receptor flexibility during receptor-ligand binding is a challenging task in computational drug design since it is associated with a large increase in the conformational search space. In the present study, we have devised an in silico design strategy incorporating receptor flexibility in virtual screening to identify potential lead compounds as inhibitors for flexible proteins. We have considered BACE1 (β-secretase), a key target protease from a therapeutic perspective for Alzheimer's disease, as the highly flexible receptor. The protein undergoes significant conformational transitions from open to closed form upon ligand binding, which makes it a difficult target for inhibitor design. We have designed a hybrid structure-activity model containing both ligand based descriptors and energetic descriptors obtained from molecular docking based on a dataset of structurally diverse BACE1 inhibitors. An ensemble of receptor conformations have been used in the docking study, further improving the prediction ability of the model. The designed model that shows significant prediction ability judged by several statistical parameters has been used to screen an in house developed 3-D structural library of 731 phytochemicals. 24 highly potent, novel BACE1 inhibitors with predicted activity (Ki) ≤ 50 nM have been identified. Detailed analysis reveals pharmacophoric features of these novel inhibitors required to inhibit BACE1.

  7. Machine learning in virtual screening.

    Science.gov (United States)

    Melville, James L; Burke, Edmund K; Hirst, Jonathan D

    2009-05-01

    In this review, we highlight recent applications of machine learning to virtual screening, focusing on the use of supervised techniques to train statistical learning algorithms to prioritize databases of molecules as active against a particular protein target. Both ligand-based similarity searching and structure-based docking have benefited from machine learning algorithms, including naïve Bayesian classifiers, support vector machines, neural networks, and decision trees, as well as more traditional regression techniques. Effective application of these methodologies requires an appreciation of data preparation, validation, optimization, and search methodologies, and we also survey developments in these areas.

  8. Molecular fingerprint similarity search in virtual screening.

    Science.gov (United States)

    Cereto-Massagué, Adrià; Ojeda, María José; Valls, Cristina; Mulero, Miquel; Garcia-Vallvé, Santiago; Pujadas, Gerard

    2015-01-01

    Molecular fingerprints have been used for a long time now in drug discovery and virtual screening. Their ease of use (requiring little to no configuration) and the speed at which substructure and similarity searches can be performed with them - paired with a virtual screening performance similar to other more complex methods - is the reason for their popularity. However, there are many types of fingerprints, each representing a different aspect of the molecule, which can greatly affect search performance. This review focuses on commonly used fingerprint algorithms, their usage in virtual screening, and the software packages and online tools that provide these algorithms.

  9. Virtual screening - what does it give us?

    Science.gov (United States)

    Köppen, Herbert

    2009-05-01

    In current pharmaceutical research, lead compounds of high quality and structural diversity are key to the successful optimization of development candidates. In-house compound libraries at pharmaceutical companies, tested using HTS assays, are the major source of leads for new projects. However, these physically existing compounds, stored in microtiter plates in dispensaries, represent only a tiny fraction of the drug-like chemical space. Virtual screening offers many possibilities for new structures beyond those found in in-house libraries. During the last decade, a huge number of different virtual screening methods have been reported and used to search for novel bioactive compounds for many targets. This review addresses the current status of virtual screening, highlighting achievements as well as challenges, along with the value of virtual screening, and recent examples of successful applications.

  10. Yeast two-hybrid screen.

    Science.gov (United States)

    Makuch, Lauren

    2014-01-01

    Yeast two-hybrid is a method for screening large numbers of gene products (encoded by cDNA libraries) for their ability to interact with a protein of interest. This system can also be used for characterizing and manipulating candidate protein: protein interactions. Interactions between proteins are monitored by the growth of yeast plated on selective media.

  11. Exploiting PubChem for Virtual Screening

    Science.gov (United States)

    Xie, Xiang-Qun

    2011-01-01

    Importance of the field PubChem is a public molecular information repository, a scientific showcase of the NIH Roadmap Initiative. The PubChem database holds over 27 million records of unique chemical structures of compounds (CID) derived from nearly 70 million substance depositions (SID), and contains more than 449,000 bioassay records with over thousands of in vitro biochemical and cell-based screening bioassays established, with targeting more than 7000 proteins and genes linking to over 1.8 million of substances. Areas covered in this review This review builds on recent PubChem-related computational chemistry research reported by other authors while providing readers with an overview of the PubChem database, focusing on its increasing role in cheminformatics, virtual screening and toxicity prediction modeling. What the reader will gain These publicly available datasets in PubChem provide great opportunities for scientists to perform cheminformatics and virtual screening research for computer-aided drug design. However, the high volume and complexity of the datasets, in particular the bioassay-associated false positives/negatives and highly imbalanced datasets in PubChem, also creates major challenges. Several approaches regarding the modeling of PubChem datasets and development of virtual screening models for bioactivity and toxicity predictions are also reviewed. Take home message Novel data-mining cheminformatics tools and virtual screening algorithms are being developed and used to retrieve, annotate and analyze the large-scale and highly complex PubChem biological screening data for drug design. PMID:21691435

  12. Virtual Screening with AutoDock: Theory and Practice.

    Science.gov (United States)

    Cosconati, Sandro; Forli, Stefano; Perryman, Alex L; Harris, Rodney; Goodsell, David S; Olson, Arthur J

    2010-06-01

    IMPORTANCE TO THE FIELD: Virtual screening is a computer-based technique for identifying promising compounds to bind to a target molecule of known structure. Given the rapidly increasing number of protein and nucleic acid structures, virtual screening continues to grow as an effective method for the discovery of new inhibitors and drug molecules. AREAS COVERED IN THIS REVIEW: We describe virtual screening methods that are available in the AutoDock suite of programs, and several of our successes in using AutoDock virtual screening in pharmaceutical lead discovery. WHAT THE READER WILL GAIN: A general overview of the challenges of virtual screening is presented, along with the tools available in the AutoDock suite of programs for addressing these challenges. TAKE HOME MESSAGE: Virtual screening is an effective tool for the discovery of compounds for use as leads in drug discovery, and the free, open source program AutoDock is an effective tool for virtual screening.

  13. Virtual Screening with AutoDock: Theory and Practice

    Science.gov (United States)

    Cosconati, Sandro; Forli, Stefano; Perryman, Alex L.; Harris, Rodney; Goodsell, David S.; Olson, Arthur J.

    2011-01-01

    Importance to the field Virtual screening is a computer-based technique for identifying promising compounds to bind to a target molecule of known structure. Given the rapidly increasing number of protein and nucleic acid structures, virtual screening continues to grow as an effective method for the discovery of new inhibitors and drug molecules. Areas covered in this review We describe virtual screening methods that are available in the AutoDock suite of programs, and several of our successes in using AutoDock virtual screening in pharmaceutical lead discovery. What the reader will gain A general overview of the challenges of virtual screening is presented, along with the tools available in the AutoDock suite of programs for addressing these challenges. Take home message Virtual screening is an effective tool for the discovery of compounds for use as leads in drug discovery, and the free, open source program AutoDock is an effective tool for virtual screening. PMID:21532931

  14. Performance Studies on Distributed Virtual Screening

    Directory of Open Access Journals (Sweden)

    Jens Krüger

    2014-01-01

    Full Text Available Virtual high-throughput screening (vHTS is an invaluable method in modern drug discovery. It permits screening large datasets or databases of chemical structures for those structures binding possibly to a drug target. Virtual screening is typically performed by docking code, which often runs sequentially. Processing of huge vHTS datasets can be parallelized by chunking the data because individual docking runs are independent of each other. The goal of this work is to find an optimal splitting maximizing the speedup while considering overhead and available cores on Distributed Computing Infrastructures (DCIs. We have conducted thorough performance studies accounting not only for the runtime of the docking itself, but also for structure preparation. Performance studies were conducted via the workflow-enabled science gateway MoSGrid (Molecular Simulation Grid. As input we used benchmark datasets for protein kinases. Our performance studies show that docking workflows can be made to scale almost linearly up to 500 concurrent processes distributed even over large DCIs, thus accelerating vHTS campaigns significantly.

  15. Virtual screening of electron acceptor materials for organic photovoltaic applications

    Science.gov (United States)

    Halls, Mathew D.; Djurovich, Peter J.; Giesen, David J.; Goldberg, Alexander; Sommer, Jonathan; McAnally, Eric; Thompson, Mark E.

    2013-10-01

    Virtual screening involves the generation of structure libraries, automated analysis to predict properties related to application performance and subsequent screening to identify lead systems and estimate critical structure-property limits across a targeted chemical design space. This approach holds great promise for informing experimental discovery and development efforts for next-generation materials, such as organic semiconductors. In this work, the virtual screening approach is illustrated for nitrogen-substituted pentacene molecules to identify systems for development as electron acceptor materials for use in organic photovoltaic (OPV) devices. A structure library of tetra-azapentacenes (TAPs) was generated by substituting four nitrogens for CH at 12 sites on the pentacene molecular framework. Molecular properties (e.g. ELUMO, Eg and μ) were computed for each candidate structure using hybrid DFT at the B3LYP/6-311G** level of theory. The resulting TAPs library was then analyzed with respect to intrinsic properties associated with OPV acceptor performance. Marcus reorganization energies for charge transport for the most favorable TAP candidates were then calculated to further determine suitability as OPV electron acceptors. The synthesis, characterization and OPV device testing of TAP materials is underway, guided by these results.

  16. Hybrid Recommender System for Joining Virtual Communities

    Directory of Open Access Journals (Sweden)

    Leila Esmaeili

    2012-03-01

    Full Text Available The variety of social networks and virtual communities has created problematic for users of different ages and preferences; in addition, since the true nature of groups is not clearly outlined, users are uncertain about joining various virtual groups and usually face the trouble of joining the undesired ones. As a solution, in this study, we introduced the hybrid community recommender system which offers customized recommendations based on user preferences. Although techniques such as content based filtering and collaborative filtering methods are available, these techniques are not enough efficient and in some cases make problems and bring limitations to users. Our method is based on a combination of content based filtering and collaborative filtering methods. It is created by selecting related features of users based on supervised entropy as well as using association rules and classification method. Supposing users in each community or group share similar characteristics, by hierarchical clustering, heterogeneous members are identified and removed. Unlike other methods, this is also applicable for users who have just joined the social network where they do not have any connections or group memberships. In such situations, this method could still offer recommendations.

  17. Pharmacophore-based virtual screening versus docking-based virtual screening: a benchmark comparison against eight targets.

    Science.gov (United States)

    Chen, Zhi; Li, Hong-lin; Zhang, Qi-jun; Bao, Xiao-guang; Yu, Kun-qian; Luo, Xiao-min; Zhu, Wei-liang; Jiang, Hua-liang

    2009-12-01

    This study was conducted to compare the efficiencies of two virtual screening approaches, pharmacophore-based virtual screening (PBVS) and docking-based virtual screening (DBVS) methods. All virtual screens were performed on two data sets of small molecules with both actives and decoys against eight structurally diverse protein targets, namely angiotensin converting enzyme (ACE), acetylcholinesterase (AChE), androgen receptor (AR), D-alanyl-D-alanine carboxypeptidase (DacA), dihydrofolate reductase (DHFR), estrogen receptors alpha (ERalpha), HIV-1 protease (HIV-pr), and thymidine kinase (TK). Each pharmacophore model was constructed based on several X-ray structures of protein-ligand complexes. Virtual screens were performed using four screening standards, the program Catalyst for PBVS and three docking programs (DOCK, GOLD and Glide) for DBVS. Of the sixteen sets of virtual screens (one target versus two testing databases), the enrichment factors of fourteen cases using the PBVS method were higher than those using DBVS methods. The average hit rates over the eight targets at 2% and 5% of the highest ranks of the entire databases for PBVS are much higher than those for DBVS. The PBVS method outperformed DBVS methods in retrieving actives from the databases in our tested targets, and is a powerful method in drug discovery.

  18. Virtual infrastructure management in private and hybrid clouds.

    Energy Technology Data Exchange (ETDEWEB)

    Sotomayor, B.; Montero, R. S.; Llorente, I. M.; Foster, I.; Mathematics and Computer Science; Univ. of Chicago; Univ. Complutense of Madrid

    2009-01-01

    One of the many definitions of 'cloud' is that of an infrastructure-as-a-service (IaaS) system, in which IT infrastructure is deployed in a provider's data center as virtual machines. With IaaS clouds growing popularity, tools and technologies are emerging that can transform an organization's existing infrastructure into a private or hybrid cloud. OpenNebula is an open source, virtual infrastructure manager that deploys virtualized services on both a local pool of resources and external IaaS clouds. Haizea, a resource lease manager, can act as a scheduling back end for OpenNebula, providing features not found in other cloud software or virtualization-based data center management software.

  19. Virtual high throughput screening (vHTS) - A perspective

    OpenAIRE

    Subramaniam, Sangeetha; Mehrotra, Monica; Gupta, Dinesh,

    2008-01-01

    With the exponential rise in the number of viable novel drug targets, computational methods are being increasingly applied to accelerate the drug discovery process. Virtual High Throughput Screening (vHTS) is one such established methodology to identify drug candidates from large collection of compound libraries. Although it complements the expensive and time consuming High Throughput Screening (HTS) of compound libraries, vHTS possess inherent challenges. The successful vHTS requires the car...

  20. Hybrid Feedforward-Feedback Noise Control Using Virtual Sensors

    Science.gov (United States)

    Bean, Jacob; Fuller, Chris; Schiller, Noah

    2016-01-01

    Several approaches to active noise control using virtual sensors are evaluated for eventual use in an active headrest. Specifically, adaptive feedforward, feedback, and hybrid control structures are compared. Each controller incorporates the traditional filtered-x least mean squares algorithm. The feedback controller is arranged in an internal model configuration to draw comparisons with standard feedforward control theory results. Simulation and experimental results are presented that illustrate each controllers ability to minimize the pressure at both physical and virtual microphone locations. The remote microphone technique is used to obtain pressure estimates at the virtual locations. It is shown that a hybrid controller offers performance benefits over the traditional feedforward and feedback controllers. Stability issues associated with feedback and hybrid controllers are also addressed. Experimental results show that 15-20 dB reduction in broadband disturbances can be achieved by minimizing the measured pressure, whereas 10-15 dB reduction is obtained when minimizing the estimated pressure at a virtual location.

  1. Discovery of novel human acrosin inhibitors by virtual screening

    Science.gov (United States)

    Liu, Xuefei; Dong, Guoqiang; Zhang, Jue; Qi, Jingjing; Zheng, Canhui; Zhou, Youjun; Zhu, Ju; Sheng, Chunquan; Lü, Jiaguo

    2011-10-01

    Human acrosin is an attractive target for the discovery of male contraceptive drugs. For the first time, structure-based drug design was applied to discover structurally diverse human acrosin inhibitors. A parallel virtual screening strategy in combination with pharmacophore-based and docking-based techniques was used to screen the SPECS database. From 16 compounds selected by virtual screening, a total of 10 compounds were found to be human acrosin inhibitors. Compound 2 was found to be the most potent hit (IC50 = 14 μM) and its binding mode was investigated by molecular dynamics simulations. The hit interacted with human acrosin mainly through hydrophobic and hydrogen-bonding interactions, which provided a good starting structure for further optimization studies.

  2. Quantum probability ranking principle for ligand-based virtual screening

    Science.gov (United States)

    Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

    2017-02-01

    Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.

  3. Quantum probability ranking principle for ligand-based virtual screening.

    Science.gov (United States)

    Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

    2017-04-01

    Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.

  4. Virtual Screening and Structure Generation Applied to Drug Design

    Institute of Scientific and Technical Information of China (English)

    FAN B.T.; CHEN H. F.; XIE L.; YUAN S. G.; A. PANAYE; J-P. DOUCET

    2004-01-01

    The methods of computer-aided drug design can be divided into two categories according to whether or not the structures of receptors are known1, corresponding to two principal strategies:(1) searching the bio-active ligands against virtual combinatorial libraries and calculating the affinity energy between ligand and receptor by docking ; (2) QSAR and 3D-structure data-mining.3D-QSAR method is now applied widely to drug discovery, but this method is generally limited to refine the structures of known bio-active compounds. During the process of drug design, we have usually the prejudice that certain groups or structural fragments will play or not important roles on the activity. This will sometimes be misleading, and prevent us from obtaining expected results.The method of generating firstly diverse structures, then screening out the promising structures by means of a computational method or QSAR model, is an efficient way for drug discovery. We developed an efficient virtual and rational drag design method. It combines virtual bioactive compound generation using genetic algorithms with 3D-QSAR model and docking. Using this method can generate a lot of highly diverse molecules and find virtual active lead compounds. The method was validated by the study on a set of anti-tumor drugs, colchicine analogs2. With the constraints of pharmacophore obtained determined by DISCO, 97 virtual bioactive compounds were generated,and their anti-tumor activities were predicted by CoMFA. 8 structures with high activity were selected and screened by 3D-QSAR model. The most active generated structure was further investigated by modifying its structure in order to increase the activity (see fig.1). This drug design method could also avoid the conflict between the insufficiency of active structures and the great quantity of compounds needed for high-throughput screening. This method has been also applied to anti-HIV drug design.We have developed equally another approach of virtual

  5. The virtual heart as a platform for screening drug cardiotoxicity.

    Science.gov (United States)

    Yuan, Yongfeng; Bai, Xiangyun; Luo, Cunjin; Wang, Kuanquan; Zhang, Henggui

    2015-12-01

    To predict the safety of a drug at an early stage in its development is a major challenge as there is a lack of in vitro heart models that correlate data from preclinical toxicity screening assays with clinical results. A biophysically detailed computer model of the heart, the virtual heart, provides a powerful tool for simulating drug-ion channel interactions and cardiac functions during normal and disease conditions and, therefore, provides a powerful platform for drug cardiotoxicity screening. In this article, we first review recent progress in the development of theory on drug-ion channel interactions and mathematical modelling. Then we propose a family of biomarkers that can quantitatively characterize the actions of a drug on the electrical activity of the heart at multi-physical scales including cellular and tissue levels. We also conducted some simulations to demonstrate the application of the virtual heart to assess the pro-arrhythmic effects of cisapride and amiodarone. Using the model we investigated the mechanisms responsible for the differences between the two drugs on pro-arrhythmogenesis, even though both prolong the QT interval of ECGs. Several challenges for further development of a virtual heart as a platform for screening drug cardiotoxicity are discussed.

  6. The virtual heart as a platform for screening drug cardiotoxicity

    Science.gov (United States)

    Yuan, Yongfeng; Bai, Xiangyun; Luo, Cunjin; Wang, Kuanquan

    2015-01-01

    To predict the safety of a drug at an early stage in its development is a major challenge as there is a lack of in vitro heart models that correlate data from preclinical toxicity screening assays with clinical results. A biophysically detailed computer model of the heart, the virtual heart, provides a powerful tool for simulating drug–ion channel interactions and cardiac functions during normal and disease conditions and, therefore, provides a powerful platform for drug cardiotoxicity screening. In this article, we first review recent progress in the development of theory on drug–ion channel interactions and mathematical modelling. Then we propose a family of biomarkers that can quantitatively characterize the actions of a drug on the electrical activity of the heart at multi‐physical scales including cellular and tissue levels. We also conducted some simulations to demonstrate the application of the virtual heart to assess the pro‐arrhythmic effects of cisapride and amiodarone. Using the model we investigated the mechanisms responsible for the differences between the two drugs on pro‐arrhythmogenesis, even though both prolong the QT interval of ECGs. Several challenges for further development of a virtual heart as a platform for screening drug cardiotoxicity are discussed. Linked Articles This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23 PMID:25363597

  7. Combining docking with pharmacophore filtering for improved virtual screening

    Directory of Open Access Journals (Sweden)

    Peach Megan L

    2009-05-01

    Full Text Available Abstract Background Virtual screening is used to distinguish potential leads from inactive compounds in a database of chemical samples. One method for accomplishing this is by docking compounds into the structure of a receptor binding site in order to rank-order compounds by the quality of the interactions they form with the receptor. It is generally established that docking can be reasonably successful at generating good poses of a ligand in an active site. However, the scoring functions that are used with docking are typically not successful at correctly ranking ligands according to binding affinity or even distinguishing correct poses of a given ligand from incorrect ones. Results We have developed a simple method for reducing the number of false positives in a virtual screen, meaning ligands which are scored highly by the docking program but do not bind well in reality. This method uses a docking program for pose generation without regard to scoring, followed by filtering with receptor-based pharmacophore searches. We applied it to three test-case targets: neuraminidase A, cyclin-dependent kinase 2, and the C1 domain of protein kinase C. Conclusion The pharmacophore filtering method can perform better than more traditional docking + scoring methods, and allows the advantages of both docking-based and pharmacophore-based approaches to virtual screening to be fully realized.

  8. Hybrid Contacts for CZT Virtual Frisch-grid Detectors

    Energy Technology Data Exchange (ETDEWEB)

    Camarda G.; Bolotnikov, A.E.; Chan, W.; Cui, Y.; Gul R.; Hossain, A.; Kim, K.; Yang, G.; James, R.B.

    2011-08-22

    In our previous design of virtual Frisch-grid CdZnTe (CZT) detectors, the charge drift-lines can be terminated at the side surfaces before the carriers reach the collecting anode; this results in a loss of signal from the interacting events near the detector's edges. Here, we describe our new design for the anode contact that reduces these edge effects by focusing the electric field towards the detectors' central axes. Four detectors were fabricated with the new hybrid anode contact, and their performances were evaluated and compared to those from the previous design for our virtual Frisch-grid detectors. The results obtained for all four showed similar improvement: therefore, we illustrate them with the findings from one detector.

  9. Structure-Based Virtual Screening of Commercially Available Compound Libraries.

    Science.gov (United States)

    Kireev, Dmitri

    2016-01-01

    Virtual screening (VS) is an efficient hit-finding tool. Its distinctive strength is that it allows one to screen compound libraries that are not available in the lab. Moreover, structure-based (SB) VS also enables an understanding of how the hit compounds bind the protein target, thus laying ground work for the rational hit-to-lead progression. SBVS requires a very limited experimental effort and is particularly well suited for academic labs and small biotech companies that, unlike pharmaceutical companies, do not have physical access to quality small-molecule libraries. Here, we describe SBVS of commercial compound libraries for Mer kinase inhibitors. The screening protocol relies on the docking algorithm Glide complemented by a post-docking filter based on structural protein-ligand interaction fingerprints (SPLIF).

  10. Systematic hybrid LOH: a new method to reduce false positives and negatives during screening of yeast gene deletion libraries

    DEFF Research Database (Denmark)

    Alvaro, D.; Sunjevaric, I.; Reid, R. J.

    2006-01-01

    We have developed a new method, systematic hybrid loss of heterozygosity, to facilitate genomic screens utilizing the yeast gene deletion library. Screening is performed using hybrid diploid strains produced through mating the library haploids with strains from a different genetic background...... mating a library gene deletion haploid to such a conditional centromere strain, which corresponds to the chromosome carrying the gene deletion, loss of heterozygosity (LOH) at the gene deletion locus can be generated in these otherwise hybrid diploids. The use of hybrid diploid strains permits...... complementation of any spurious recessive mutations in the library strain, facilitating attribution of the observed phenotype to the documented gene deletion and dramatically reducing false positive results commonly obtained in library screens. The systematic hybrid LOH method can be applied to virtually any...

  11. Virtual screening and its integration with modern drug design technologies.

    Science.gov (United States)

    Guido, Rafael V C; Oliva, Glaucius; Andricopulo, Adriano D

    2008-01-01

    Drug discovery is a highly complex and costly process, which demands integrated efforts in several relevant aspects involving innovation, knowledge, information, technologies, expertise, R&D investments and management skills. The shift from traditional to genomics- and proteomics-based drug research has fundamentally transformed key R&D strategies in the pharmaceutical industry addressed to the design of new chemical entities as drug candidates against a variety of biological targets. Therefore, drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. The combination of available knowledge of several 3D protein structures with hundreds of thousands of small-molecules have attracted the attention of scientists from all over the world for the application of structure- and ligand-based drug design approaches. In this context, virtual screening technologies have largely enhanced the impact of computational methods applied to chemistry and biology and the goal of applying such methods is to reduce large compound databases and to select a limited number of promising candidates for drug design. This review provides a perspective of the utility of virtual screening in drug design and its integration with other important drug discovery technologies such as high-throughput screening (HTS) and QSAR, highlighting the present challenges, limitations, and future perspectives in medicinal chemistry.

  12. Screening and dotting virtual slides: A new challenge for cytotechnologists

    Directory of Open Access Journals (Sweden)

    Walid E Khalbuss

    2013-01-01

    Full Text Available Digital images are increasingly being used in cytopathology. Whole-slide imaging (WSI is a digital imaging modality that uses computerized technology to scan and convert entire cytology glass slides into digital images that can be viewed on a digital display using the image viewer software. Digital image acquisition of cytology glass slides has improved significantly over the years due to the use of liquid-based preparations and advances in WSI scanning technology such as automatic multipoint pre-scan focus technology or z-stack scanning technology. Screening cytotechnologists are responsible for every cell that is present on an imaged slide. One of the challenges users have to overcome is to establish a technique to review systematically the entire imaged slide and to dot selected abnormal or significant findings. The scope of this article is to review the current user interface technology available for virtual slide navigation when screening digital slides in cytology. WSI scanner vendors provide tools, built into the image viewer software that allow for a more systematic navigation of the virtual slides, such as auto-panning, keyboard-controlled slide navigation and track map. Annotation tools can improve communication between the screener and the final reviewer or can be used for education. The tracking functionality allows recording of the WSI navigation process and provides a mechanism for confirmation of slide coverage by the screening cytotechnologist as well as a useful tool for quality assurance. As the WSI technology matures, additional features and tools to support navigation of a cytology virtual slide are anticipated.

  13. Dockres: a computer program that analyzes the output of virtual screening of small molecules

    Directory of Open Access Journals (Sweden)

    Zhou Ming-Ming

    2010-01-01

    Full Text Available Abstract Background This paper describes a computer program named Dockres that is designed to analyze and summarize results of virtual screening of small molecules. The program is supplemented with utilities that support the screening process. Foremost among these utilities are scripts that run the virtual screening of a chemical library on a large number of processors in parallel. Methods Dockres and some of its supporting utilities are written Fortran-77; other utilities are written as C-shell scripts. They support the parallel execution of the screening. The current implementation of the program handles virtual screening with Autodock-3 and Autodock-4, but can be extended to work with the output of other programs. Results Analysis of virtual screening by Dockres led to both active and selective lead compounds. Conclusions Analysis of virtual screening was facilitated and enhanced by Dockres in both the authors' laboratories as well as laboratories elsewhere.

  14. Exploration of multiple Sortase A protein conformations in virtual screening

    Science.gov (United States)

    Gao, Chunxia; Uzelac, Ivana; Gottfries, Johan; Eriksson, Leif A.

    2016-02-01

    Methicillin resistant Staphylococcus aureus (MRSA) has become a major health concern which has brought about an urgent need for new therapeutic agents. As the S. aureus Sortase A (SrtA) enzyme contributes to the adherence of the bacteria to the host cells, inhibition thereof by small molecules could be employed as potential antivirulence agents, also towards resistant strains. Albeit several virtual docking SrtA campaigns have been reported, no strongly inhibitatory non-covalent binders have as yet emerged therefrom. In order to better understand the binding modes of small molecules, and the effect of different receptor structures employed in the screening, we herein report on an exploratory study employing 10 known binders and 500 decoys on 100 SrtA structures generated from regular or steered molecular dynamics simulations on four different SrtA crystal/NMR structures. The results suggest a correlation between the protein structural flexibility and the virtual screening performance, and confirm the noted immobilization of the β6/β7 loop upon substrate binding. The NMR structures reported appear to perform slightly better than the Xray-crystal structures, but the binding modes fluctuate tremendously, and it might be suspected that the catalytic site is not necessarily the preferred site of binding for some of the reported active compounds.

  15. A Quantum-Based Similarity Method in Virtual Screening.

    Science.gov (United States)

    Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

    2015-10-02

    One of the most widely-used techniques for ligand-based virtual screening is similarity searching. This study adopted the concepts of quantum mechanics to present as state-of-the-art similarity method of molecules inspired from quantum theory. The representation of molecular compounds in mathematical quantum space plays a vital role in the development of quantum-based similarity approach. One of the key concepts of quantum theory is the use of complex numbers. Hence, this study proposed three various techniques to embed and to re-represent the molecular compounds to correspond with complex numbers format. The quantum-based similarity method that developed in this study depending on complex pure Hilbert space of molecules called Standard Quantum-Based (SQB). The recall of retrieved active molecules were at top 1% and top 5%, and significant test is used to evaluate our proposed methods. The MDL drug data report (MDDR), maximum unbiased validation (MUV) and Directory of Useful Decoys (DUD) data sets were used for experiments and were represented by 2D fingerprints. Simulated virtual screening experiment show that the effectiveness of SQB method was significantly increased due to the role of representational power of molecular compounds in complex numbers forms compared to Tanimoto benchmark similarity measure.

  16. A Quantum-Based Similarity Method in Virtual Screening

    Directory of Open Access Journals (Sweden)

    Mohammed Mumtaz Al-Dabbagh

    2015-10-01

    Full Text Available One of the most widely-used techniques for ligand-based virtual screening is similarity searching. This study adopted the concepts of quantum mechanics to present as state-of-the-art similarity method of molecules inspired from quantum theory. The representation of molecular compounds in mathematical quantum space plays a vital role in the development of quantum-based similarity approach. One of the key concepts of quantum theory is the use of complex numbers. Hence, this study proposed three various techniques to embed and to re-represent the molecular compounds to correspond with complex numbers format. The quantum-based similarity method that developed in this study depending on complex pure Hilbert space of molecules called Standard Quantum-Based (SQB. The recall of retrieved active molecules were at top 1% and top 5%, and significant test is used to evaluate our proposed methods. The MDL drug data report (MDDR, maximum unbiased validation (MUV and Directory of Useful Decoys (DUD data sets were used for experiments and were represented by 2D fingerprints. Simulated virtual screening experiment show that the effectiveness of SQB method was significantly increased due to the role of representational power of molecular compounds in complex numbers forms compared to Tanimoto benchmark similarity measure.

  17. Assessing the utility and limitations of high throughput virtual screening

    Directory of Open Access Journals (Sweden)

    Paul Daniel Phillips

    2016-05-01

    Full Text Available Due to low cost, speed, and unmatched ability to explore large numbers of compounds, high throughput virtual screening and molecular docking engines have become widely utilized by computational scientists. It is generally accepted that docking engines, such as AutoDock, produce reliable qualitative results for ligand-macromolecular receptor binding, and molecular docking results are commonly reported in literature in the absence of complementary wet lab experimental data. In this investigation, three variants of the sixteen amino acid peptide, α-conotoxin MII, were docked to a homology model of the a3β2-nicotinic acetylcholine receptor. DockoMatic version 2.0 was used to perform a virtual screen of each peptide ligand to the receptor for ten docking trials consisting of 100 AutoDock cycles per trial. The results were analyzed for both variation in the calculated binding energy obtained from AutoDock, and the orientation of bound peptide within the receptor. The results show that, while no clear correlation exists between consistent ligand binding pose and the calculated binding energy, AutoDock is able to determine a consistent positioning of bound peptide in the majority of trials when at least ten trials were evaluated.

  18. Virtual fragment screening for novel inhibitors of 6-phosphogluconate dehydrogenase.

    Science.gov (United States)

    Ruda, Gian Filippo; Campbell, Gordon; Alibu, Vincent P; Barrett, Michael P; Brenk, Ruth; Gilbert, Ian H

    2010-07-15

    The enzyme 6-phosphogluconate dehydrogenase is a potential drug target for the parasitic protozoan Trypanosoma brucei, the causative organism of human African trypanosomiasis. This enzyme has a polar active site to accommodate the phosphate, hydroxyl and carboxylate groups of the substrate, 6-phosphogluconate. A virtual fragment screen was undertaken of the enzyme to discover starting points for the development of inhibitors which are likely to have appropriate physicochemical properties for an orally bioavailable compound. A virtual screening library was developed, consisting of compounds with functional groups that could mimic the phosphate group of the substrate, but which have a higher pKa. Following docking, hits were clustered and appropriate compounds purchased and assayed against the enzyme. Three fragments were identified that had IC50 values in the low micromolar range and good ligand efficiencies. Based on these initial hits, analogues were procured and further active compounds were identified. Some of the fragments identified represent potential starting points for a medicinal chemistry programme to develop potent drug-like inhibitors of the enzyme. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  19. In Silico Genomic Fingerprints of the Bacillus anthracis Group Obtained by Virtual Hybridization

    Science.gov (United States)

    Jaimes-Díaz, Hueman; Larios-Serrato, Violeta; Lloret-Sánchez, Teresa; Olguín-Ruiz, Gabriela; Sánchez-Vallejo, Carlos; Carreño-Durán, Luis; Maldonado-Rodríguez, Rogelio; Méndez-Tenorio, Alfonso

    2015-01-01

    In this study we evaluate the capacity of Virtual Hybridization to identify between highly related bacterial strains. Eight genomic fingerprints were obtained by virtual hybridization for the Bacillus anthracis genome set, and a set of 15,264 13-nucleotide short probes designed to produce genomic fingerprints unique for each organism. The data obtained from each genomic fingerprint were used to obtain hybridization patterns simulating a DNA microarray. Two virtual hybridization methods were used: the Direct and the Extended method to identify the number of potential hybridization sites and thus determine the minimum sensitivity value to discriminate between genomes with 99.9% similarity. Genomic fingerprints were compared using both methods and phylogenomic trees were constructed to verify that the minimum detection value is 0.000017. Results obtained from the genomic fingerprints suggest that the distribution in the trees is correct, as compared to other taxonomic methods. Specific virtual hybridization sites for each of the genomes studied were also identified. PMID:27600214

  20. Classification and virtual screening of androgen receptor antagonists.

    Science.gov (United States)

    Li, Jiazhong; Gramatica, Paola

    2010-05-24

    Computational tools, such as quantitative structure-activity relationship (QSAR), are highly useful as screening support for prioritization of substances of very high concern (SVHC). From the practical point of view, QSAR models should be effective to pick out more active rather than inactive compounds, expressed as sensitivity in classification works. This research investigates the classification of a big data set of endocrine-disrupting chemicals (EDCs)-androgen receptor (AR) antagonists, mainly aiming to improve the external sensitivity and to screen for potential AR binders. The kNN, lazy IB1, and ADTree methods and the consensus approach were used to build different models, which improve the sensitivity on external chemicals from 57.1% (literature) to 76.4%. Additionally, the models' predictive abilities were further validated on a blind collected data set (sensitivity: 85.7%). Then the proposed classifiers were used: (i) to distinguish a set of AR binders into antagonists and agonists; (ii) to screen a combined estrogen receptor binder database to find out possible chemicals that can bind to both AR and ER; and (iii) to virtually screen our in-house environmental chemical database. The in silico screening results suggest: (i) that some compounds can affect the normal endocrine system through a complex mechanism binding both to ER and AR; (ii) new EDCs, which are nonER binders, but can in silico bind to AR, are recognized; and (iii) about 20% of compounds in a big data set of environmental chemicals are predicted as new AR antagonists. The priority should be given to them to experimentally test the binding activities with AR.

  1. Course Crash in Hybrid Space: An Exploration and Recommendations for Virtual Course Space

    Science.gov (United States)

    Gerard, Joseph G.; Gerard, Reena Lederman; Casile, Maureen

    2010-01-01

    Understanding what hybrid space is, much less understanding what happens in that virtual realm, can raise difficult questions. For example, our campus's question "How do we define hybrid?" has kept us busy and guessing for over a year now. In this article, we offer a few suggestions on how to proceed with hybrid issues, including how to deal with…

  2. Ligand-based virtual screening under partial shape constraints

    Science.gov (United States)

    von Behren, Mathias M.; Rarey, Matthias

    2017-03-01

    Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure. The new method is integrated into the LBVS tool mRAISE providing multiple options for such constraints. The applied constraints can either be derived automatically from a protein-ligand complex structure or by manual selection of ligand atoms. In this way, the descriptor directly encodes the fit of a ligand into the binding site. Furthermore, the conservation of close contacts between the binding site surface and the query ligand can be enforced. We validated our new method on the DUD and DUD-E datasets. Although the statistical performance remains on the same level, detailed analysis reveal that for certain and especially very flexible targets a significant improvement can be achieved. This is further highlighted looking at the quality of calculated molecular alignments using the recently introduced mRAISE dataset. The new partial shape constraints improved the overall quality of molecular alignments especially for difficult targets with highly flexible or different sized molecules. The software tool mRAISE is freely available on Linux operating systems for evaluation purposes and academic use (see http://www.zbh.uni-hamburg.de/raise).

  3. Ligand-based virtual screening under partial shape constraints

    Science.gov (United States)

    von Behren, Mathias M.; Rarey, Matthias

    2017-04-01

    Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure. The new method is integrated into the LBVS tool mRAISE providing multiple options for such constraints. The applied constraints can either be derived automatically from a protein-ligand complex structure or by manual selection of ligand atoms. In this way, the descriptor directly encodes the fit of a ligand into the binding site. Furthermore, the conservation of close contacts between the binding site surface and the query ligand can be enforced. We validated our new method on the DUD and DUD-E datasets. Although the statistical performance remains on the same level, detailed analysis reveal that for certain and especially very flexible targets a significant improvement can be achieved. This is further highlighted looking at the quality of calculated molecular alignments using the recently introduced mRAISE dataset. The new partial shape constraints improved the overall quality of molecular alignments especially for difficult targets with highly flexible or different sized molecules. The software tool mRAISE is freely available on Linux operating systems for evaluation purposes and academic use (see http://www.zbh.uni-hamburg.de/raise).

  4. PoLi: A Virtual Screening Pipeline Based on Template Pocket and Ligand Similarity.

    Science.gov (United States)

    Roy, Ambrish; Srinivasan, Bharath; Skolnick, Jeffrey

    2015-08-24

    Often in pharmaceutical research the goal is to identify small molecules that can interact with and appropriately modify the biological behavior of a new protein target. Unfortunately, most proteins lack both known structures and small molecule binders, prerequisites of many virtual screening, VS, approaches. For such proteins, ligand homology modeling, LHM, that copies ligands from homologous and perhaps evolutionarily distant template proteins, has been shown to be a powerful VS approach to identify possible binding ligands. However, if we want to target a specific pocket for which there is no homologous holo template protein structure, then LHM will not work. To address this issue, in a new pocket-based approach, PoLi, we generalize LHM by exploiting the fact that the number of distinct small molecule ligand-binding pockets in proteins is small. PoLi identifies similar ligand-binding pockets in a holo template protein library, selectively copies relevant parts of template ligands, and uses them for VS. In practice, PoLi is a hybrid structure and ligand-based VS algorithm that integrates 2D fingerprint-based and 3D shape-based similarity metrics for improved virtual screening performance. On standard DUD and DUD-E benchmark databases, using modeled receptor structures, PoLi achieves an average enrichment factor of 13.4 and 9.6, respectively, in the top 1% of the screened library. In contrast, traditional docking-based VS using AutoDock Vina and homology-based VS using FINDSITE(filt) have an average enrichment of 1.6 (3.0) and 9.0 (7.9) on the DUD (DUD-E) sets, respectively. Experimental validation of PoLi predictions on dihydrofolate reductase, DHFR, using differential scanning fluorimetry, DSF, identifies multiple ligands with diverse molecular scaffolds, thus demonstrating the advantage of PoLi over current state-of-the-art VS methods.

  5. Building a virtual ligand screening pipeline using free software: a survey.

    Science.gov (United States)

    Glaab, Enrico

    2016-03-01

    Virtual screening, the search for bioactive compounds via computational methods, provides a wide range of opportunities to speed up drug development and reduce the associated risks and costs. While virtual screening is already a standard practice in pharmaceutical companies, its applications in preclinical academic research still remain under-exploited, in spite of an increasing availability of dedicated free databases and software tools. In this survey, an overview of recent developments in this field is presented, focusing on free software and data repositories for screening as alternatives to their commercial counterparts, and outlining how available resources can be interlinked into a comprehensive virtual screening pipeline using typical academic computing facilities. Finally, to facilitate the set-up of corresponding pipelines, a downloadable software system is provided, using platform virtualization to integrate pre-installed screening tools and scripts for reproducible application across different operating systems.

  6. Hybrid simulations: combining atomistic and coarse-grained force fields using virtual sites.

    Science.gov (United States)

    Rzepiela, Andrzej J; Louhivuori, Martti; Peter, Christine; Marrink, Siewert J

    2011-06-14

    Hybrid simulations, in which part of the system is represented at atomic resolution and the remaining part at a reduced, coarse-grained, level offer a powerful way to combine the accuracy associated with the atomistic force fields to the sampling speed obtained with coarse-grained (CG) potentials. In this work we introduce a straightforward scheme to perform hybrid simulations, making use of virtual sites to couple the two levels of resolution. With the help of these virtual sites interactions between molecules at different levels of resolution, i.e. between CG and atomistic molecules, are treated the same way as the pure CG-CG interactions. To test our method, we combine the Gromos atomistic force field with a number of coarse-grained potentials, obtained through several approaches that are designed to obtain CG potentials based on an existing atomistic model, namely iterative Boltzmann inversion, force matching, and a potential of mean force subtraction procedure (SB). We also explore the use of the MARTINI force field for the CG potential. A simple system, consisting of atomistic butane molecules dissolved in CG butane, is used to study the performance of our hybrid scheme. Based on the potentials of mean force for atomistic butane in CG solvent, and the properties of 1:1 mixtures of atomistic and CG butane which should exhibit ideal mixing behavior, we conclude that the MARTINI and SB potentials are particularly suited to be combined with the atomistic force field. The MARTINI potential is subsequently used to perform hybrid simulations of atomistic dialanine peptides in both CG butane and water. Compared to a fully atomistic description of the system, the hybrid description gives similar results provided that the dielectric screening of water is accounted for. Within the field of biomolecules, our method appears ideally suited to study e.g. protein-ligand binding, where the active site and ligand are modeled in atomistic detail and the rest of the protein

  7. Evaluating the predictivity of virtual screening for ABL kinase inhibitors to hinder drug resistance

    DEFF Research Database (Denmark)

    Gani, Osman A B S M; Narayanan, Dilip; Engh, Richard A

    2013-01-01

    for potential new compounds. In this study, we have taken a retrospective approach to evaluate virtual screening methods for the leukemia target kinase ABL1 and its drug-resistant mutant ABL1-T315I. 'Dual active' inhibitors against both targets were grouped together with inactive ligands chosen from different......Virtual screening methods are now widely used in early stages of drug discovery, aiming to rank potential inhibitors. However, any practical ligand set (of active or inactive compounds) chosen for deriving new virtual screening approaches cannot fully represent all relevant chemical space...

  8. Consensus virtual screening approaches to predict protein ligands.

    Science.gov (United States)

    Kukol, Andreas

    2011-09-01

    In order to exploit the advantages of receptor-based virtual screening, namely time/cost saving and specificity, it is important to rely on algorithms that predict a high number of active ligands at the top ranks of a small molecule database. Towards that goal consensus methods combining the results of several docking algorithms were developed and compared against the individual algorithms. Furthermore, a recently proposed rescoring method based on drug efficiency indices was evaluated. Among AutoDock Vina 1.0, AutoDock 4.2 and GemDock, AutoDock Vina was the best performing single method in predicting high affinity ligands from a database of known ligands and decoys. The rescoring of predicted binding energies with the water/octanol partition coefficient did not lead to an improvement averaged over ten receptor targets. Various consensus algorithms were investigated and a simple combination of AutoDock and AutoDock Vina results gave the most consistent performance that showed early enrichment of known ligands for all receptor targets investigated. In case a number of ligands is known for a specific target, every method proposed in this study should be evaluated. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  9. The Minnesota pelvic trainer: a hybrid VR/physical pelvis for providing virtual mentorship.

    Science.gov (United States)

    Konchada, Vamsi; Shen, Yunhe; Burke, Dan; Argun, Omer B; Weinhaus, Anthony; Erdman, Arthur G; Sweet, Robert M

    2011-01-01

    Obtaining accurate understanding of three dimensional structures and their relationships is important in learning human anatomy. To leverage the learning advantages of using both physical and virtual models, we built a hybrid platform consisting of virtual and mannequin pelvis, motion tracking interface, anatomy and pathology knowledge base. The virtual mentorship concept is to allow learners to conveniently manipulate and explore the virtual pelvic structures through the mannequin model and VR interface, and practice on anatomy identification tasks and pathology quizzes more intuitively and interactively than in a traditional self-study classroom, and to reduce the demands of access to dissection lab or wet lab.

  10. Designing Modulators of Monoamine Transporters using Virtual Screening Techniques

    Directory of Open Access Journals (Sweden)

    Ole Valente Mortensen

    2015-09-01

    Full Text Available The plasma-membrane monoamine transporters (MATs, including the serotonin (SERT, norepinephrine (NET and dopamine (DAT transporters, serve a pivotal role in limiting monoamine-mediated neurotransmission through the reuptake of their respective monoamine neurotransmitters. The transporters are the main target of clinically used psychostimulants and antidepressants. Despite the availability of several potent and selective MAT substrates and inhibitors the continuing need for therapeutic drugs to treat brain disorders involving aberrant monoamine signaling provides a compelling reason to identify novel ways of targeting and modulating the MATs. Designing novel modulators of MAT function have been limited by the lack of three dimensional structure information of the individual MATs. However, crystal structures of LeuT, a bacterial homologue of MATs, in a substrate-bound occluded, substrate-free outward-open, and an apo inward-open state and also with competitive and noncompetitive inhibitors have been determined. In addition, several structures of the drosophila DAT have also been resolved. Together with computational modeling and experimental data gathered over the past decade, these structures have dramatically advanced our understanding of several aspects of SERT, NET, and DAT transporter function, including some of the molecular determinants of ligand interaction at orthosteric substrate and inhibitor binding pockets. In addition progress has been made in the understanding of how allosteric modulation of MAT function can be achieved. Here we will review all the efforts up to date that has been made through computational approaches employing structural models of MATs to design small molecule modulators to the orthosteric and allosteric sites using virtual screening techniques.

  11. Virtual Screening and Molecular Design Based on Hierarchical Qsar Technology

    Science.gov (United States)

    Kuz'min, Victor E.; Artemenko, A. G.; Muratov, Eugene N.; Polischuk, P. G.; Ognichenko, L. N.; Liahovsky, A. V.; Hromov, A. I.; Varlamova, E. V.

    This chapter is devoted to the hierarchical QSAR technology (HiT QSAR) based on simplex representation of molecular structure (SiRMS) and its application to different QSAR/QSPR tasks. The essence of this technology is a sequential solution (with the use of the information obtained on the previous steps) of the QSAR paradigm by a series of enhanced models based on molecular structure description (in a specific order from 1D to 4D). Actually, it's a system of permanently improved solutions. Different approaches for domain applicability estimation are implemented in HiT QSAR. In the SiRMS approach every molecule is represented as a system of different simplexes (tetratomic fragments with fixed composition, structure, chirality, and symmetry). The level of simplex descriptors detailed increases consecutively from the 1D to 4D representation of the molecular structure. The advantages of the approach presented are an ability to solve QSAR/QSPR tasks for mixtures of compounds, the absence of the "molecular alignment" problem, consideration of different physical-chemical properties of atoms (e.g., charge, lipophilicity), and the high adequacy and good interpretability of obtained models and clear ways for molecular design. The efficiency of HiT QSAR was demonstrated by its comparison with the most popular modern QSAR approaches on two representative examination sets. The examples of successful application of the HiT QSAR for various QSAR/QSPR investigations on the different levels (1D-4D) of the molecular structure description are also highlighted. The reliability of developed QSAR models as the predictive virtual screening tools and their ability to serve as the basis of directed drug design was validated by subsequent synthetic, biological, etc. experiments. The HiT QSAR is realized as the suite of computer programs termed the "HiT QSAR" software that so includes powerful statistical capabilities and a number of useful utilities.

  12. Designing modulators of monoamine transporters using virtual screening techniques

    Science.gov (United States)

    Mortensen, Ole V.; Kortagere, Sandhya

    2015-01-01

    The plasma-membrane monoamine transporters (MATs), including the serotonin (SERT), norepinephrine (NET) and dopamine (DAT) transporters, serve a pivotal role in limiting monoamine-mediated neurotransmission through the reuptake of their respective monoamine neurotransmitters. The transporters are the main target of clinically used psychostimulants and antidepressants. Despite the availability of several potent and selective MAT substrates and inhibitors the continuing need for therapeutic drugs to treat brain disorders involving aberrant monoamine signaling provides a compelling reason to identify novel ways of targeting and modulating the MATs. Designing novel modulators of MAT function have been limited by the lack of three dimensional structure information of the individual MATs. However, crystal structures of LeuT, a bacterial homolog of MATs, in a substrate-bound occluded, substrate-free outward-open, and an apo inward-open state and also with competitive and non-competitive inhibitors have been determined. In addition, several structures of the Drosophila DAT have also been resolved. Together with computational modeling and experimental data gathered over the past decade, these structures have dramatically advanced our understanding of several aspects of SERT, NET, and DAT transporter function, including some of the molecular determinants of ligand interaction at orthosteric substrate and inhibitor binding pockets. In addition progress has been made in the understanding of how allosteric modulation of MAT function can be achieved. Here we will review all the efforts up to date that has been made through computational approaches employing structural models of MATs to design small molecule modulators to the orthosteric and allosteric sites using virtual screening techniques. PMID:26483692

  13. Critical assessment of the automated AutoDock as a new docking tool for virtual screening.

    Science.gov (United States)

    Park, Hwangseo; Lee, Jinuk; Lee, Sangyoub

    2006-11-15

    A major problem in virtual screening concerns the accuracy of the binding free energy between a target protein and a putative ligand. Here we report an example supporting the outperformance of the AutoDock scoring function in virtual screening in comparison to the other popular docking programs. The original AutoDock program is in itself inefficient to be used in virtual screening because the grids of interaction energy have to be calculated for each putative ligand in chemical database. However, the automation of the AutoDock program with the potential grids defined in common for all putative ligands leads to more than twofold increase in the speed of virtual database screening. The utility of the automated AutoDock in virtual screening is further demonstrated by identifying the actual inhibitors of various target enzymes in chemical databases with accuracy higher than the other docking tools including DOCK and FlexX. These results exemplify the usefulness of the automated AutoDock as a new promising tool in structure-based virtual screening. (c) 2006 Wiley-Liss, Inc.

  14. In Silico Genomic Fingerprints of the Bacillus anthracis Group Obtained by Virtual Hybridization

    Directory of Open Access Journals (Sweden)

    Hueman Jaimes-Díaz

    2015-02-01

    Full Text Available In this study we evaluate the capacity of Virtual Hybridization to identify between highly related bacterial strains. Eight genomic fingerprints were obtained by virtual hybridization for the Bacillus anthracis genome set, and a set of 15,264 13-nucleotide short probes designed to produce genomic fingerprints unique for each organism. The data obtained from each genomic fingerprint were used to obtain hybridization patterns simulating a DNA microarray. Two virtual hybridization methods were used: the Direct and the Extended method to identify the number of potential hybridization sites and thus determine the minimum sensitivity value to discriminate between genomes with 99.9% similarity. Genomic fingerprints were compared using both methods and phylogenomic trees were constructed to verify that the minimum detection value is 0.000017. Results obtained from the genomic fingerprints suggest that the distribution in the trees is correct, as compared to other taxonomic methods. Specific virtual hybridization sites for each of the genomes studied were also identified.

  15. Protein structure prediction provides comparable performance to crystallographic structures in docking-based virtual screening.

    Science.gov (United States)

    Du, Hongying; Brender, Jeffrey R; Zhang, Jian; Zhang, Yang

    2015-01-01

    Structure based virtual screening has largely been limited to protein targets for which either an experimental structure is available or a strongly homologous template exists so that a high-resolution model can be constructed. The performance of state of the art protein structure predictions in virtual screening in systems where only weakly homologous templates are available is largely untested. Using the challenging DUD database of structural decoys, we show here that even using templates with only weak sequence homology (identity) structural models can be constructed by I-TASSER which achieve comparable enrichment rates to using the experimental bound crystal structure in the majority of the cases studied. For 65% of the targets, the I-TASSER models, which are constructed essentially in the apo conformations, reached 70% of the virtual screening performance of using the holo-crystal structures. A correlation was observed between the success of I-TASSER in modeling the global fold and local structures in the binding pockets of the proteins versus the relative success in virtual screening. The virtual screening performance can be further improved by the recognition of chemical features of the ligand compounds. These results suggest that the combination of structure-based docking and advanced protein structure modeling methods should be a valuable approach to the large-scale drug screening and discovery studies, especially for the proteins lacking crystallographic structures.

  16. Novel Data Mining Methods for Virtual Screening of Biological Active Chemical Compounds

    KAUST Repository

    Soufan, Othman M.

    2016-11-23

    Drug discovery is a process that takes many years and hundreds of millions of dollars to reveal a confident conclusion about a specific treatment. Part of this sophisticated process is based on preliminary investigations to suggest a set of chemical compounds as candidate drugs for the treatment. Computational resources have been playing a significant role in this part through a step known as virtual screening. From a data mining perspective, availability of rich data resources is key in training prediction models. Yet, the difficulties imposed by big expansion in data and its dimensionality are inevitable. In this thesis, I address the main challenges that come when data mining techniques are used for virtual screening. In order to achieve an efficient virtual screening using data mining, I start by addressing the problem of feature selection and provide analysis of best ways to describe a chemical compound for an enhanced screening performance. High-throughput screening (HTS) assays data used for virtual screening are characterized by a great class imbalance. To handle this problem of class imbalance, I suggest using a novel algorithm called DRAMOTE to narrow down promising candidate chemicals aimed at interaction with specific molecular targets before they are experimentally evaluated. Existing works are mostly proposed for small-scale virtual screening based on making use of few thousands of interactions. Thus, I propose enabling large-scale (or big) virtual screening through learning millions of interaction while exploiting any relevant dependency for a better accuracy. A novel solution called DRABAL that incorporates structure learning of a Bayesian Network as a step to model dependency between the HTS assays, is showed to achieve significant improvements over existing state-of-the-art approaches.

  17. Power flow analysis for droop controlled LV hybrid AC-DC microgrids with virtual impedance

    DEFF Research Database (Denmark)

    Li, Chendan; Chaudhary, Sanjay; Vasquez, Juan Carlos

    2014-01-01

    The AC-DC hybrid microgrid is an effective form of utilizing different energy resources and the analysis of this system requires a proper power flow algorithm. This paper proposes a suitable power flow algorithm for LV hybrid AC-DC microgrid based on droop control and virtual impedance. Droop...... and virtual impedance concepts for AC network, DC network and interlinking converter are reviewed so as to model it in the power flow analysis. The validation of the algorithm is verified by comparing it with steady state results from detailed time domain simulation. The effectiveness of the proposed...

  18. FINDSITE(X): a structure-based, small molecule virtual screening approach with application to all identified human GPCRs.

    Science.gov (United States)

    Zhou, Hongyi; Skolnick, Jeffrey

    2012-06-01

    We have developed FINDSITE(X), an extension of FINDSITE, a protein threading based algorithm for the inference of protein binding sites, biochemical function and virtual ligand screening, that removes the limitation that holo protein structures (those containing bound ligands) of a sufficiently large set of distant evolutionarily related proteins to the target be solved; rather, predicted protein structures and experimental ligand binding information are employed. To provide the predicted protein structures, a fast and accurate version of our recently developed TASSER(VMT), TASSER(VMT)-lite, for template-based protein structural modeling applicable up to 1000 residues is developed and tested, with comparable performance to the top CASP9 servers. Then, a hybrid approach that combines structure alignments with an evolutionary similarity score for identifying functional relationships between target and proteins with binding data has been developed. By way of illustration, FINDSITE(X) is applied to 998 identified human G-protein coupled receptors (GPCRs). First, TASSER(VMT)-lite provides updates of all human GPCR structures previously modeled in our lab. We then use these structures and the new function similarity detection algorithm to screen all human GPCRs against the ZINC8 nonredundant (TC identity > 30% to the target from the binding data library) on a 168 human GPCR set with known binding data, the average enrichment factor in the top 1% of the compound library (EF(0.01)) is 22.7, whereas EF(0.01) by FINDSITE is 7.1. For virtual screening when just the target and its native ligands are excluded, the average EF(0.01) reaches 41.4. We also analyze off-target interactions for the 168 protein test set. All predicted structures, virtual screening data and off-target interactions for the 998 human GPCRs are available at http://cssb.biology.gatech.edu/skolnick/webservice/gpcr/index.html .

  19. Potent Human Telomerase Inhibitors: Molecular Dynamic Simulations, Multiple Pharmacophore-Based Virtual Screening, and Biochemical Assays.

    Science.gov (United States)

    Shirgahi Talari, Faezeh; Bagherzadeh, Kowsar; Golestanian, Sahand; Jarstfer, Michael; Amanlou, Massoud

    2015-12-28

    Telomere maintenance is a universal cancer hallmark, and small molecules that disrupt telomere maintenance generally have anticancer properties. Since the vast majority of cancer cells utilize telomerase activity for telomere maintenance, the enzyme has been considered as an anticancer drug target. Recently, rational design of telomerase inhibitors was made possible by the determination of high resolution structures of the catalytic telomerase subunit from a beetle and subsequent molecular modeling of the human telomerase complex. A hybrid strategy including docking, pharmacophore-based virtual screening, and molecular dynamics simulations (MDS) were used to identify new human telomerase inhibitors. Docking methodology was applied to investigate the ssDNA telomeric sequence and two well-known human telomerase inhibitors' (BIBR1532 and MST-312) modes of interactions with hTERT TEN domain. Subsequently molecular dynamic simulations were performed to monitor and compare hTERT TEN domain, TEN-ssDNA, TEN-BIBR1532, TEN-MST-312, and TEN-ssDNA-BIBR1532 behavior in a dynamic environment. Pharmacophore models were generated considering the inhibitors manner in the TEN domain anchor site. These exploratory studies identified several new potent inhibitors whose IC50 values were generated experimentally in a low micromolar range with the aid of biochemical assays, including both the direct telomerase and the telomeric repeat amplification protocol (TRAP) assays. The results suggest that the current models of human telomerase are useful templates for rational inhibitor design.

  20. Precision and recall estimates for two-hybrid screens.

    Science.gov (United States)

    Huang, Hailiang; Bader, Joel S

    2009-02-01

    Yeast two-hybrid screens are an important method to map pairwise protein interactions. This method can generate spurious interactions (false discoveries), and true interactions can be missed (false negatives). Previously, we reported a capture-recapture estimator for bait-specific precision and recall. Here, we present an improved method that better accounts for heterogeneity in bait-specific error rates. For yeast, worm and fly screens, we estimate the overall false discovery rates (FDRs) to be 9.9%, 13.2% and 17.0% and the false negative rates (FNRs) to be 51%, 42% and 28%. Bait-specific FDRs and the estimated protein degrees are then used to identify protein categories that yield more (or fewer) false positive interactions and more (or fewer) interaction partners. While membrane proteins have been suggested to have elevated FDRs, the current analysis suggests that intrinsic membrane proteins may actually have reduced FDRs. Hydrophobicity is positively correlated with decreased error rates and fewer interaction partners. These methods will be useful for future two-hybrid screens, which could use ultra-high-throughput sequencing for deeper sampling of interacting bait-prey pairs. All software (C source) and datasets are available as supplemental files and at http://www.baderzone.org under the Lesser GPL v. 3 license.

  1. Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates.

    Science.gov (United States)

    Svensson, Fredrik; Engen, Karin; Lundbäck, Thomas; Larhed, Mats; Sköld, Christian

    2015-09-28

    Transition state and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study, a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over 5 million compounds, and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction.

  2. Computational protein-ligand docking and virtual drug screening with the AutoDock suite.

    Science.gov (United States)

    Forli, Stefano; Huey, Ruth; Pique, Michael E; Sanner, Michel F; Goodsell, David S; Olson, Arthur J

    2016-05-01

    Computational docking can be used to predict bound conformations and free energies of binding for small-molecule ligands to macromolecular targets. Docking is widely used for the study of biomolecular interactions and mechanisms, and it is applied to structure-based drug design. The methods are fast enough to allow virtual screening of ligand libraries containing tens of thousands of compounds. This protocol covers the docking and virtual screening methods provided by the AutoDock suite of programs, including a basic docking of a drug molecule with an anticancer target, a virtual screen of this target with a small ligand library, docking with selective receptor flexibility, active site prediction and docking with explicit hydration. The entire protocol will require ∼5 h.

  3. Virtual Screening of Indonesian Herbal Database as HIV-1 Protease Inhibitor.

    Science.gov (United States)

    Yanuar, Arry; Suhartanto, Heru; Munim, Abdul; Anugraha, Bram Hik; Syahdi, Rezi Riadhi

    2014-01-01

    HIV-1 (Human immunodeficiency virus type 1)׳s infection is considered as one of most harmful disease known by human, the survivability rate of the host reduced significantly when it developed into AIDS. HIV drug resistance is one of the main problems of its treatment and several drug designs have been done to find new leads compound as the cure. In this study, in silico virtual screening approach was used to find lead molecules from the library or database of natural compounds as HIV-1 protease inhibitor. Virtual screening against Indonesian Herbal Database with AutoDock was performed on HIV-1 protease. From the virtual screening, top ten compounds obtained were 8-Hydroxyapigenin 8-(2",4"-disulfatoglucuronide), Isoscutellarein 4'-methyl ether, Amaranthin, Torvanol A, Ursonic acid, 5-Carboxypyranocyanidin 3-O-(6"-O-malonyl-beta-glucopyranoside), Oleoside, Jacoumaric acid, Platanic acid and 5-Carboxypyranocyanidin 3-O-beta-glucopyranoside.

  4. LBVS: an online platform for ligand-based virtual screening using publicly accessible databases.

    Science.gov (United States)

    Zheng, Minghao; Liu, Zhihong; Yan, Xin; Ding, Qianzhi; Gu, Qiong; Xu, Jun

    2014-11-01

    Abundant data on compound bioactivity and publicly accessible chemical databases increase opportunities for ligand-based drug discovery. In order to make full use of the data, an online platform for ligand-based virtual screening (LBVS) using publicly accessible databases has been developed. LBVS adopts Bayesian learning approach to create virtual screening models because of its noise tolerance, speed, and efficiency in extracting knowledge from data. LBVS currently includes data derived from BindingDB and ChEMBL. Three validation approaches have been employed to evaluate the virtual screening models created from LBVS. The tenfold cross validation results of twenty different LBVS models demonstrate that LBVS achieves an average AUC value of 0.86. Our internal and external testing results indicate that LBVS is predictive for lead identifications. LBVS can be publicly accessed at http://rcdd.sysu.edu.cn/lbvs.

  5. An Enhancement of Bayesian Inference Network for Ligand-Based Virtual Screening using Features Selection

    Directory of Open Access Journals (Sweden)

    Ali Ahmed

    2011-01-01

    Full Text Available Problem statement: Similarity based Virtual Screening (VS deals with a large amount of data containing irrelevant and/or redundant fragments or features. Recent use of Bayesian network as an alternative for existing tools for similarity based VS has received noticeable attention of the researchers in the field of chemoinformatics. Approach: To this end, different models of Bayesian network have been developed. In this study, we enhance the Bayesian Inference Network (BIN using a subset of selected molecules features. Results: In this approach, a few features were filtered from the molecular fingerprint features based on a features selection approach. Conclusion: Simulated virtual screening experiments with MDL Drug Data Report (MDDR data sets showed that the proposed method provides simple ways of enhancing the cost effectiveness of ligand-based virtual screening searches, especially for higher diversity data set.

  6. Virtual Screening Approaches towards the Discovery of Toll-Like Receptor Modulators

    Directory of Open Access Journals (Sweden)

    Lucía Pérez-Regidor

    2016-09-01

    Full Text Available This review aims to summarize the latest efforts performed in the search for novel chemical entities such as Toll-like receptor (TLR modulators by means of virtual screening techniques. This is an emergent research field with only very recent (and successful contributions. Identification of drug-like molecules with potential therapeutic applications for the treatment of a variety of TLR-regulated diseases has attracted considerable interest due to the clinical potential. Additionally, the virtual screening databases and computational tools employed have been overviewed in a descriptive way, widening the scope for researchers interested in the field.

  7. Virtual Screening Approaches towards the Discovery of Toll-Like Receptor Modulators

    Science.gov (United States)

    Pérez-Regidor, Lucía; Zarioh, Malik; Ortega, Laura; Martín-Santamaría, Sonsoles

    2016-01-01

    This review aims to summarize the latest efforts performed in the search for novel chemical entities such as Toll-like receptor (TLR) modulators by means of virtual screening techniques. This is an emergent research field with only very recent (and successful) contributions. Identification of drug-like molecules with potential therapeutic applications for the treatment of a variety of TLR-regulated diseases has attracted considerable interest due to the clinical potential. Additionally, the virtual screening databases and computational tools employed have been overviewed in a descriptive way, widening the scope for researchers interested in the field. PMID:27618029

  8. 1001 Ways to run AutoDock Vina for virtual screening.

    Science.gov (United States)

    Jaghoori, Mohammad Mahdi; Bleijlevens, Boris; Olabarriaga, Silvia D

    2016-03-01

    Large-scale computing technologies have enabled high-throughput virtual screening involving thousands to millions of drug candidates. It is not trivial, however, for biochemical scientists to evaluate the technical alternatives and their implications for running such large experiments. Besides experience with the molecular docking tool itself, the scientist needs to learn how to run it on high-performance computing (HPC) infrastructures, and understand the impact of the choices made. Here, we review such considerations for a specific tool, AutoDock Vina, and use experimental data to illustrate the following points: (1) an additional level of parallelization increases virtual screening throughput on a multi-core machine; (2) capturing of the random seed is not enough (though necessary) for reproducibility on heterogeneous distributed computing systems; (3) the overall time spent on the screening of a ligand library can be improved by analysis of factors affecting execution time per ligand, including number of active torsions, heavy atoms and exhaustiveness. We also illustrate differences among four common HPC infrastructures: grid, Hadoop, small cluster and multi-core (virtual machine on the cloud). Our analysis shows that these platforms are suitable for screening experiments of different sizes. These considerations can guide scientists when choosing the best computing platform and set-up for their future large virtual screening experiments.

  9. VSDK: Virtual screening of small molecules using AutoDock Vina on Windows platform.

    Science.gov (United States)

    Baba, Natsumi; Akaho, Eiichi

    2011-01-01

    Screening of ligand molecules to target proteins using computer-aided docking is a critical step in rational drug discovery. Based on this circumstance, we attempted to develop a virtual screening application system, named VSDK Virtual Screening by Docking, which can function under the Windows platform. This is a user-friendly, flexible, and versatile tool which can be used by users who are familiar with Windows OS. The virtual screening performance was tested for an arbitrarily-selected receptor, FGFR tyrosine kinase (pdb code: 1agw), by using ligands downloaded from ZINC database with its grid size of x,y,z = 30,30,30 and run number of 10. It took 90 minutes for 100 molecules for this virtual screening. VSDK is freely available at the designated URL, and a simplified manual can be downloaded from VSDK home page. This tool will have a more challenging scope and achievement as the computer speed and accuracy are increased and secured in the future. The database is available for free at http://www.pharm.kobegakuin.ac.jp/˜akaho/english_top.html.

  10. Teaching Basic Field Skills Using Screen-Based Virtual Reality Landscapes

    Science.gov (United States)

    Houghton, J.; Robinson, A.; Gordon, C.; Lloyd, G. E. E.; Morgan, D. J.

    2016-12-01

    We are using screen-based virtual reality landscapes, created using the Unity 3D game engine, to augment the training geoscience students receive in preparing for fieldwork. Students explore these landscapes as they would real ones, interacting with virtual outcrops to collect data, determine location, and map the geology. Skills for conducting field geological surveys - collecting, plotting and interpreting data; time management and decision making - are introduced interactively and intuitively. As with real landscapes, the virtual landscapes are open-ended terrains with embedded data. This means the game does not structure student interaction with the information as it is through experience the student learns the best methods to work successfully and efficiently. These virtual landscapes are not replacements for geological fieldwork rather virtual spaces between classroom and field in which to train and reinforcement essential skills. Importantly, these virtual landscapes offer accessible parallel provision for students unable to visit, or fully partake in visiting, the field. The project has received positive feedback from both staff and students. Results show students find it easier to focus on learning these basic field skills in a classroom, rather than field setting, and make the same mistakes as when learning in the field, validating the realistic nature of the virtual experience and providing opportunity to learn from these mistakes. The approach also saves time, and therefore resources, in the field as basic skills are already embedded. 70% of students report increased confidence with how to map boundaries and 80% have found the virtual training a useful experience. We are also developing landscapes based on real places with 3D photogrammetric outcrops, and a virtual urban landscape in which Engineering Geology students can conduct a site investigation. This project is a collaboration between the University of Leeds and Leeds College of Art, UK, and all

  11. A virtual experiment showing single particle motion on a linearly vibrating screen-deck

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    A virtual sieving experimental simulation system was built using physical simulation principles.The effects of vibration frequency and amplitude,the inclination angle of the screen-deck and the vibration direction angle of screen on single particle kinematics were predicted.Properties such as the average velocity and the average throw height were studied.The results show that the amplitude and the angle of vibration have a great effect on particle average velocity and average height.The vibration frequency ...

  12. ChemScreener: A Distributed Computing Tool for Scaffold based Virtual Screening.

    Science.gov (United States)

    Karthikeyan, Muthukumarasamy; Pandit, Deepak; Vyas, Renu

    2015-01-01

    In this work we present ChemScreener, a Java-based application to perform virtual library generation combined with virtual screening in a platform-independent distributed computing environment. ChemScreener comprises a scaffold identifier, a distinct scaffold extractor, an interactive virtual library generator as well as a virtual screening module for subsequently selecting putative bioactive molecules. The virtual libraries are annotated with chemophore-, pharmacophore- and toxicophore-based information for compound prioritization. The hits selected can then be further processed using QSAR, docking and other in silico approaches which can all be interfaced within the ChemScreener framework. As a sample application, in this work scaffold selectivity, diversity, connectivity and promiscuity towards six important therapeutic classes have been studied. In order to illustrate the computational power of the application, 55 scaffolds extracted from 161 anti-psychotic compounds were enumerated to produce a virtual library comprising 118 million compounds (17 GB) and annotated with chemophore, pharmacophore and toxicophore based features in a single step which would be non-trivial to perform with many standard software tools today on libraries of this size.

  13. Design and Development of ChemInfoCloud: An Integrated Cloud Enabled Platform for Virtual Screening.

    Science.gov (United States)

    Karthikeyan, Muthukumarasamy; Pandit, Deepak; Bhavasar, Arvind; Vyas, Renu

    2015-01-01

    The power of cloud computing and distributed computing has been harnessed to handle vast and heterogeneous data required to be processed in any virtual screening protocol. A cloud computing platorm ChemInfoCloud was built and integrated with several chemoinformatics and bioinformatics tools. The robust engine performs the core chemoinformatics tasks of lead generation, lead optimisation and property prediction in a fast and efficient manner. It has also been provided with some of the bioinformatics functionalities including sequence alignment, active site pose prediction and protein ligand docking. Text mining, NMR chemical shift (1H, 13C) prediction and reaction fingerprint generation modules for efficient lead discovery are also implemented in this platform. We have developed an integrated problem solving cloud environment for virtual screening studies that also provides workflow management, better usability and interaction with end users using container based virtualization, OpenVz.

  14. A Multi-Projector Calibration Method for Virtual Reality Simulators with Analytically Defined Screens

    Directory of Open Access Journals (Sweden)

    Cristina Portalés

    2017-06-01

    Full Text Available The geometric calibration of projectors is a demanding task, particularly for the industry of virtual reality simulators. Different methods have been developed during the last decades to retrieve the intrinsic and extrinsic parameters of projectors, most of them being based on planar homographies and some requiring an extended calibration process. The aim of our research work is to design a fast and user-friendly method to provide multi-projector calibration on analytically defined screens, where a sample is shown for a virtual reality Formula 1 simulator that has a cylindrical screen. The proposed method results from the combination of surveying, photogrammetry and image processing approaches, and has been designed by considering the spatial restrictions of virtual reality simulators. The method has been validated from a mathematical point of view, and the complete system—which is currently installed in a shopping mall in Spain—has been tested by different users.

  15. Implementing relevance feedback in ligand-based virtual screening using Bayesian inference network.

    Science.gov (United States)

    Abdo, Ammar; Salim, Naomie; Ahmed, Ali

    2011-10-01

    Recently, the use of the Bayesian network as an alternative to existing tools for similarity-based virtual screening has received noticeable attention from researchers in the chemoinformatics field. The main aim of the Bayesian network model is to improve the retrieval effectiveness of similarity-based virtual screening. To this end, different models of the Bayesian network have been developed. In our previous works, the retrieval performance of the Bayesian network was observed to improve significantly when multiple reference structures or fragment weightings were used. In this article, the authors enhance the Bayesian inference network (BIN) using the relevance feedback information. In this approach, a few high-ranking structures of unknown activity were filtered from the outputs of BIN, based on a single active reference structure, to form a set of active reference structures. This set of active reference structures was used in two distinct techniques for carrying out such BIN searching: reweighting the fragments in the reference structures and group fusion techniques. Simulated virtual screening experiments with three MDL Drug Data Report data sets showed that the proposed techniques provide simple ways of enhancing the cost-effectiveness of ligand-based virtual screening searches, especially for higher diversity data sets.

  16. Identification of mangiferin as a potential Glucokinase activator by structure-based virtual ligand screening.

    Science.gov (United States)

    Min, Qiuxia; Cai, Xinpei; Sun, Weiguang; Gao, Fei; Li, Zhimei; Zhang, Qian; Wan, Luo-Sheng; Li, Hua; Chen, Jiachun

    2017-03-20

    The natural product mangiferin (compound 7) has been identified as a potential glucokinase activator by structure-based virtual ligand screening. It was proved by enzyme activation experiment and cell-based assays in vitro, with potency in micromolar range. Meanwhile, this compound showed good antihyperglycemic activity in db/db mice without obvious side effects such as excessive hypoglycaemia.

  17. Phenylpyrroles, a new chemolibrary virtual screening class of 5-HT7 receptor ligands.

    Science.gov (United States)

    Paillet-Loilier, Magalie; Fabis, Frédéric; Lepailleur, Alban; Bureau, Ronan; Butt-Gueulle, Sabrina; Dauphin, François; Delarue, Catherine; Vaudry, Hubert; Rault, Sylvain

    2005-08-15

    Virtual screening studies have identified a series of phenylpyrroles as novel 5-HT7 receptor ligands. The synthesis and the affinity for the 5-HT7 receptor of these phenylpyrroles are described. Some of these compounds exhibited high affinity for the 5-HT7 receptors.

  18. Optimization of enrichment for virtual ligand screening using an established FRED-Surflex approach

    NARCIS (Netherlands)

    Du, J.; Bleylevens, I.W.M.; Bitorina, A.V.; Nicolaes, G.A.F.

    2012-01-01

    Virtual ligand screening (VLS) is an in silico technology used for the productive and cost effective search for novel hit or lead compounds. VLS can be divided into rigid body docking (e.g. FRED) and flexible body docking (e.g. Surflex) procedures. Theoretically, rigid body docking VLS is fast but l

  19. Binding-site assessment by virtual fragment screening.

    Directory of Open Access Journals (Sweden)

    Niu Huang

    Full Text Available The accurate prediction of protein druggability (propensity to bind high-affinity drug-like small molecules would greatly benefit the fields of chemical genomics and drug discovery. We have developed a novel approach to quantitatively assess protein druggability by computationally screening a fragment-like compound library. In analogy to NMR-based fragment screening, we dock approximately 11,000 fragments against a given binding site and compute a computational hit rate based on the fraction of molecules that exceed an empirically chosen score cutoff. We perform a large-scale evaluation of the approach on four datasets, totaling 152 binding sites. We demonstrate that computed hit rates correlate with hit rates measured experimentally in a previously published NMR-based screening method. Secondly, we show that the in silico fragment screening method can be used to distinguish known druggable and non-druggable targets, including both enzymes and protein-protein interaction sites. Finally, we explore the sensitivity of the results to different receptor conformations, including flexible protein-protein interaction sites. Besides its original aim to assess druggability of different protein targets, this method could be used to identifying druggable conformations of flexible binding site for lead discovery, and suggesting strategies for growing or joining initial fragment hits to obtain more potent inhibitors.

  20. Large-scale virtual screening on public cloud resources with Apache Spark.

    Science.gov (United States)

    Capuccini, Marco; Ahmed, Laeeq; Schaal, Wesley; Laure, Erwin; Spjuth, Ola

    2017-01-01

    Structure-based virtual screening is an in-silico method to screen a target receptor against a virtual molecular library. Applying docking-based screening to large molecular libraries can be computationally expensive, however it constitutes a trivially parallelizable task. Most of the available parallel implementations are based on message passing interface, relying on low failure rate hardware and fast network connection. Google's MapReduce revolutionized large-scale analysis, enabling the processing of massive datasets on commodity hardware and cloud resources, providing transparent scalability and fault tolerance at the software level. Open source implementations of MapReduce include Apache Hadoop and the more recent Apache Spark. We developed a method to run existing docking-based screening software on distributed cloud resources, utilizing the MapReduce approach. We benchmarked our method, which is implemented in Apache Spark, docking a publicly available target receptor against [Formula: see text]2.2 M compounds. The performance experiments show a good parallel efficiency (87%) when running in a public cloud environment. Our method enables parallel Structure-based virtual screening on public cloud resources or commodity computer clusters. The degree of scalability that we achieve allows for trying out our method on relatively small libraries first and then to scale to larger libraries. Our implementation is named Spark-VS and it is freely available as open source from GitHub (https://github.com/mcapuccini/spark-vs).Graphical abstract.

  1. Virtual screening: an in silico tool for interlacing the chemical universe with the proteome.

    Science.gov (United States)

    Westermaier, Yvonne; Barril, Xavier; Scapozza, Leonardo

    2015-01-01

    In silico screening both in the forward (traditional virtual screening) and reverse sense (inverse virtual screening (IVS)) are helpful techniques for interlacing the chemical universe of small molecules with the proteome. The former, which is using a protein structure and a large chemical database, is well-known by the scientific community. We have chosen here to provide an overview on the latter, focusing on validation and target prioritization strategies. By comparing it to complementary or alternative wet-lab approaches, we put IVS in the broader context of chemical genomics, target discovery and drug design. By giving examples from the literature and an own example on how to validate the approach, we provide guidance on the issues related to IVS. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Virtual screening and biological characterization of novel histone arginine methyltransferase PRMT1 inhibitors.

    Science.gov (United States)

    Heinke, Ralf; Spannhoff, Astrid; Meier, Rene; Trojer, Patrick; Bauer, Ingo; Jung, Manfred; Sippl, Wolfgang

    2009-01-01

    Lysine and arginine methyltransferases participate in the posttranslational modification of histones and regulate key cellular functions. Protein arginine methyltransferase 1 (PRMT1) has been identified as an essential component of mixed lineage leukemia (MLL) oncogenic complexes, revealing its potential as a novel therapeutic target in human cancer. The first potent arginine methyltransferase inhibitors were recently discovered by random- and target-based screening approaches. Herein we report virtual and biological screening for novel inhibitors of PRMT1. Structure-based virtual screening (VS) of the Chembridge database composed of 328 000 molecules was performed with a combination of ligand- and target-based in silico approaches. Nine inhibitors were identified from the top-scored docking solutions; these were experimentally tested using human PRMT1 and an antibody-based assay with a time-resolved fluorescence readout. Among several aromatic amines, an aliphatic amine and an amide were also found to be active in the micromolar range.

  3. Molecular field technology applied to virtual screening and finding the bioactive conformation.

    Science.gov (United States)

    Cheeseright, Tim; Mackey Phd, Mark; Rose Phd, Sally; Vinter Phd, Andy

    2007-01-01

    Virtual screening is being applied to reduce the high-throughput screening bottleneck in many pharmaceutical companies and to reduce compound wastage. Cresset's ligand-based virtual screening technology using molecular fields can facilitate rapid identification of novel chemotypes from biologically testing only 200 - 1000 compounds. Four molecular fields calculated using the interaction of different probe atoms with the ligand are sufficient to describe how a ligand binds to its protein. Compounds with similar fields to known active ligands are predicted to have a high probability of showing similar activity. As binding is related to field similarity, this property has been exploited further to predict the bioactive conformation of small sets of structurally diverse active ligands starting from the two-dimensional structures alone without knowledge of the target site structure.

  4. Molecular dynamics-based virtual screening: accelerating the drug discovery process by high-performance computing.

    Science.gov (United States)

    Ge, Hu; Wang, Yu; Li, Chanjuan; Chen, Nanhao; Xie, Yufang; Xu, Mengyan; He, Yingyan; Gu, Xinchun; Wu, Ruibo; Gu, Qiong; Zeng, Liang; Xu, Jun

    2013-10-28

    High-performance computing (HPC) has become a state strategic technology in a number of countries. One hypothesis is that HPC can accelerate biopharmaceutical innovation. Our experimental data demonstrate that HPC can significantly accelerate biopharmaceutical innovation by employing molecular dynamics-based virtual screening (MDVS). Without using HPC, MDVS for a 10K compound library with tens of nanoseconds of MD simulations requires years of computer time. In contrast, a state of the art HPC can be 600 times faster than an eight-core PC server is in screening a typical drug target (which contains about 40K atoms). Also, careful design of the GPU/CPU architecture can reduce the HPC costs. However, the communication cost of parallel computing is a bottleneck that acts as the main limit of further virtual screening improvements for drug innovations.

  5. Largest Common Chemical Feature Subtree as a Virtual Screening Method

    DEFF Research Database (Denmark)

    Kristensen, Thomas Greve; Pedersen, Christian Storm; Thomsen, Rene

    We investigate the effectiveness of using a tree comparison based method to screen for drug candidates. Molecules are represented as trees in which ring systems are reduced to single nodes. These trees are compared to the tree of a selected known binder and the molecules are ranked according...... to the normalized size of their largest common subtree. The nodes of the molecular trees contains information about the atoms or ring systems they represent (e.g. charge and hydrogen donor/acceptor properties). In this way we can restrict which nodes are matched when calculating the size of the largest common...

  6. The GOSTT concept and hybrid mixed/virtual/augmented reality environment radioguided surgery.

    Science.gov (United States)

    Valdés Olmos, R A; Vidal-Sicart, S; Giammarile, F; Zaknun, J J; Van Leeuwen, F W; Mariani, G

    2014-06-01

    these protocols the generated virtual SPECT/CT elements are visually superimposed in the body of the patient in the operating room to directly facilitate, by means of visualization on screen or using head-mounted devices, the localization of radioactive and/or fluorescent targets by minimal invasive approaches in areas of complex anatomy. All these technological advances will play an increasing role in the future extension and the clinical impact of the GOSTT concept.

  7. Structure based virtual screening-driven identification of monastrol as a potent urease inhibitor.

    Science.gov (United States)

    Rashid, Umer; Batool, Iram; Wadood, Abdul; Khan, Ajmal; ul-Haq, Zaheer; Chaudhary, Muhammad Iqbal; Ansari, Farzana Latif

    2013-06-01

    Virtual screening uses computer based methods to discover new ligands on the basis of biological structures. Among all virtual screening methods structure based docking has received considerable attention. In an attempt to identify new ligands as urease inhibitors, structure-based virtual screening (SBVS) of an in-house database of 10,000 organic compounds was carried out. The X-ray crystallographic structure of Bacillus pasteurii (BP) in complex with acetohydroxamic acid (PDB Code 4UBP) was used as a protein structure. As a starting point, ~10,000 compounds of our in-house database were analyzed to check redundancy and the compounds found repeated were removed from the database. Finally 6993 compounds were docked into the active site of BP urease using GOLD and MOE-Dock software. A remarkable feature of this study was the identification of monastrol, a well-known KSP inhibitor already in clinical trials, as a novel urease inhibitor. The hits identified were further evaluated by molecular docking and on examination of the affinity predictions, twenty-seven analogs of monastrol were synthesized by a multicomponent Biginelli reaction followed by their in vitro screening as urease inhibitors. Finally twelve compounds were identified as new urease inhibitors. The excellent in vitro activity suggested that these compounds may serve as viable lead compounds for the treatment of urease related problems.

  8. Identification of VDR Antagonists among Nuclear Receptor Ligands Using Virtual Screening

    Directory of Open Access Journals (Sweden)

    Kelly Teske

    2014-04-01

    Full Text Available Herein, we described the development of two virtual screens to identify new vitamin D receptor (VDR antagonists among nuclear receptor (NR ligands. Therefore, a database of 14330 nuclear receptor ligands and their NR affinities was assembled using the online available “Binding Database.” Two different virtual screens were carried out in conjunction with a reported VDR crystal structure applying a stringent and less stringent pharmacophore model to filter docked NR ligand conformations. The pharmacophore models were based on the spatial orientation of the hydroxyl functionalities of VDR's natural ligands 1,25(OH2D3 and 25(OH2D3. The first virtual screen identified 32 NR ligands with a calculated free energy of VDR binding of more than -6.0 kJ/mol. All but nordihydroguaiaretic acid (NDGA are VDR ligands, which inhibited the interaction between VDR and coactivator peptide SRC2-3 with an IC50 value of 15.8 μM. The second screen identified 162 NR ligands with a calculated free energy of VDR binding of more than -6.0 kJ/mol. More than half of these ligands were developed to bind VDR followed by ERα/β ligands (26%, TRα/β ligands (7%, and LxRα/β ligands (7%. The binding between VDR and ERα ligand H6036 as well as TRα/β ligand triiodothyronine and a homoserine analog thereof was confirmed by fluorescence polarization.

  9. Discovery of binding proteins for a protein target using protein-protein docking-based virtual screening.

    Science.gov (United States)

    Zhang, Changsheng; Tang, Bo; Wang, Qian; Lai, Luhua

    2014-10-01

    Target structure-based virtual screening, which employs protein-small molecule docking to identify potential ligands, has been widely used in small-molecule drug discovery. In the present study, we used a protein-protein docking program to identify proteins that bind to a specific target protein. In the testing phase, an all-to-all protein-protein docking run on a large dataset was performed. The three-dimensional rigid docking program SDOCK was used to examine protein-protein docking on all protein pairs in the dataset. Both the binding affinity and features of the binding energy landscape were considered in the scoring function in order to distinguish positive binding pairs from negative binding pairs. Thus, the lowest docking score, the average Z-score, and convergency of the low-score solutions were incorporated in the analysis. The hybrid scoring function was optimized in the all-to-all docking test. The docking method and the hybrid scoring function were then used to screen for proteins that bind to tumor necrosis factor-α (TNFα), which is a well-known therapeutic target for rheumatoid arthritis and other autoimmune diseases. A protein library containing 677 proteins was used for the screen. Proteins with scores among the top 20% were further examined. Sixteen proteins from the top-ranking 67 proteins were selected for experimental study. Two of these proteins showed significant binding to TNFα in an in vitro binding study. The results of the present study demonstrate the power and potential application of protein-protein docking for the discovery of novel binding proteins for specific protein targets.

  10. Serious games for screening pre-dementia conditions: from virtuality to reality? A pilot project.

    Science.gov (United States)

    Zucchella, Chiara; Sinforiani, Elena; Tassorelli, Cristina; Cavallini, Elena; Tost-Pardell, Daniela; Grau, Sergi; Pazzi, Stefania; Puricelli, Stefano; Bernini, Sara; Bottiroli, Sara; Vecchi, Tomaso; Sandrini, Giorgio; Nappi, Giuseppe

    2014-01-01

    Conventional cognitive assessment is based on a pencil-and-paper neuropsychological evaluation, which is time consuming, expensive and requires the involvement of several professionals. Information and communication technology could be exploited to allow the development of tools that are easy to use, reduce the amount of data processing, and provide controllable test conditions. Serious games (SGs) have the potential to be new and effective tools in the management and treatment of cognitive impairments Serious games for screening pre-dementia conditions: from virtuality to reality? A pilot project in the elderly. Moreover, by adopting SGs in 3D virtual reality settings, cognitive functions might be evaluated using tasks that simulate daily activities, increasing the "ecological validity" of the assessment. In this commentary we report our experience in the creation of the Smart Aging platform, a 3D SGand virtual environment-based platform for the early identification and characterization of mild cognitive impairment.

  11. Rational drug design of antineoplastic agents using 3D-QSAR, cheminformatic, and virtual screening approaches.

    Science.gov (United States)

    Vucicevic, Jelica; Nikolic, Katarina; Mitchell, John B O

    2017-07-12

    Computer-Aided Drug Design has strongly accelerated the development of novel antineoplastic agents by helping in the hit identification, optimization, and evaluation. Computational approaches such as cheminformatic search, virtual screening, pharmacophore modeling, molecular docking and dynamics have been developed and applied to explain the activity of bioactive molecules, design novel agents, increase the success rate of drug research, and decrease the total costs of drug discovery. Similarity searches and virtual screening are used to identify molecules with an increased probability to interact with drug targets of interest, while the other computational approaches are applied for the design and evaluation of molecules with enhanced activity and improved safety profile. In this review are described the main in silico techniques used in rational drug design of antineoplastic agents and presented optimal combinations of computational methods for design of more efficient antineoplastic drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Virtual screening for HIV protease inhibitors: a comparison of AutoDock 4 and Vina.

    Science.gov (United States)

    Chang, Max W; Ayeni, Christian; Breuer, Sebastian; Torbett, Bruce E

    2010-08-04

    The AutoDock family of software has been widely used in protein-ligand docking research. This study compares AutoDock 4 and AutoDock Vina in the context of virtual screening by using these programs to select compounds active against HIV protease. Both programs were used to rank the members of two chemical libraries, each containing experimentally verified binders to HIV protease. In the case of the NCI Diversity Set II, both AutoDock 4 and Vina were able to select active compounds significantly better than random (AUC = 0.69 and 0.68, respectively; pAutoDock 4 and Vina were equally capable, though both exhibited a size-related bias in scoring. However, as Vina executes more quickly and is able to more accurately rank larger molecules, researchers should look to it first when undertaking a virtual screen.

  13. Ligand-Based Virtual Screening in a Search for Novel Anti-HIV-1 Chemotypes.

    Science.gov (United States)

    Kurczyk, Agata; Warszycki, Dawid; Musiol, Robert; Kafel, Rafał; Bojarski, Andrzej J; Polanski, Jaroslaw

    2015-10-26

    In a search for new anti-HIV-1 chemotypes, we developed a multistep ligand-based virtual screening (VS) protocol combining machine learning (ML) methods with the privileged structures (PS) concept. In its learning step, the VS protocol was based on HIV integrase (IN) inhibitors fetched from the ChEMBL database. The performances of various ML methods and PS weighting scheme were evaluated and applied as VS filtering criteria. Finally, a database of 1.5 million commercially available compounds was virtually screened using a multistep ligand-based cascade, and 13 selected unique structures were tested by measuring the inhibition of HIV replication in infected cells. This approach resulted in the discovery of two novel chemotypes with moderate antiretroviral activity, that, together with their topological diversity, make them good candidates as lead structures for future optimization.

  14. Discovery of novel small-molecule inhibitors of BRD4 using structure-based virtual screening.

    Science.gov (United States)

    Vidler, Lewis R; Filippakopoulos, Panagis; Fedorov, Oleg; Picaud, Sarah; Martin, Sarah; Tomsett, Michael; Woodward, Hannah; Brown, Nathan; Knapp, Stefan; Hoelder, Swen

    2013-10-24

    Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.

  15. Combining pharmacophore fingerprints and PLS-discriminant analysis for virtual screening and SAR elucidation

    DEFF Research Database (Denmark)

    Askjær, Sune; Langgård, Morten

    2008-01-01

    fingerprints proved superior to the TGT and TGD fingerprints. Examples of SAR elucidation based on PLS-DA model interpretation of model coefficients using a reversible pharmacophore fingerprint are given. In addition, we tested the hypothesis that feature combinations coming from the analysis of two...... the lead optimization toward a final drug candidate. This paper presents a combined approach to solving these two problems of ligand-based virtual screening and elucidation of SAR based on interplay between pharmacophore fingerprints and interpretation of PLS-discriminant analysis (PLS-DA) models....... The virtual screening capability of the PLS-DA method is compared to group fusion maximum similarity searching in a test using four graph-based pharmacophore fingerprints over a range of 10 diverse targets. The PLS-DA method was generally found to do better than the Smax method. The GpiDAPH3 and PCH...

  16. Identification of DNA primase inhibitors via a combined fragment-based and virtual screening

    Science.gov (United States)

    Ilic, Stefan; Akabayov, Sabine R.; Arthanari, Haribabu; Wagner, Gerhard; Richardson, Charles C.; Akabayov, Barak

    2016-11-01

    The structural differences between bacterial and human primases render the former an excellent target for drug design. Here we describe a technique for selecting small molecule inhibitors of the activity of T7 DNA primase, an ideal model for bacterial primases due to their common structural and functional features. Using NMR screening, fragment molecules that bind T7 primase were identified and then exploited in virtual filtration to select larger molecules from the ZINC database. The molecules were docked to the primase active site using the available primase crystal structure and ranked based on their predicted binding energies to identify the best candidates for functional and structural investigations. Biochemical assays revealed that some of the molecules inhibit T7 primase-dependent DNA replication. The binding mechanism was delineated via NMR spectroscopy. Our approach, which combines fragment based and virtual screening, is rapid and cost effective and can be applied to other targets.

  17. Spiroimidazolidinone NPC1L1 inhibitors. 1: Discovery by 3D-similarity-based virtual screening.

    Science.gov (United States)

    McMasters, Daniel R; Garcia-Calvo, Margarita; Maiorov, Vladimir; McCann, Margaret E; Meurer, Roger D; Bull, Herbert G; Lisnock, Jeanmarie; Howell, Kobporn L; Devita, Robert J

    2009-06-01

    A series of spiroimidazolidinone NPC1L1 inhibitors was discovered by virtual screening of the Merck corporate sample repository using 3D-similarity-based screening. Selection of 330 compounds for testing in an in vitro NPC1L1 binding assay yielded six hits in six distinct chemical series. Follow-up 2D similarity searching yielded several sub- to low-micromolar leads; among these was spiroimidazolidinone 10, with an IC(50) of 2.5 microM. Compound 10 provided a useful scaffold to initiate a medicinal chemistry campaign.

  18. The virtual slide in the promotion of cytologic and hystologic quality in oncologic screenings.

    Science.gov (United States)

    Bondi, Arrigo; Pierotti, Paola; Crucitti, Paola; Lega, Stefania

    2010-01-01

    A regional experience environment in virtual microscopy and digital pathology comprehending the digital cytology is presented. The project has been conducted in Emilia-Romagna and it has been planned for the promotion and the quality assessment in screening cytology and histology for the prevention of the tumors of uterine cervix, breast and colon-rectum cancers. During the project it has been envisaged the design of a dedicated picture archive and communication system (PACS) for cooperative diagnosis, didactics and training, teleconsulting, documentation of rare cases and pilot experiences; furthermore selected cases are catalogued in the PACS with the aim of the check of the diagnostic concordance in the oncologic screening.

  19. GeauxDock: Accelerating Structure-Based Virtual Screening with Heterogeneous Computing.

    Directory of Open Access Journals (Sweden)

    Ye Fang

    Full Text Available Computational modeling of drug binding to proteins is an integral component of direct drug design. Particularly, structure-based virtual screening is often used to perform large-scale modeling of putative associations between small organic molecules and their pharmacologically relevant protein targets. Because of a large number of drug candidates to be evaluated, an accurate and fast docking engine is a critical element of virtual screening. Consequently, highly optimized docking codes are of paramount importance for the effectiveness of virtual screening methods. In this communication, we describe the implementation, tuning and performance characteristics of GeauxDock, a recently developed molecular docking program. GeauxDock is built upon the Monte Carlo algorithm and features a novel scoring function combining physics-based energy terms with statistical and knowledge-based potentials. Developed specifically for heterogeneous computing platforms, the current version of GeauxDock can be deployed on modern, multi-core Central Processing Units (CPUs as well as massively parallel accelerators, Intel Xeon Phi and NVIDIA Graphics Processing Unit (GPU. First, we carried out a thorough performance tuning of the high-level framework and the docking kernel to produce a fast serial code, which was then ported to shared-memory multi-core CPUs yielding a near-ideal scaling. Further, using Xeon Phi gives 1.9× performance improvement over a dual 10-core Xeon CPU, whereas the best GPU accelerator, GeForce GTX 980, achieves a speedup as high as 3.5×. On that account, GeauxDock can take advantage of modern heterogeneous architectures to considerably accelerate structure-based virtual screening applications. GeauxDock is open-sourced and publicly available at www.brylinski.org/geauxdock and https://figshare.com/articles/geauxdock_tar_gz/3205249.

  20. Shape based virtual screening and molecular docking towards designing novel pancreatic lipase inhibitors

    OpenAIRE

    Veeramachaneni, Ganesh Kumar; Raj, K Kranthi; Chalasani,Leela Madhuri; Annamraju, Sai Krishna; Bondili JS; Talluri, Venkateswara Rao

    2015-01-01

    Increase in obesity rates and obesity associated health issues became one of the greatest health concerns in the present world population. With alarming increase in obese percentage there is a need to design new drugs related to the obesity targets. Among the various targets linked to obesity, pancreatic lipase was one of the promising targets for obesity treatment. Using the in silico methods like structure based virtual screening, QikProp, docking studies and binding energy calculations thr...

  1. GeauxDock: Accelerating Structure-Based Virtual Screening with Heterogeneous Computing

    Science.gov (United States)

    Fang, Ye; Ding, Yun; Feinstein, Wei P.; Koppelman, David M.; Moreno, Juana; Jarrell, Mark; Ramanujam, J.; Brylinski, Michal

    2016-01-01

    Computational modeling of drug binding to proteins is an integral component of direct drug design. Particularly, structure-based virtual screening is often used to perform large-scale modeling of putative associations between small organic molecules and their pharmacologically relevant protein targets. Because of a large number of drug candidates to be evaluated, an accurate and fast docking engine is a critical element of virtual screening. Consequently, highly optimized docking codes are of paramount importance for the effectiveness of virtual screening methods. In this communication, we describe the implementation, tuning and performance characteristics of GeauxDock, a recently developed molecular docking program. GeauxDock is built upon the Monte Carlo algorithm and features a novel scoring function combining physics-based energy terms with statistical and knowledge-based potentials. Developed specifically for heterogeneous computing platforms, the current version of GeauxDock can be deployed on modern, multi-core Central Processing Units (CPUs) as well as massively parallel accelerators, Intel Xeon Phi and NVIDIA Graphics Processing Unit (GPU). First, we carried out a thorough performance tuning of the high-level framework and the docking kernel to produce a fast serial code, which was then ported to shared-memory multi-core CPUs yielding a near-ideal scaling. Further, using Xeon Phi gives 1.9× performance improvement over a dual 10-core Xeon CPU, whereas the best GPU accelerator, GeForce GTX 980, achieves a speedup as high as 3.5×. On that account, GeauxDock can take advantage of modern heterogeneous architectures to considerably accelerate structure-based virtual screening applications. GeauxDock is open-sourced and publicly available at www.brylinski.org/geauxdock and https://figshare.com/articles/geauxdock_tar_gz/3205249. PMID:27420300

  2. GeauxDock: Accelerating Structure-Based Virtual Screening with Heterogeneous Computing.

    Science.gov (United States)

    Fang, Ye; Ding, Yun; Feinstein, Wei P; Koppelman, David M; Moreno, Juana; Jarrell, Mark; Ramanujam, J; Brylinski, Michal

    2016-01-01

    Computational modeling of drug binding to proteins is an integral component of direct drug design. Particularly, structure-based virtual screening is often used to perform large-scale modeling of putative associations between small organic molecules and their pharmacologically relevant protein targets. Because of a large number of drug candidates to be evaluated, an accurate and fast docking engine is a critical element of virtual screening. Consequently, highly optimized docking codes are of paramount importance for the effectiveness of virtual screening methods. In this communication, we describe the implementation, tuning and performance characteristics of GeauxDock, a recently developed molecular docking program. GeauxDock is built upon the Monte Carlo algorithm and features a novel scoring function combining physics-based energy terms with statistical and knowledge-based potentials. Developed specifically for heterogeneous computing platforms, the current version of GeauxDock can be deployed on modern, multi-core Central Processing Units (CPUs) as well as massively parallel accelerators, Intel Xeon Phi and NVIDIA Graphics Processing Unit (GPU). First, we carried out a thorough performance tuning of the high-level framework and the docking kernel to produce a fast serial code, which was then ported to shared-memory multi-core CPUs yielding a near-ideal scaling. Further, using Xeon Phi gives 1.9× performance improvement over a dual 10-core Xeon CPU, whereas the best GPU accelerator, GeForce GTX 980, achieves a speedup as high as 3.5×. On that account, GeauxDock can take advantage of modern heterogeneous architectures to considerably accelerate structure-based virtual screening applications. GeauxDock is open-sourced and publicly available at www.brylinski.org/geauxdock and https://figshare.com/articles/geauxdock_tar_gz/3205249.

  3. Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening.

    Science.gov (United States)

    Miller, Zachary; Kim, Keun-Sik; Lee, Do-Min; Kasam, Vinod; Baek, Si Eun; Lee, Kwang Hyun; Zhang, Yan-Yan; Ao, Lin; Carmony, Kimberly; Lee, Na-Ra; Zhou, Shou; Zhao, Qingquan; Jang, Yujin; Jeong, Hyun-Young; Zhan, Chang-Guo; Lee, Wooin; Kim, Dong-Eun; Kim, Kyung Bo

    2015-02-26

    We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.

  4. Prospective performance evaluation of selected common virtual screening tools. Case study: Cyclooxygenase (COX) 1 and 2.

    Science.gov (United States)

    Kaserer, Teresa; Temml, Veronika; Kutil, Zsofia; Vanek, Tomas; Landa, Premysl; Schuster, Daniela

    2015-01-01

    Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds. In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then additionally predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biological activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true positive and true negative hits, and hitlist composition. Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors.

  5. Freely accessible databases of commercial compounds for high- throughput virtual screenings.

    Science.gov (United States)

    Moura Barbosa, Arménio Jorge; Del Rio, Alberto

    2012-01-01

    In the last decades computer-aided drug design techniques have been successfully used to guide the selection of new hit compounds with biological activity. These methods, that include a broad range of chemoinformatic and computational chemistry algorithms, are still disciplines in full bloom. In particular, virtual screening procedures have celebrated a great popularity for the rapid and cost-effective assessment of large chemical libraries of commercial compounds. While the usage of in silico techniques promises an effective speed-up at the early-stage of the development of new active compounds, computational projects starting from scratch with raw chemical data are often associated with resource- and time-consuming preparation protocols, almost blunting the advantages of using these techniques. In order to help facing these difficulties, in the last years several chemoinformatic projects and tools have emerged in literature and have been useful in preparing curated databases of chemical compounds for high-throughput virtual screening purposes. The review will focus on the detailed analysis of free databases of commercial chemical compounds that are currently employed in virtual screening campaigns for drug design. The scope of this review is to compare such databases and suggest the reader on how and in which conditions the usage of these databases could be recommended.

  6. Combining in silico and in cerebro approaches for virtual screening and pose prediction in SAMPL4.

    Science.gov (United States)

    Voet, Arnout R D; Kumar, Ashutosh; Berenger, Francois; Zhang, Kam Y J

    2014-04-01

    The SAMPL challenges provide an ideal opportunity for unbiased evaluation and comparison of different approaches used in computational drug design. During the fourth round of this SAMPL challenge, we participated in the virtual screening and binding pose prediction on inhibitors targeting the HIV-1 integrase enzyme. For virtual screening, we used well known and widely used in silico methods combined with personal in cerebro insights and experience. Regular docking only performed slightly better than random selection, but the performance was significantly improved upon incorporation of additional filters based on pharmacophore queries and electrostatic similarities. The best performance was achieved when logical selection was added. For the pose prediction, we utilized a similar consensus approach that amalgamated the results of the Glide-XP docking with structural knowledge and rescoring. The pose prediction results revealed that docking displayed reasonable performance in predicting the binding poses. However, prediction performance can be improved utilizing scientific experience and rescoring approaches. In both the virtual screening and pose prediction challenges, the top performance was achieved by our approaches. Here we describe the methods and strategies used in our approaches and discuss the rationale of their performances.

  7. An effective docking strategy for virtual screening based on multi-objective optimization algorithm

    Directory of Open Access Journals (Sweden)

    Kang Ling

    2009-02-01

    Full Text Available Abstract Background Development of a fast and accurate scoring function in virtual screening remains a hot issue in current computer-aided drug research. Different scoring functions focus on diverse aspects of ligand binding, and no single scoring can satisfy the peculiarities of each target system. Therefore, the idea of a consensus score strategy was put forward. Integrating several scoring functions, consensus score re-assesses the docked conformations using a primary scoring function. However, it is not really robust and efficient from the perspective of optimization. Furthermore, to date, the majority of available methods are still based on single objective optimization design. Results In this paper, two multi-objective optimization methods, called MOSFOM, were developed for virtual screening, which simultaneously consider both the energy score and the contact score. Results suggest that MOSFOM can effectively enhance enrichment and performance compared with a single score. For three different kinds of binding sites, MOSFOM displays an excellent ability to differentiate active compounds through energy and shape complementarity. EFMOGA performed particularly well in the top 2% of database for all three cases, whereas MOEA_Nrg and MOEA_Cnt performed better than the corresponding individual scoring functions if the appropriate type of binding site was selected. Conclusion The multi-objective optimization method was successfully applied in virtual screening with two different scoring functions that can yield reasonable binding poses and can furthermore, be ranked with the potentially compromised conformations of each compound, abandoning those conformations that can not satisfy overall objective functions.

  8. Screening in crystalline liquids protects energetic carriers in hybrid perovskites

    Science.gov (United States)

    Zhu, Haiming; Miyata, Kiyoshi; Fu, Yongping; Wang, Jue; Joshi, Prakriti P.; Niesner, Daniel; Williams, Kristopher W.; Jin, Song; Zhu, X.-Y.

    2016-09-01

    Hybrid lead halide perovskites exhibit carrier properties that resemble those of pristine nonpolar semiconductors despite static and dynamic disorder, but how carriers are protected from efficient scattering with charged defects and optical phonons is unknown. Here, we reveal the carrier protection mechanism by comparing three single-crystal lead bromide perovskites: CH3NH3PbBr3, CH(NH2)2PbBr3, and CsPbBr3. We observed hot fluorescence emission from energetic carriers with ~102-picosecond lifetimes in CH3NH3PbBr3 or CH(NH2)2PbBr3, but not in CsPbBr3. The hot fluorescence is correlated with liquid-like molecular reorientational motions, suggesting that dynamic screening protects energetic carriers via solvation or large polaron formation on time scales competitive with that of ultrafast cooling. Similar protections likely exist for band-edge carriers. The long-lived energetic carriers may enable hot-carrier solar cells with efficiencies exceeding the Shockley-Queisser limit.

  9. Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening.

    Science.gov (United States)

    Neves, Bruno J; Dantas, Rafael F; Senger, Mario R; Melo-Filho, Cleber C; Valente, Walter C G; de Almeida, Ana C M; Rezende-Neto, João M; Lima, Elid F C; Paveley, Ross; Furnham, Nicholas; Muratov, Eugene; Kamentsky, Lee; Carpenter, Anne E; Braga, Rodolpho C; Silva-Junior, Floriano P; Andrade, Carolina Horta

    2016-08-11

    Schistosomiasis is a debilitating neglected tropical disease, caused by flatworms of Schistosoma genus. The treatment relies on a single drug, praziquantel (PZQ), making the discovery of new compounds extremely urgent. In this work, we integrated QSAR-based virtual screening (VS) of Schistosoma mansoni thioredoxin glutathione reductase (SmTGR) inhibitors and high content screening (HCS) aiming to discover new antischistosomal agents. Initially, binary QSAR models for inhibition of SmTGR were developed and validated using the Organization for Economic Co-operation and Development (OECD) guidance. Using these models, we prioritized 29 compounds for further testing in two HCS platforms based on image analysis of assay plates. Among them, 2-[2-(3-methyl-4-nitro-5-isoxazolyl)vinyl]pyridine and 2-(benzylsulfonyl)-1,3-benzothiazole, two compounds representing new chemical scaffolds have activity against schistosomula and adult worms at low micromolar concentrations and therefore represent promising antischistosomal hits for further hit-to-lead optimization.

  10. Optimal strategies for virtual screening of induced-fit and flexible target in the 2015 D3R Grand Challenge

    Science.gov (United States)

    Ye, Zhaofeng; Baumgartner, Matthew P.; Wingert, Bentley M.; Camacho, Carlos J.

    2016-09-01

    Induced fit or protein flexibility can make a given structure less useful for docking and/or scoring. The 2015 Drug Design Data Resource (D3R) Grand Challenge provided a unique opportunity to prospectively test optimal strategies for virtual screening in these type of targets: heat shock protein 90 (HSP90), a protein with multiple ligand-induced binding modes; and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a kinase with a large flexible pocket. Using previously known co-crystal structures, we tested predictions from methods that keep the receptor structure fixed and used (a) multiple receptor/ligand co-crystals as binding templates for minimization or docking ("close"), (b) methods that align or dock to a single receptor ("cross"), and (c) a hybrid approach that chose from multiple bound ligands as initial templates for minimization to a single receptor ("min-cross"). Pose prediction using our "close" models resulted in average ligand RMSDs of 0.32 and 1.6 Å for HSP90 and MAP4K4, respectively, the most accurate models of the community-wide challenge. On the other hand, affinity ranking using our "cross" methods performed well overall despite the fact that a fixed receptor cannot model ligand-induced structural changes,. In addition, "close" methods that leverage the co-crystals of the different binding modes of HSP90 also predicted the best affinity ranking. Our studies suggest that analysis of changes on the receptor structure upon ligand binding can help select an optimal virtual screening strategy.

  11. VSDocker: a tool for parallel high-throughput virtual screening using AutoDock on Windows-based computer clusters.

    Science.gov (United States)

    Prakhov, Nikita D; Chernorudskiy, Alexander L; Gainullin, Murat R

    2010-05-15

    VSDocker is an original program that allows using AutoDock4 for optimized virtual ligand screening on computer clusters or multiprocessor workstations. This tool is the first implementation of parallel high-performance virtual screening of ligands for MS Windows-based computer systems. VSDocker 2.0 is freely available for non-commercial use at http://www.bio.nnov.ru/projects/vsdocker2/ nikita.prakhov@gmail.com Supplementary data are available at Bioinformatics online.

  12. VS-APPLE: A Virtual Screening Algorithm Using Promiscuous Protein-Ligand Complexes.

    Science.gov (United States)

    Okuno, Tatsuya; Kato, Koya; Terada, Tomoki P; Sasai, Masaki; Chikenji, George

    2015-06-22

    As the number of structurally resolved protein-ligand complexes increases, the ligand-binding pockets of many proteins have been found to accommodate multiple different compounds. Effective use of these structural data is important for developing virtual screening (VS) methods that identify bioactive compounds. Here, we introduce a VS method, VS-APPLE (Virtual Screening Algorithm using Promiscuous Protein-Ligand complExes), based on promiscuous protein-ligand binding structures. In VS-APPLE, multiple ligands bound to a pocket are combined into a query template for screening. Both the structural match between a test compound and the multiple-ligand template and the possible collisions between the test compound and the target protein are evaluated by an efficient geometric hashing method. The performance of VS-APPLE was examined on a filtered, clustered version of the Directory of Useful Decoys data set. In Area Under the Curve analyses of this data set, VS-APPLE outperformed several popular screening programs. Judging from the performance of VS-APPLE, the structural data of promiscuous protein-ligand bindings could be further analyzed and exploited for developing VS methods.

  13. DOVIS: an implementation for high-throughput virtual screening using AutoDock.

    Science.gov (United States)

    Zhang, Shuxing; Kumar, Kamal; Jiang, Xiaohui; Wallqvist, Anders; Reifman, Jaques

    2008-02-27

    Molecular-docking-based virtual screening is an important tool in drug discovery that is used to significantly reduce the number of possible chemical compounds to be investigated. In addition to the selection of a sound docking strategy with appropriate scoring functions, another technical challenge is to in silico screen millions of compounds in a reasonable time. To meet this challenge, it is necessary to use high performance computing (HPC) platforms and techniques. However, the development of an integrated HPC system that makes efficient use of its elements is not trivial. We have developed an application termed DOVIS that uses AutoDock (version 3) as the docking engine and runs in parallel on a Linux cluster. DOVIS can efficiently dock large numbers (millions) of small molecules (ligands) to a receptor, screening 500 to 1,000 compounds per processor per day. Furthermore, in DOVIS, the docking session is fully integrated and automated in that the inputs are specified via a graphical user interface, the calculations are fully integrated with a Linux cluster queuing system for parallel processing, and the results can be visualized and queried. DOVIS removes most of the complexities and organizational problems associated with large-scale high-throughput virtual screening, and provides a convenient and efficient solution for AutoDock users to use this software in a Linux cluster platform.

  14. Integration of virtual and high throughput screening in lead discovery settings.

    Science.gov (United States)

    Polgár, Tímea; Keseru, György M

    2011-12-01

    In the last decade mass screening strategies became the main source of leads in drug discovery settings. Although high throughput (HTS) and virtual screening (VS) realize the same concept the different nature of these lead discovery strategies (experimental vs theoretical) results that they are typically applied separately. The majority of drug leads are still identified by hit-to-lead optimization of screening hits. Structural information on the target as well as on bound ligands, however, make structure-based and ligand-based virtual screening available for the identification of alternative chemical starting points. Although, the two techniques have rarely been used together on the same target, here we review the existing prominent studies on their true integration. Various approaches have been shown to apply the combination of HTS and VS and to better use them in lead generation. Although several attempts on their integration have only been considered at a conceptual level, there are numerous applications underlining its relevance that early-stage pharmaceutical drug research could benefit from a combined approach.

  15. LiSIs: An Online Scientific Workflow System for Virtual Screening.

    Science.gov (United States)

    Kannas, Christos C; Kalvari, Ioanna; Lambrinidis, George; Neophytou, Christiana M; Savva, Christiana G; Kirmitzoglou, Ioannis; Antoniou, Zinonas; Achilleos, Kleo G; Scherf, David; Pitta, Chara A; Nicolaou, Christos A; Mikros, Emanuel; Promponas, Vasilis J; Gerhauser, Clarissa; Mehta, Rajendra G; Constantinou, Andreas I; Pattichis, Constantinos S

    2015-01-01

    Modern methods of drug discovery and development in recent years make a wide use of computational algorithms. These methods utilise Virtual Screening (VS), which is the computational counterpart of experimental screening. In this manner the in silico models and tools initial replace the wet lab methods saving time and resources. This paper presents the overall design and implementation of a web based scientific workflow system for virtual screening called, the Life Sciences Informatics (LiSIs) platform. The LiSIs platform consists of the following layers: the input layer covering the data file input; the pre-processing layer covering the descriptors calculation, and the docking preparation components; the processing layer covering the attribute filtering, compound similarity, substructure matching, docking prediction, predictive modelling and molecular clustering; post-processing layer covering the output reformatting and binary file merging components; output layer covering the storage component. The potential of LiSIs platform has been demonstrated through two case studies designed to illustrate the preparation of tools for the identification of promising chemical structures. The first case study involved the development of a Quantitative Structure Activity Relationship (QSAR) model on a literature dataset while the second case study implemented a docking-based virtual screening experiment. Our results show that VS workflows utilizing docking, predictive models and other in silico tools as implemented in the LiSIs platform can identify compounds in line with expert expectations. We anticipate that the deployment of LiSIs, as currently implemented and available for use, can enable drug discovery researchers to more easily use state of the art computational techniques in their search for promising chemical compounds. The LiSIs platform is freely accessible (i) under the GRANATUM platform at: http://www.granatum.org and (ii) directly at: http://lisis.cs.ucy.ac.cy.

  16. Virtual daily living test to screen for mild cognitive impairment using kinematic movement analysis.

    Science.gov (United States)

    Seo, Kyoungwon; Kim, Jae-Kwan; Oh, Dong Hoon; Ryu, Hokyoung; Choi, Hojin

    2017-01-01

    Questionnaires or computer-based tests for assessing activities of daily living are well-known approaches to screen for mild cognitive impairment (MCI). However, questionnaires are subjective and computerized tests only collect simple performance data with conventional input devices such as a mouse and keyboard. This study explored the validity and discriminative power of a virtual daily living test as a new diagnostic approach to assess MCI. Twenty-two healthy controls and 20 patients with MCI were recruited. The virtual daily living test presents two complex daily living tasks in an immersive virtual reality environment. The tasks were conducted based on subject body movements and detailed behavioral data (i.e., kinematic measures) were collected. Performance in both the proposed virtual daily living test and conventional neuropsychological tests for patients with MCI was compared to healthy controls. Kinematic measures considered in this study, such as body movement trajectory, time to completion, and speed, classified patients with MCI from healthy controls, F(8, 33) = 5.648, p classification of patients with MCI compared to the healthy control group, Wilks' Lambda = 0.451, p < 0.001.

  17. Combining structure-based pharmacophore modeling, virtual screening, and in silico ADMET analysis to discover novel tetrahydro-quinoline based pyruvate kinase isozyme M2 activators with antitumor activity

    Directory of Open Access Journals (Sweden)

    Chen C

    2014-09-01

    Full Text Available Can Chen,1,2,* Ting Wang,1,3,* Fengbo Wu,1,* Wei Huang,4 Gu He,1 Liang Ouyang,1 Mingli Xiang,1 Cheng Peng,4 Qinglin Jiang1,2 1State Key Laboratory of Biotherapy and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 2College of Pharmacy and the First Affiliated Hospital, Chengdu Medical College, Chengdu, 3Department of Cardiology, Genenal Hospital of Chengdu Military Command, Chengdu, 4State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China*These authors contributed equally to this workAbstract: Compared with normal differentiated cells, cancer cells upregulate the expression of pyruvate kinase isozyme M2 (PKM2 to support glycolytic intermediates for anabolic processes, including the synthesis of nucleic acids, amino acids, and lipids. In this study, a combination of the structure-based pharmacophore modeling and a hybrid protocol of virtual screening methods comprised of pharmacophore model-based virtual screening, docking-based virtual screening, and in silico ADMET (absorption, distribution, metabolism, excretion and toxicity analysis were used to retrieve novel PKM2 activators from commercially available chemical databases. Tetrahydroquinoline derivatives were identified as potential scaffolds of PKM2 activators. Thus, the hybrid virtual screening approach was applied to screen the focused tetrahydroquinoline derivatives embedded in the ZINC database. Six hit compounds were selected from the final hits and experimental studies were then performed. Compound 8 displayed a potent inhibitory effect on human lung cancer cells. Following treatment with Compound 8, cell viability, apoptosis, and reactive oxygen species (ROS production were examined in A549 cells. Finally, we evaluated the effects of Compound 8 on mice xenograft tumor models in vivo. These results may provide important

  18. A cross docking pipeline for improving pose prediction and virtual screening performance

    Science.gov (United States)

    Kumar, Ashutosh; Zhang, Kam Y. J.

    2017-08-01

    Pose prediction and virtual screening performance of a molecular docking method depend on the choice of protein structures used for docking. Multiple structures for a target protein are often used to take into account the receptor flexibility and problems associated with a single receptor structure. However, the use of multiple receptor structures is computationally expensive when docking a large library of small molecules. Here, we propose a new cross-docking pipeline suitable to dock a large library of molecules while taking advantage of multiple target protein structures. Our method involves the selection of a suitable receptor for each ligand in a screening library utilizing ligand 3D shape similarity with crystallographic ligands. We have prospectively evaluated our method in D3R Grand Challenge 2 and demonstrated that our cross-docking pipeline can achieve similar or better performance than using either single or multiple-receptor structures. Moreover, our method displayed not only decent pose prediction performance but also better virtual screening performance over several other methods.

  19. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2014-05-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  20. Dynamic ligand-based pharmacophore modeling and virtual screening to identify mycobacterial cyclopropane synthase inhibitors

    Indian Academy of Sciences (India)

    CHINMAYEE CHOUDHURY; U DEVA PRIYAKUMAR; G NARAHARI SASTRY

    2016-05-01

    Multidrug resistance in Mycobacterium tuberculosis (M. Tb) and its coexistence with HIV arethe biggest therapeutic challenges in anti-M. Tb drug discovery. The current study reports a Virtual Screening(VS) strategy to identify potential inhibitors of Mycobacterial cyclopropane synthase (CmaA1), an importantM. Tb target considering the above challenges. Five ligand-based pharmacophore models were generatedfrom 40 different conformations of the cofactors of CmaA1 taken from molecular dynamics (MD) simulationstrajectories of CmaA1. The screening abilities of these models were validated by screening 23 inhibitors and1398 non-inhibitors of CmaA1. A VS protocol was designed with four levels of screening i.e., ligand-basedpharmacophore screening, structure-based pharmacophore screening, docking and absorption, distribution,metabolism, excretion and the toxicity (ADMET) filters. In an attempt towards repurposing the existing drugsto inhibit CmaA1, 6,429 drugs reported in DrugBank were considered for screening. To find compounds thatinhibit multiple targets of M. Tb as well as HIV, we also chose 701 and 11,109 compounds showing activitybelow 1 μM range on M. Tb and HIV cell lines, respectively, collected from ChEMBL database. Thus, a totalof 18,239 compounds were screened against CmaA1, and 12 compounds were identified as potential hits forCmaA1 at the end of the fourth step. Detailed analysis of the structures revealed these compounds to interactwith key active site residues of CmaA1.

  1. Ensemble-Based Virtual Screening Led to the Discovery of New Classes of Potent Tyrosinase Inhibitors.

    Science.gov (United States)

    Choi, Joonhyeok; Choi, Kwang-Eun; Park, Sung Jean; Kim, Sun Yeou; Jee, Jun-Goo

    2016-02-22

    In this study, we report new classes of potent tyrosinase inhibitors identified by enhanced structure-based virtual screening prediction; the enzyme and melanin content assays were also confirmed. Tyrosinase, a type-3 copper protein, participates in two distinct reactions, hydroxylation of tyrosine to DOPA and conversion of DOPA to dopaquinone, in melanin biosynthesis. Although numerous inhibitors of this reaction have been reported, there is a lag in the discovery of the new functional moieties. In order to improve the performance of virtual screening, we first produced an ensemble of 10,000 structures using molecular dynamics simulation. Quantum mechanical calculation was used to determine the partial charges of catalytic copper ions based on the met and deoxy states. Second, we selected a structure showing an optimal receiver operating characteristic (ROC) curve with known direct binders and their physicochemically matched decoys. The structure revealed more than 10-fold higher enrichment at 1% of the ROC curve than those observed in X-ray structures. Third, high-throughput virtual screening with DOCK 3.6 was performed using a library consisting of approximately 400,000 small molecules derived from the ZINC database. Fourth, we obtained the top 60 molecules and tested their inhibition of mushroom tyrosinase. The extended assays included 21 analogs of the 21 initial hits to test their inhibition properties. Here, the moieties of tetrazole and triazole were identified as new binding cores interacting with the dicopper catalytic center. All 42 inhibitors showed inhibitory constant, Ki, values ranging from 11.1 nM and 33.4 μM, with a tetrazole compound exhibiting the strongest activity. Among the 42 molecules, five displayed more than 30% reduction in melanin production when treated in B16F10 melanoma cells; cell viability was >90% at 20 μM. Particularly, a thiosemicarbazone-containing compound reduced melanin content by 55%.

  2. Virtual screening studies reveal linarin as a potential natural inhibitor targeting CDK4 in retinoblastoma.

    Science.gov (United States)

    Sivashanmugam, Muthukumaran; Raghunath, Chandana; Vetrivel, Umashankar

    2013-10-01

    To find out whether linarin can be used as a potential natural inhibitor to target CDK4 in retinoblastoma using virtual screening studies. In this study, molecular modeling and protein structure optimization was performed for crystal structure of CDK4 (PDB id: 3G33), and was subjected to Molecular Dynamics (MD) simulation for 10 nanoseconds, as a preparatory process for docking. Furthermore, the stable conformation obtained in the MD simulation was utilized for virtual screening against the library of natural compounds in Indian Plant Anticancer Compounds Database (InPACdb) using AutoDock Vina. Finally, best docked ligands were revalidated individually through semi-flexible docking by AutoDock 4.0. The CDK4 structure was stereochemically optimized to fix clashes and bad angles, which placed 96.4% residues in the core region of Ramachandran plot. The final structure of CDK4 that emerged after MD simulation was proven to be highly stable as per different validation tools. Virtual screening and docking was carried out for CDK4 against optimized ligands from InPACdb through AutoDock Vina. This inferred Linarin (Inpacdb AC.NO. acd0073) as a potential therapeutic agent with binding energy of -8.9 kJ/mol. Furthermore, it was also found to be valid as per AutoDock 4.0 semi-flexible docking procedure, with the binding energy of -8.18 kJ/mol and Ki value of 1.01 μM. The docking results indicate linarin, a flavonoid plant compound, as a potential inhibitor of CDK4 compared to some of the currently practiced anticancer drugs for retinoblastoma. This finding can be extended to experimental validation to assess the in vivo efficacy of the identified compound.

  3. Comparison of ligand- and structure-based virtual screening on the DUD data set.

    Science.gov (United States)

    von Korff, Modest; Freyss, Joel; Sander, Thomas

    2009-02-01

    Several in-house developed descriptors and our in-house docking tool ActDock were compared with virtual screening on the data set of useful decoys (DUD). The results were compared with the chemical fingerprint descriptor from ChemAxon and with the docking results of the original DUD publication. The DUD is the first published data set providing active molecules, decoys, and references for crystal structures of ligand-target complexes. The DUD was designed for the purpose of evaluating docking programs. It contains 2950 active compounds against a total of 40 target proteins. Furthermore, for every ligand the data set contains 36 structurally dissimilar decoy compounds with similar physicochemical properties. We extracted the ligands from the target proteins to extend the applicability of the data set to include ligand based virtual screening. From the 40 target proteins, 37 contained ligands that we used as query molecules for virtual screening evaluation. With this data set a large comparison was done between four different chemical fingerprints, a topological pharmacophore descriptor, the Flexophore descriptor, and ActDock. The Actelion docking tool relies on a MM2 forcefield and a pharmacophore point interaction statistic for scoring; the details are described in this publication. In terms of enrichment rates the chemical fingerprint descriptors performed better than the Flexophore and the docking tool. After removing molecules chemically similar to the query molecules the Flexophore descriptor outperformed the chemical descriptors and the topological pharmacophore descriptors. With the similarity matrix calculations used in this study it was shown that the Flexophore is well suited to find new chemical entities via "scaffold hopping". The Flexophore descriptor can be explored with a Java applet at http://www.cheminformatics.ch in the submenu Tools-->Flexophore. Its usage is free of charge and does not require registration.

  4. Performance-Driven Hybrid Full-Body Character Control for Navigation and Interaction in Virtual Environments

    Science.gov (United States)

    Mousas, Christos; Anagnostopoulos, Christos-Nikolaos

    2017-06-01

    This paper presents a hybrid character control interface that provides the ability to synthesize in real-time a variety of actions based on the user's performance capture. The proposed methodology enables three different performance interaction modules: the performance animation control that enables the direct mapping of the user's pose to the character, the motion controller that synthesizes the desired motion of the character based on an activity recognition methodology, and the hybrid control that lies within the performance animation and the motion controller. With the methodology presented, the user will have the freedom to interact within the virtual environment, as well as the ability to manipulate the character and to synthesize a variety of actions that cannot be performed directly by him/her, but which the system synthesizes. Therefore, the user is able to interact with the virtual environment in a more sophisticated fashion. This paper presents examples of different scenarios based on the three different full-body character control methodologies.

  5. Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Discovery of Novel Akt2 Inhibitors

    Directory of Open Access Journals (Sweden)

    Jia Fei, Lu Zhou, Tao Liu, Xiang-Yang Tang

    2013-01-01

    Full Text Available Akt2 is considered as a potential target for cancer therapy. In order to find novel Akt2 inhibitors which have different scaffolds, structure-based pharmacophore model and 3D-QSAR pharmacophore model were built and validated by different methods. Then, they were used for chemical databases virtual screening. The selected compounds were further analyzed and refined using drug-like filters and ADMET analysis. Finally, seven hits with different scaffolds were picked out for docking studies. These seven hits were predicted to have high inhibitory activity and good ADMET properties, they may act as novel leads for Akt2 inhibitors designing.

  6. Virtual screening strategies in medicinal chemistry: the state of the art and current challenges.

    Science.gov (United States)

    Braga, Rodolpho C; Alves, Vinicius M; Silva, Arthur C; Nascimento, Marilia N; Silva, Flavia C; Liao, Luciano M; Andrade, Carolina H

    2014-01-01

    Virtual screening (VS) techniques are well-established tools in the modern drug discovery process, mainly used for hit finding in drug discovery. The availability of knowledge of structural information, which includes an increasing number of 3D protein structures and the readiness of free databases of commercially available smallmolecules, provides a broad platform for VS. This review summarizes the current developments in VS regarding chemical databases and highlights the achievements as well as the challenges with an emphasis on a recent example of the successful application for the identification of new hits for sterol 14α-demethylase (CYP51) of Trypanosoma cruzi.

  7. Virtual Screening Models for Prediction of HIV-1 RT Associated RNase H Inhibition

    DEFF Research Database (Denmark)

    Poongavanam, Vasanthanathan; Kongsted, Jacob

    2013-01-01

    The increasing resistance to current therapeutic agents for HIV drug regiment remains a major problem for effective acquired immune deficiency syndrome (AIDS) therapy. Many potential inhibitors have today been developed which inhibits key cellular pathways in the HIV cycle. Inhibition of HIV-1...... of choice in terms of best retrieval of active from inactive compounds and efficiency and efficacy schemes. Moreover, shape similarity, machine learning and FLAP models could also be used for further validation or filtration in virtual screening processes. The best models could potentially be use...

  8. Promising Aedes aegypti repellent chemotypes identified through integrated QSAR, virtual screening, synthesis, and bioassay.

    Science.gov (United States)

    Oliferenko, Polina V; Oliferenko, Alexander A; Poda, Gennadiy I; Osolodkin, Dmitry I; Pillai, Girinath G; Bernier, Ulrich R; Tsikolia, Maia; Agramonte, Natasha M; Clark, Gary G; Linthicum, Kenneth J; Katritzky, Alan R

    2013-01-01

    Molecular field topology analysis, scaffold hopping, and molecular docking were used as complementary computational tools for the design of repellents for Aedes aegypti, the insect vector for yellow fever, chikungunya, and dengue fever. A large number of analogues were evaluated by virtual screening with Glide molecular docking software. This produced several dozen hits that were either synthesized or procured from commercial sources. Analysis of these compounds by a repellent bioassay resulted in a few highly active chemicals (in terms of minimum effective dosage) as viable candidates for further hit-to-lead and lead optimization effort.

  9. Benchmarking Data Sets for the Evaluation of Virtual Ligand Screening Methods: Review and Perspectives.

    Science.gov (United States)

    Lagarde, Nathalie; Zagury, Jean-François; Montes, Matthieu

    2015-07-27

    Virtual screening methods are commonly used nowadays in drug discovery processes. However, to ensure their reliability, they have to be carefully evaluated. The evaluation of these methods is often realized in a retrospective way, notably by studying the enrichment of benchmarking data sets. To this purpose, numerous benchmarking data sets were developed over the years, and the resulting improvements led to the availability of high quality benchmarking data sets. However, some points still have to be considered in the selection of the active compounds, decoys, and protein structures to obtain optimal benchmarking data sets.

  10. Inhibitors of the Yersinia protein tyrosine phosphatase through high throughput and virtual screening approaches.

    Science.gov (United States)

    Hu, Xin; Vujanac, Milos; Southall, Noel; Stebbins, C Erec

    2013-02-15

    The bacterial protein tyrosine phosphatase YopH is an essential virulence determinant in Yersinia pestis and a potential antibacterial drug target. Here we report our studies of screening for small molecule inhibitors of YopH using both high throughput and in silico approaches. The identified inhibitors represent a diversity of chemotypes and novel pTyr mimetics, providing a starting point for further development and fragment-based design of multi-site binding inhibitors. We demonstrate that the applications of high throughput and virtual screening, when guided by structural binding mode analysis, is an effective approach for identifying potent and selective inhibitors of YopH and other protein phosphatases for rational drug design. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Virtual fragment screening: an exploration of various docking and scoring protocols for fragments using Glide

    Science.gov (United States)

    Kawatkar, Sameer; Wang, Hongming; Czerminski, Ryszard; Joseph-McCarthy, Diane

    2009-08-01

    Fragment-based drug discovery approaches allow for a greater coverage of chemical space and generally produce high efficiency ligands. As such, virtual and experimental fragment screening are increasingly being coupled in an effort to identify new leads for specific therapeutic targets. Fragment docking is employed to create target-focussed subset of compounds for testing along side generic fragment libraries. The utility of the program Glide with various scoring schemes for fragment docking is discussed. Fragment docking results for two test cases, prostaglandin D2 synthase and DNA ligase, are presented and compared to experimental screening data. Self-docking, cross-docking, and enrichment studies are performed. For the enrichment runs, experimental data exists indicating that the docking decoys in fact do not inhibit the corresponding enzyme being examined. Results indicate that even for difficult test cases fragment docking can yield enrichments significantly better than random.

  12. Structure-based virtual screening campaigns on curcuminoids as potent ligands for histone deacetylase-2

    Directory of Open Access Journals (Sweden)

    Enade Perdana Istyastono

    2016-03-01

    Full Text Available Curcumin was reported to reverse the decrease in histone deacetylase-2 (HDAC2 protein expression in inflammatory diseases of the lung, including chronic obstructive pulmonary disease (COPD, severe asthma, and asthma in smokers. This indicates that curcumin is a potent ligand for HDAC2. The construction and retrospective validation of a structure-based virtual screening (SBVS protocol to identify potent ligands for HDAC2 are presented in this article. The validated protocol was subsequently employed to screen curcumin and other curcuminoids found in Curcuma longa, i.e. demethoxy curcumin and bis-demethoxy curcumin, and to examine their interactions to HDAC2 in the atomic level. The results show that curcumin, demethoxy curcumin and bis-demethoxy curcumin are potent HDAC2 ligands. The insights from their interactions to HDAC2 resulted from the molecular docking simulations presented in this article could be employed further in the design and discovery potent HDAC2 ligands.

  13. Molecular Shape Analysis-Guided Virtual Screening Platform for Adenosine Kinase Inhibitors.

    Science.gov (United States)

    Bhutoria, Savita; Das, Ballari; Ghoshal, Nanda

    2016-01-01

    We propose a new application of molecular shape descriptors in hierarchical selection during virtual screening (VS). Here, a structure-based pharmacophore and docking-guided VS protocol have been evolved to identify inhibitors against adenosine kinase (AK). The knowledge gained on the shape requirements has been extrapolated in classifying active and inactive molecules against this target. This classification enabled us to pick the appropriate ligand conformation in the binding site. We have suggested a set of hierarchical filters for VS, from a simple molecular shape analysis (MSA) descriptor-based recursive models to docking scores. This approach permits a systematic study to understand the importance of spatial requirements and limitations for inhibitors against AK. Finally, the guidelines on how to select compounds for AK to achieve success have been highlighted. The utility of this approach has been suggested by giving an example of database screening for plausible active compounds.

  14. Novel inhibitors to Taenia solium Cu/Zn superoxide dismutase identified by virtual screening

    Science.gov (United States)

    García-Gutiérrez, P.; Landa-Piedra, A.; Rodríguez-Romero, A.; Parra-Unda, R.; Rojo-Domínguez, A.

    2011-12-01

    We describe in this work a successful virtual screening and experimental testing aimed to the identification of novel inhibitors of superoxide dismutase of the worm Taenia solium ( TsCu/Zn-SOD), a human parasite. Conformers from LeadQuest® database of drug-like compounds were selected and then docked on the surface of TsCu/Zn-SOD. Results were screened looking for ligand contacts with receptor side-chains not conserved in the human homologue, with a subsequent development of a score optimization by a set of energy minimization steps, aimed to identify lead compounds for in vitro experiments. Six out of fifty experimentally tested compounds showed μM inhibitory activity toward TsCu/Zn-SOD. Two of them showed species selectivity since did not inhibit the homologous human enzyme when assayed in vitro.

  15. Molecular Shape Analysis-Guided Virtual Screening Platform for Adenosine Kinase Inhibitors

    Science.gov (United States)

    Bhutoria, Savita; Das, Ballari; Ghoshal, Nanda

    2016-01-01

    We propose a new application of molecular shape descriptors in hierarchical selection during virtual screening (VS). Here, a structure-based pharmacophore and docking-guided VS protocol have been evolved to identify inhibitors against adenosine kinase (AK). The knowledge gained on the shape requirements has been extrapolated in classifying active and inactive molecules against this target. This classification enabled us to pick the appropriate ligand conformation in the binding site. We have suggested a set of hierarchical filters for VS, from a simple molecular shape analysis (MSA) descriptor-based recursive models to docking scores. This approach permits a systematic study to understand the importance of spatial requirements and limitations for inhibitors against AK. Finally, the guidelines on how to select compounds for AK to achieve success have been highlighted. The utility of this approach has been suggested by giving an example of database screening for plausible active compounds. PMID:27478367

  16. The virtual slide in the promotion of cytologic and hystologic quality in oncologic screenings

    Directory of Open Access Journals (Sweden)

    Arrigo Bondi

    2010-06-01

    Full Text Available A regional experience environment in virtual microscopy and digital pathology comprehending the digital cytology is presented. The project has been conducted in Emilia-Romagna and it has been planned for the promotion and the quality assessment in screening cytology and histology for the prevention of the tumors of uterine cervix, breast and colon-rectum cancers. During the project it has been envisaged the design of a dedicated picture archive and communication system (PACS for cooperative diagnosis, didactics and training, teleconsulting, documentation of rare cases and pilot experiences; furthermore selected cases are catalogued in the PACS with the aim of the check of the diagnostic concordance in the oncologic screening.

  17. Benchmarking methods and data sets for ligand enrichment assessment in virtual screening.

    Science.gov (United States)

    Xia, Jie; Tilahun, Ermias Lemma; Reid, Terry-Elinor; Zhang, Liangren; Wang, Xiang Simon

    2015-01-01

    Retrospective small-scale virtual screening (VS) based on benchmarking data sets has been widely used to estimate ligand enrichments of VS approaches in the prospective (i.e. real-world) efforts. However, the intrinsic differences of benchmarking sets to the real screening chemical libraries can cause biased assessment. Herein, we summarize the history of benchmarking methods as well as data sets and highlight three main types of biases found in benchmarking sets, i.e. "analogue bias", "artificial enrichment" and "false negative". In addition, we introduce our recent algorithm to build maximum-unbiased benchmarking sets applicable to both ligand-based and structure-based VS approaches, and its implementations to three important human histone deacetylases (HDACs) isoforms, i.e. HDAC1, HDAC6 and HDAC8. The leave-one-out cross-validation (LOO CV) demonstrates that the benchmarking sets built by our algorithm are maximum-unbiased as measured by property matching, ROC curves and AUCs.

  18. Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach.

    Science.gov (United States)

    Wang, Ching Y; Ai, Ni; Arora, Sonia; Erenrich, Eric; Nagarajan, Karthigeyan; Zauhar, Randy; Young, Douglas; Welsh, William J

    2006-12-01

    The physiological roles of estrogen in sexual differentiation and development, female and male reproductive processes, and bone health are complex and diverse. Numerous natural and synthetic chemical compounds, commonly known as endocrine disrupting chemicals (EDCs), have been shown to alter the physiological effects of estrogen in humans and wildlife. As such, these EDCs may cause unanticipated and even undesirable effects. Large-scale in vitro and in vivo screening of chemicals to assess their estrogenic activity would demand a prodigious investment of time, labor, and money and would require animal testing on an unprecedented scale. Approaches in silico are increasingly recognized as playing a vital role in screening and prioritizing chemicals to extend limited resources available for experimental testing. Here, we evaluated a multistep procedure that is suitable for in silico (virtual) screening of large chemical databases to identify compounds exhibiting estrogenic activity. This procedure incorporates Shape Signatures, a novel computational tool that rapidly compares molecules on the basis of similarity in shape, polarity, and other bio-relevant properties. Using 4-hydroxy tamoxifen (4-OH TAM) and diethylstilbestrol (DES) as input queries, we employed this scheme to search a sample database of approximately 200,000 commercially available organic chemicals for matches (hits). Of the eight compounds identified computationally as potentially (anti)estrogenic, biological evaluation confirmed two as heretofore unknown estrogen antagonists. Subsequent radioligand binding assays confirmed that two of these three compounds exhibit antiestrogenic activities comparable to 4-OH TAM. Molecular modeling studies of these ligands docked inside the binding pocket of estrogen receptor alpha (ERalpha) elucidated key ligand-receptor interactions that corroborate these experimental findings. The present study demonstrates the utility of our computational scheme for this and

  19. Sensate abstraction: hybrid strategies for multi-dimensional data in expressive virtual reality contexts

    Science.gov (United States)

    West, Ruth; Gossmann, Joachim; Margolis, Todd; Schulze, Jurgen P.; Lewis, J. P.; Hackbarth, Ben; Mostafavi, Iman

    2009-02-01

    ATLAS in silico is an interactive installation/virtual environment that provides an aesthetic encounter with metagenomics data (and contextual metadata) from the Global Ocean Survey (GOS). The installation creates a visceral experience of the abstraction of nature in to vast data collections - a practice that connects expeditionary science of the 19th Century with 21st Century expeditions like the GOS. Participants encounter a dream-like, highly abstract, and datadriven virtual world that combines the aesthetics of fine-lined copper engraving and grid-like layouts of 19th Century scientific representation with 21st Century digital aesthetics including wireframes and particle systems. It is resident at the Calit2 Immersive visualization Laboratory on the campus of UC San Diego, where it continues in active development. The installation utilizes a combination of infrared motion tracking, custom computer vision, multi-channel (10.1) spatialized interactive audio, 3D graphics, data sonification, audio design, networking, and the VarrierTM 60 tile, 100-million pixel barrier strip auto-stereoscopic display. Here we describe the physical and audio display systems for the installation and a hybrid strategy for multi-channel spatialized interactive audio rendering in immersive virtual reality that combines amplitude, delay and physical modeling-based, real-time spatialization approaches for enhanced expressivity in the virtual sound environment that was developed in the context of this artwork. The desire to represent a combination of qualitative and quantitative multidimensional, multi-scale data informs the artistic process and overall system design. We discuss the resulting aesthetic experience in relation to the overall system.

  20. Desirability-based multi-criteria virtual screening of selective antimicrobial cyclic β-hairpin cationic peptidomimetics.

    Science.gov (United States)

    Cruz-Monteagudo, Maykel; Romero, Yansy; Cordeiro, M Natália D S; Borges, Fernanda

    2013-01-01

    Today, emerging and increasing resistance to antibiotics has become a threat to public health worldwide. Antimicrobial peptides own unique action mechanisms making peptide antibiotics an attractive therapeutic option against resistant bacteria. However, their high haemolytic activity lacks the selectivity required for a human antibiotic. Therefore, additional efforts are needed to develop new antimicrobial peptides that possess greater selectivity for bacterial cells over erythrocytes. In this article, we introduce a chemoinformatics approach to simultaneously deal with these two conflicting properties consisting on a multi-criteria virtual screening strategy based on the use of a desirability-based multi-criteria classifier combined with similarity and chemometrics concepts. Here we propose a new quantitative feature encoding information related to the desirability, the degree of credibility ascribed to this desirability and the similarity of a candidate to a highly desirable query, which can be used as ranking criterion in a virtual screening campaign, the Desirability-Credibility- Similarity (DCS) Score. The enrichment ability of a multi-criteria virtual screening strategy based on the use of the DCS Score it is also assessed and compared to other virtual screening options. The results obtained evidenced that the use of the DCS score seems to be an efficient virtual screening strategy rendering promising overall and initial enrichment performance. Specifically, by using the DCS score it was possible to rank a selective antibacterial peptidomimetic earlier than a biologically inactive or non selective antibacterial peptidomimetic with a probability of ca. 0.9.

  1. Inhibitor ranking through QM based chelation calculations for virtual screening of HIV-1 RNase H inhibition.

    Directory of Open Access Journals (Sweden)

    Vasanthanathan Poongavanam

    Full Text Available Quantum mechanical (QM calculations have been used to predict the binding affinity of a set of ligands towards HIV-1 RT associated RNase H (RNH. The QM based chelation calculations show improved binding affinity prediction for the inhibitors compared to using an empirical scoring function. Furthermore, full protein fragment molecular orbital (FMO calculations were conducted and subsequently analysed for individual residue stabilization/destabilization energy contributions to the overall binding affinity in order to better understand the true and false predictions. After a successful assessment of the methods based on the use of a training set of molecules, QM based chelation calculations were used as filter in virtual screening of compounds in the ZINC database. By this, we find, compared to regular docking, QM based chelation calculations to significantly reduce the large number of false positives. Thus, the computational models tested in this study could be useful as high throughput filters for searching HIV-1 RNase H active-site molecules in the virtual screening process.

  2. Design of inhibitors of the HIV-1 integrase core domain using virtual screening.

    Science.gov (United States)

    Regon, Preetom; Gogoi, Dhrubajyoti; Rai, Ashok Kumar; Bordoloi, Manabjyoti; Bezbaruah, Rajib Lochan

    2014-01-01

    Acquired immunodeficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV). The integrase (IN) enzyme of HIV interacts with several cellular and viral proteins during the integration process. Thus, it represents an appropriate target for antiretroviral drugs (ARVs). We performed virtual screening of database compounds and designed analogues using Elvitegravir (EVG) as a standard compound. The 378 screened compounds were retrieved from ZINC, ChemSpider, PubChem, and ChemBank Chemical Databases based on chemical similarity and literature searches related to the structure of EVG. The Physiochemical properties, Bioactivity, Toxicity and Absorption, Distribution, Metabolism and Excretion of Molecules (ADME) of these compounds were predicted and docking Experiments were conducted using Molegro Virtual Docker software. The docking and ADME suggested very significant results in regard to EVG. The MolDock and Rerank scores were used to analyze the results. The compounds ZINC26507991 (-84.22), Analogue 9 (-68.49), ZINC20731658 (-66.79), ZINC00210363 (-43.44) showed better binding orientation with IN receptor model with respect to EVG (182.52). The ZINC26507991 has showed significant ADME result.

  3. Comparative virtual screening and novelty detection for NMDA-GlycineB antagonists.

    Science.gov (United States)

    Krueger, Bjoern A; Weil, Tanja; Schneider, Gisbert

    2009-12-01

    Identification of novel compound classes for a drug target is a challenging task for cheminformatics and drug design when considerable research has already been undertaken and many potent lead structures have been identified, which leaves limited unclaimed chemical space for innovation. We validated and successfully applied different state-of-the-art techniques for virtual screening (Bayesian machine learning, automated molecular docking, pharmacophore search, pharmacophore QSAR and shape analysis) of 4.6 million unique and readily available chemical structures to identify promising new and competitive antagonists of the strychnine-insensitive Glycine binding site (Glycine(B) site) of the NMDA receptor. The novelty of the identified virtual hits was assessed by scaffold analysis, putting a strong emphasis on novelty detection. The resulting hits were tested in vitro and several novel, active compounds were identified. While the majority of the computational methods tested were able to partially discriminate actives from structurally similar decoy molecules, the methods differed substantially in their prospective applicability in terms of novelty detection. The results demonstrate that although there is no single best computational method, it is most worthwhile to follow this concept of focused compound library design and screening, as there still can new bioactive compounds be found that possess hitherto unexplored scaffolds and interesting variations of known chemotypes.

  4. Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction.

    Directory of Open Access Journals (Sweden)

    Khaled H Barakat

    Full Text Available BACKGROUND: Nucleotide excision repair (NER removes many types of DNA lesions including those induced by UV radiation and platinum-based therapy. Resistance to platinum-based therapy correlates with high expression of ERCC1, a major element of the NER machinery. The interaction between ERCC1 and XPA is essential for a successful NER function. Therefore, one way to regulate NER is by inhibiting the activity of ERCC1 and XPA. METHODOLOGY/PRINCIPAL FINDINGS: Here we continued our earlier efforts aimed at the identification and characterization of novel inhibitors of the ERCC1-XPA interaction. We used a refined virtual screening approach combined with a biochemical and biological evaluation of the compounds for their ability to interact with ERCC1 and to sensitize cells to UV radiation. Our findings reveal a new validated ERCC1-XPA inhibitor that significantly sensitized colon cancer cells to UV radiation indicating a strong inhibition of the ERCC1-XPA interaction. CONCLUSIONS: NER is a major factor in acquiring resistance to platinum-based therapy. Regulating the NER pathway has the potential of improving the efficacy of platinum treatments. One approach that we followed is to inhibit the essential interaction between the two NER elements, ERCC1 and XPA. Here, we performed virtual screening against the ERCC1-XPA interaction and identified novel inhibitors that block the XPA-ERCC1 binding. The identified inhibitors significantly sensitized colon cancer cells to UV radiation indicating a strong inhibition of the ERCC1-XPA interaction.

  5. Virtual screening for HIV protease inhibitors: a comparison of AutoDock 4 and Vina.

    Directory of Open Access Journals (Sweden)

    Max W Chang

    Full Text Available BACKGROUND: The AutoDock family of software has been widely used in protein-ligand docking research. This study compares AutoDock 4 and AutoDock Vina in the context of virtual screening by using these programs to select compounds active against HIV protease. METHODOLOGY/PRINCIPAL FINDINGS: Both programs were used to rank the members of two chemical libraries, each containing experimentally verified binders to HIV protease. In the case of the NCI Diversity Set II, both AutoDock 4 and Vina were able to select active compounds significantly better than random (AUC = 0.69 and 0.68, respectively; p<0.001. The binding energy predictions were highly correlated in this case, with r = 0.63 and iota = 0.82. For a set of larger, more flexible compounds from the Directory of Universal Decoys, the binding energy predictions were not correlated, and only Vina was able to rank compounds significantly better than random. CONCLUSIONS/SIGNIFICANCE: In ranking smaller molecules with few rotatable bonds, AutoDock 4 and Vina were equally capable, though both exhibited a size-related bias in scoring. However, as Vina executes more quickly and is able to more accurately rank larger molecules, researchers should look to it first when undertaking a virtual screen.

  6. Discovery of selective inhibitors against EBNA1 via high throughput in silico virtual screening.

    Directory of Open Access Journals (Sweden)

    Ning Li

    Full Text Available BACKGROUND: Epstein-Barr Virus (EBV latent infection is associated with several human malignancies and is a causal agent of lymphoproliferative diseases during immunosuppression. While inhibitors of herpesvirus DNA polymerases, like gancyclovir, reduce EBV lytic cycle infection, these treatments have limited efficacy for treating latent infection. EBNA1 is an EBV-encoded DNA-binding protein required for viral genome maintenance during latent infection. METHODOLOGY: Here, we report the identification of a new class of small molecules that inhibit EBNA1 DNA binding activity. These compounds were identified by virtual screening of 90,000 low molecular mass compounds using computational docking programs with the solved crystal structure of EBNA1. Four structurally related compounds were found to inhibit EBNA1-DNA binding in biochemical assays with purified EBNA1 protein. Compounds had a range of 20-100 microM inhibition of EBNA1 in fluorescence polarization assays and were further validated for inhibition using electrophoresis mobility shift assays. These compounds exhibited no significant inhibition of an unrelated DNA binding protein. Three of these compounds inhibited EBNA1 transcription activation function in cell-based assays and reduced EBV genome copy number when incubated with a Burkitt lymphoma cell line. CONCLUSIONS: These experiments provide a proof-of-principle that virtual screening can be used to identify specific inhibitors of EBNA1 that may have potential for treatment of EBV latent infection.

  7. Inhibitor Ranking Through QM based Chelation Calculations for Virtual Screening of HIV-1 RNase H inhibition

    DEFF Research Database (Denmark)

    Poongavanam, Vasanthanathan; Svendsen, Casper Steinmann; Kongsted, Jacob

    2014-01-01

    Quantum mechanical (QM) calculations have been used to predict the binding affinity of a set of ligands towards HIV-1 RT associated RNase H (RNH). The QM based chelation calculations show improved binding affinity prediction for the inhibitors compared to using an empirical scoring function. Furt....... Thus, the computational models tested in this study could be useful as high throughput filters for searching HIV-1 RNase H active-site molecules in the virtual screening process.......Quantum mechanical (QM) calculations have been used to predict the binding affinity of a set of ligands towards HIV-1 RT associated RNase H (RNH). The QM based chelation calculations show improved binding affinity prediction for the inhibitors compared to using an empirical scoring function...... of the methods based on the use of a training set of molecules, QM based chelation calculations were used as filter in virtual screening of compounds in the ZINC database. By this, we find, compared to regular docking, QM based chelation calculations to significantly reduce the large number of false positives...

  8. Identification of ALK5 inhibitor via structure-based virtual screening and ADMET prediction.

    Science.gov (United States)

    Lin, Aibin; Cai, Zhongqi; Hu, Guoping; Li, Qiang

    2015-01-01

    TGF-β plays a critical role in the initiation and progression of fibrosis in various organ systems such as kidney, heart, lung and liver. TGF-β and its receptors (ALK5 and TβR II) are able to control the cellular growth and promote several biological responses. To date, many pharmaceutical companies have employed virtual screening to identify potent inhibitors against ALK5. Nevertheless, none of these studies had involved the in silico ADMET evaluation and Raccoon filtering. In our experiment, all 57423 molecules were downloaded from TCM database and were filtered and converted to PDBQT formats by Raccoon software. Then 24 189 structures were run through AutoDock Vina in PyRx 0.8, 164 molecules were selected and further evaluated by ADMET Predictor 6.5, and 56 structures were selected and docked by Glide 6.2. Finally, the top 10 hits were identified as promising oral ALK5 inhibitors according to their Glide scores. The Glide scores of the best two compounds, 40686 and 33534, were -10.75 and -10.30 kcal/mol, respectively. This research provides a set of combined and detailed virtual screening protocol and is helpful for explaining the mechanism of receptor-ligand interactions.

  9. Impact of template choice on homology model efficiency in virtual screening.

    Science.gov (United States)

    Rataj, Krzysztof; Witek, Jagna; Mordalski, Stefan; Kosciolek, Tomasz; Bojarski, Andrzej J

    2014-06-23

    Homology modeling is a reliable method of predicting the three-dimensional structures of proteins that lack NMR or X-ray crystallographic data. It employs the assumption that a structural resemblance exists between closely related proteins. Despite the availability of many crystal structures of possible templates, only the closest ones are chosen for homology modeling purposes. To validate the aforementioned approach, we performed homology modeling of four serotonin receptors (5-HT1AR, 5-HT2AR, 5-HT6R, 5-HT7R) for virtual screening purposes, using 10 available G-Protein Coupled Receptors (GPCR) templates with diverse evolutionary distances to the targets, with various approaches to alignment construction and model building. The resulting models were further validated in two steps by means of ligand docking and enrichment calculation, using Glide software. The final quality of the models was determined in virtual screening-like experiments by the AUROC score of the resulting ROC curves. The outcome of this research showed that no correlation between sequence identity and model quality was found, leading to the conclusion that the closest phylogenetic relative is not always the best template for homology modeling.

  10. Design of inhibitors of the HIV-1 integrase core domain using virtual screening

    Science.gov (United States)

    Regon, Preetom; Gogoi, Dhrubajyoti; Rai, Ashok Kumar; Bordoloi, Manabjyoti; Bezbaruah, Rajib Lochan

    2014-01-01

    Acquired immunodeficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV). The integrase (IN) enzyme of HIV interacts with several cellular and viral proteins during the integration process. Thus, it represents an appropriate target for antiretroviral drugs (ARVs). We performed virtual screening of database compounds and designed analogues using Elvitegravir (EVG) as a standard compound. The 378 screened compounds were retrieved from ZINC, ChemSpider, PubChem, and ChemBank Chemical Databases based on chemical similarity and literature searches related to the structure of EVG. The Physiochemical properties, Bioactivity, Toxicity and Absorption, Distribution, Metabolism and Excretion of Molecules (ADME) of these compounds were predicted and docking Experiments were conducted using Molegro Virtual Docker software. The docking and ADME suggested very significant results in regard to EVG. The MolDock and Rerank scores were used to analyze the results. The compounds ZINC26507991 (-84.22), Analogue 9 (-68.49), ZINC20731658 (-66.79), ZINC00210363 (-43.44) showed better binding orientation with IN receptor model with respect to EVG (182.52). The ZINC26507991 has showed significant ADME result. PMID:24616558

  11. Contact-based ligand-clustering approach for the identification of active compounds in virtual screening

    Directory of Open Access Journals (Sweden)

    Mantsyzov AB

    2012-09-01

    Full Text Available Alexey B Mantsyzov,1 Guillaume Bouvier,2 Nathalie Evrard-Todeschi,1 Gildas Bertho11Université Paris Descartes, Sorbonne, Paris, France; 2Institut Pasteur, Paris, FranceAbstract: Evaluation of docking results is one of the most important problems for virtual screening and in silico drug design. Modern approaches for the identification of active compounds in a large data set of docked molecules use energy scoring functions. One of the general and most significant limitations of these methods relates to inaccurate binding energy estimation, which results in false scoring of docked compounds. Automatic analysis of poses using self-organizing maps (AuPosSOM represents an alternative approach for the evaluation of docking results based on the clustering of compounds by the similarity of their contacts with the receptor. A scoring function was developed for the identification of the active compounds in the AuPosSOM clustered dataset. In addition, the AuPosSOM efficiency for the clustering of compounds and the identification of key contacts considered as important for its activity, were also improved. Benchmark tests for several targets revealed that together with the developed scoring function, AuPosSOM represents a good alternative to the energy-based scoring functions for the evaluation of docking results.Keywords: scoring, docking, virtual screening, CAR, AuPosSOM

  12. Fragment virtual screening based on Bayesian categorization for discovering novel VEGFR-2 scaffolds.

    Science.gov (United States)

    Zhang, Yanmin; Jiao, Yu; Xiong, Xiao; Liu, Haichun; Ran, Ting; Xu, Jinxing; Lu, Shuai; Xu, Anyang; Pan, Jing; Qiao, Xin; Shi, Zhihao; Lu, Tao; Chen, Yadong

    2015-11-01

    The discovery of novel scaffolds against a specific target has long been one of the most significant but challengeable goals in discovering lead compounds. A scaffold that binds in important regions of the active pocket is more favorable as a starting point because scaffolds generally possess greater optimization possibilities. However, due to the lack of sufficient chemical space diversity of the databases and the ineffectiveness of the screening methods, it still remains a great challenge to discover novel active scaffolds. Since the strengths and weaknesses of both fragment-based drug design and traditional virtual screening (VS), we proposed a fragment VS concept based on Bayesian categorization for the discovery of novel scaffolds. This work investigated the proposal through an application on VEGFR-2 target. Firstly, scaffold and structural diversity of chemical space for 10 compound databases were explicitly evaluated. Simultaneously, a robust Bayesian classification model was constructed for screening not only compound databases but also their corresponding fragment databases. Although analysis of the scaffold diversity demonstrated a very unevenly distribution of scaffolds over molecules, results showed that our Bayesian model behaved better in screening fragments than molecules. Through a literature retrospective research, several generated fragments with relatively high Bayesian scores indeed exhibit VEGFR-2 biological activity, which strongly proved the effectiveness of fragment VS based on Bayesian categorization models. This investigation of Bayesian-based fragment VS can further emphasize the necessity for enrichment of compound databases employed in lead discovery by amplifying the diversity of databases with novel structures.

  13. CSBB-ConeExclusion, adapting structure based solution virtual screening to libraries on solid support.

    Science.gov (United States)

    Shave, Steven; Auer, Manfred

    2013-12-23

    Combinatorial chemical libraries produced on solid support offer fast and cost-effective access to a large number of unique compounds. If such libraries are screened directly on-bead, the speed at which chemical space can be explored by chemists is much greater than that addressable using solution based synthesis and screening methods. Solution based screening has a large supporting body of software such as structure-based virtual screening tools which enable the prediction of protein-ligand complexes. Use of these techniques to predict the protein bound complexes of compounds synthesized on solid support neglects to take into account the conjugation site on the small molecule ligand. This may invalidate predicted binding modes, the linker may be clashing with protein atoms. We present CSBB-ConeExclusion, a methodology and computer program which provides a measure of the applicability of solution dockings to solid support. Output is given in the form of statistics for each docking pose, a unique 2D visualization method which can be used to determine applicability at a glance, and automatically generated PyMol scripts allowing visualization of protein atom incursion into a defined exclusion volume. CSBB-ConeExclusion is then exemplarically used to determine the optimum attachment point for a purine library targeting cyclin-dependent kinase 2 CDK2.

  14. Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification.

    Science.gov (United States)

    Ballester, Pedro J; Mangold, Martina; Howard, Nigel I; Robinson, Richard L Marchese; Abell, Chris; Blumberger, Jochen; Mitchell, John B O

    2012-12-07

    One of the initial steps of modern drug discovery is the identification of small organic molecules able to inhibit a target macromolecule of therapeutic interest. A small proportion of these hits are further developed into lead compounds, which in turn may ultimately lead to a marketed drug. A commonly used screening protocol used for this task is high-throughput screening (HTS). However, the performance of HTS against antibacterial targets has generally been unsatisfactory, with high costs and low rates of hit identification. Here, we present a novel computational methodology that is able to identify a high proportion of structurally diverse inhibitors by searching unusually large molecular databases in a time-, cost- and resource-efficient manner. This virtual screening methodology was tested prospectively on two versions of an antibacterial target (type II dehydroquinase from Mycobacterium tuberculosis and Streptomyces coelicolor), for which HTS has not provided satisfactory results and consequently practically all known inhibitors are derivatives of the same core scaffold. Overall, our protocols identified 100 new inhibitors, with calculated K(i) ranging from 4 to 250 μM (confirmed hit rates are 60% and 62% against each version of the target). Most importantly, over 50 new active molecular scaffolds were discovered that underscore the benefits that a wide application of prospectively validated in silico screening tools is likely to bring to antibacterial hit identification.

  15. LASSO-ligand activity by surface similarity order: a new tool for ligand based virtual screening.

    Science.gov (United States)

    Reid, Darryl; Sadjad, Bashir S; Zsoldos, Zsolt; Simon, Aniko

    2008-01-01

    Virtual Ligand Screening (VLS) has become an integral part of the drug discovery process for many pharmaceutical companies. Ligand similarity searches provide a very powerful method of screening large databases of ligands to identify possible hits. If these hits belong to new chemotypes the method is deemed even more successful. eHiTS LASSO uses a new interacting surface point types (ISPT) molecular descriptor that is generated from the 3D structure of the ligand, but unlike most 3D descriptors it is conformation independent. Combined with a neural network machine learning technique, LASSO screens molecular databases at an ultra fast speed of 1 million structures in under 1 min on a standard PC. The results obtained from eHiTS LASSO trained on relatively small training sets of just 2, 4 or 8 actives are presented using the diverse directory of useful decoys (DUD) dataset. It is shown that over a wide range of receptor families, eHiTS LASSO is consistently able to enrich screened databases and provides scaffold hopping ability.

  16. MOLA: a bootable, self-configuring system for virtual screening using AutoDock4/Vina on computer clusters

    Directory of Open Access Journals (Sweden)

    Abreu Rui MV

    2010-10-01

    Full Text Available Abstract Background Virtual screening of small molecules using molecular docking has become an important tool in drug discovery. However, large scale virtual screening is time demanding and usually requires dedicated computer clusters. There are a number of software tools that perform virtual screening using AutoDock4 but they require access to dedicated Linux computer clusters. Also no software is available for performing virtual screening with Vina using computer clusters. In this paper we present MOLA, an easy-to-use graphical user interface tool that automates parallel virtual screening using AutoDock4 and/or Vina in bootable non-dedicated computer clusters. Implementation MOLA automates several tasks including: ligand preparation, parallel AutoDock4/Vina jobs distribution and result analysis. When the virtual screening project finishes, an open-office spreadsheet file opens with the ligands ranked by binding energy and distance to the active site. All results files can automatically be recorded on an USB-flash drive or on the hard-disk drive using VirtualBox. MOLA works inside a customized Live CD GNU/Linux operating system, developed by us, that bypass the original operating system installed on the computers used in the cluster. This operating system boots from a CD on the master node and then clusters other computers as slave nodes via ethernet connections. Conclusion MOLA is an ideal virtual screening tool for non-experienced users, with a limited number of multi-platform heterogeneous computers available and no access to dedicated Linux computer clusters. When a virtual screening project finishes, the computers can just be restarted to their original operating system. The originality of MOLA lies on the fact that, any platform-independent computer available can he added to the cluster, without ever using the computer hard-disk drive and without interfering with the installed operating system. With a cluster of 10 processors, and a

  17. MOLA: a bootable, self-configuring system for virtual screening using AutoDock4/Vina on computer clusters.

    Science.gov (United States)

    Abreu, Rui Mv; Froufe, Hugo Jc; Queiroz, Maria João Rp; Ferreira, Isabel Cfr

    2010-10-28

    Virtual screening of small molecules using molecular docking has become an important tool in drug discovery. However, large scale virtual screening is time demanding and usually requires dedicated computer clusters. There are a number of software tools that perform virtual screening using AutoDock4 but they require access to dedicated Linux computer clusters. Also no software is available for performing virtual screening with Vina using computer clusters. In this paper we present MOLA, an easy-to-use graphical user interface tool that automates parallel virtual screening using AutoDock4 and/or Vina in bootable non-dedicated computer clusters. MOLA automates several tasks including: ligand preparation, parallel AutoDock4/Vina jobs distribution and result analysis. When the virtual screening project finishes, an open-office spreadsheet file opens with the ligands ranked by binding energy and distance to the active site. All results files can automatically be recorded on an USB-flash drive or on the hard-disk drive using VirtualBox. MOLA works inside a customized Live CD GNU/Linux operating system, developed by us, that bypass the original operating system installed on the computers used in the cluster. This operating system boots from a CD on the master node and then clusters other computers as slave nodes via ethernet connections. MOLA is an ideal virtual screening tool for non-experienced users, with a limited number of multi-platform heterogeneous computers available and no access to dedicated Linux computer clusters. When a virtual screening project finishes, the computers can just be restarted to their original operating system. The originality of MOLA lies on the fact that, any platform-independent computer available can he added to the cluster, without ever using the computer hard-disk drive and without interfering with the installed operating system. With a cluster of 10 processors, and a potential maximum speed-up of 10x, the parallel algorithm of MOLA

  18. Immersive second-screen experiences using hybrid media synchronization

    NARCIS (Netherlands)

    Brandenburg, R. van; Veenhuizen, A.T.

    2013-01-01

    Most second-screen services have so far been relying on watermarking and fingerprinting for providing synchronisation with the main TV screen. In the EU FP7 HBB-Next project, a new timestamp-based inter-device synchronization system has been developed, allowing for frame-accurate synchronisation bet

  19. mRAISE: an alternative algorithmic approach to ligand-based virtual screening

    Science.gov (United States)

    von Behren, Mathias M.; Bietz, Stefan; Nittinger, Eva; Rarey, Matthias

    2016-08-01

    Ligand-based virtual screening is a well established method to find new lead molecules in todays drug discovery process. In order to be applicable in day to day practice, such methods have to face multiple challenges. The most important part is the reliability of the results, which can be shown and compared in retrospective studies. Furthermore, in the case of 3D methods, they need to provide biologically relevant molecular alignments of the ligands, that can be further investigated by a medicinal chemist. Last but not least, they have to be able to screen large databases in reasonable time. Many algorithms for ligand-based virtual screening have been proposed in the past, most of them based on pairwise comparisons. Here, a new method is introduced called mRAISE. Based on structural alignments, it uses a descriptor-based bitmap search engine (RAISE) to achieve efficiency. Alignments created on the fly by the search engine get evaluated with an independent shape-based scoring function also used for ranking of compounds. The correct ranking as well as the alignment quality of the method are evaluated and compared to other state of the art methods. On the commonly used Directory of Useful Decoys dataset mRAISE achieves an average area under the ROC curve of 0.76, an average enrichment factor at 1 % of 20.2 and an average hit rate at 1 % of 55.5. With these results, mRAISE is always among the top performing methods with available data for comparison. To access the quality of the alignments calculated by ligand-based virtual screening methods, we introduce a new dataset containing 180 prealigned ligands for 11 diverse targets. Within the top ten ranked conformations, the alignment closest to X-ray structure calculated with mRAISE has a root-mean-square deviation of less than 2.0 Å for 80.8 % of alignment pairs and achieves a median of less than 2.0 Å for eight of the 11 cases. The dataset used to rate the quality of the calculated alignments is freely available at

  20. A utility script for automating and integrating AutoDock and other associated programs for virtual screening.

    Science.gov (United States)

    Sharma, Vikas; Pattanaik, Kiran Kumar; Jayprakash, Venkatesan; Basu, Arijit; Mishra, Nibha

    2009-09-06

    AutoDock is one of the most widely used docking programs but, is under utilized for the purpose of virtual screening. In order to overcome the difficulties that arise during virtual screening with AutoDock especially for GUI users an attempt is taken to automate the entire docking process, starting from grid map generation through ligand preparation and finally docking. Additional features from software like FILTER, OMEGA, ROCS and EON are also incorporated to create a complete virtual screening platform. The program completely reduced user intervention so that the program can be left unattended for longer period of time and there by improving the computational efficacy. The script is available upon request from the authors.

  1. Virtual screening as a strategy for the identification of xenobiotics disrupting corticosteroid action.

    Directory of Open Access Journals (Sweden)

    Lyubomir G Nashev

    Full Text Available BACKGROUND: Impaired corticosteroid action caused by genetic and environmental influence, including exposure to hazardous xenobiotics, contributes to the development and progression of metabolic diseases, cardiovascular complications and immune disorders. Novel strategies are thus needed for identifying xenobiotics that interfere with corticosteroid homeostasis. 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2 and mineralocorticoid receptors (MR are major regulators of corticosteroid action. 11β-HSD2 converts the active glucocorticoid cortisol to the inactive cortisone and protects MR from activation by glucocorticoids. 11β-HSD2 has also an essential role in the placenta to protect the fetus from high maternal cortisol concentrations. METHODS AND PRINCIPAL FINDINGS: We employed a previously constructed 3D-structural library of chemicals with proven and suspected endocrine disrupting effects for virtual screening using a chemical feature-based 11β-HSD pharmacophore. We tested several in silico predicted chemicals in a 11β-HSD2 bioassay. The identified antibiotic lasalocid and the silane-coupling agent AB110873 were found to concentration-dependently inhibit 11β-HSD2. Moreover, the silane AB110873 was shown to activate MR and stimulate mitochondrial ROS generation and the production of the proinflammatory cytokine interleukin-6 (IL-6. Finally, we constructed a MR pharmacophore, which successfully identified the silane AB110873. CONCLUSIONS: Screening of virtual chemical structure libraries can facilitate the identification of xenobiotics inhibiting 11β-HSD2 and/or activating MR. Lasalocid and AB110873 belong to new classes of 11β-HSD2 inhibitors. The silane AB110873 represents to the best of our knowledge the first industrial chemical shown to activate MR. Furthermore, the MR pharmacophore can now be used for future screening purposes.

  2. Prospective virtual screening for novel p53-MDM2 inhibitors using ultrafast shape recognition

    Science.gov (United States)

    Patil, Sachin P.; Ballester, Pedro J.; Kerezsi, Cassidy R.

    2014-02-01

    The p53 protein, known as the guardian of genome, is mutated or deleted in approximately 50 % of human tumors. In the rest of the cancers, p53 is expressed in its wild-type form, but its function is inhibited by direct binding with the murine double minute 2 (MDM2) protein. Therefore, inhibition of the p53-MDM2 interaction, leading to the activation of tumor suppressor p53 protein presents a fundamentally novel therapeutic strategy against several types of cancers. The present study utilized ultrafast shape recognition (USR), a virtual screening technique based on ligand-receptor 3D shape complementarity, to screen DrugBank database for novel p53-MDM2 inhibitors. Specifically, using 3D shape of one of the most potent crystal ligands of MDM2, MI-63, as the query molecule, six compounds were identified as potential p53-MDM2 inhibitors. These six USR hits were then subjected to molecular modeling investigations through flexible receptor docking followed by comparative binding energy analysis. These studies suggested a potential role of the USR-selected molecules as p53-MDM2 inhibitors. This was further supported by experimental tests showing that the treatment of human colon tumor cells with the top USR hit, telmisartan, led to a dose-dependent cell growth inhibition in a p53-dependent manner. It is noteworthy that telmisartan has a long history of safe human use as an approved anti-hypertension drug and thus may present an immediate clinical potential as a cancer therapeutic. Furthermore, it could also serve as a structurally-novel lead molecule for the development of more potent, small-molecule p53-MDM2 inhibitors against variety of cancers. Importantly, the present study demonstrates that the adopted USR-based virtual screening protocol is a useful tool for hit identification in the domain of small molecule p53-MDM2 inhibitors.

  3. Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening

    DEFF Research Database (Denmark)

    Markt, Patrick; Petersen, Rasmus K; Flindt, Esben N;

    2008-01-01

    Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow base...

  4. Inhibitors of Helicobacter pylori protease HtrA found by 'virtual ligand' screening combat bacterial invasion of epithelia.

    Directory of Open Access Journals (Sweden)

    Martin Löwer

    Full Text Available BACKGROUND: The human pathogen Helicobacter pylori (H. pylori is a main cause for gastric inflammation and cancer. Increasing bacterial resistance against antibiotics demands for innovative strategies for therapeutic intervention. METHODOLOGY/PRINCIPAL FINDINGS: We present a method for structure-based virtual screening that is based on the comprehensive prediction of ligand binding sites on a protein model and automated construction of a ligand-receptor interaction map. Pharmacophoric features of the map are clustered and transformed in a correlation vector ('virtual ligand' for rapid virtual screening of compound databases. This computer-based technique was validated for 18 different targets of pharmaceutical interest in a retrospective screening experiment. Prospective screening for inhibitory agents was performed for the protease HtrA from the human pathogen H. pylori using a homology model of the target protein. Among 22 tested compounds six block E-cadherin cleavage by HtrA in vitro and result in reduced scattering and wound healing of gastric epithelial cells, thereby preventing bacterial infiltration of the epithelium. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that receptor-based virtual screening with a permissive ('fuzzy' pharmacophore model can help identify small bioactive agents for combating bacterial infection.

  5. Virtual screening of novel reversible inhibitors for marine alkaline protease MP.

    Science.gov (United States)

    Ji, Xiaofeng; Zheng, Yuan; Wang, Wei; Sheng, Jun; Hao, Jianhua; Sun, Mi

    2013-11-01

    Marine alkaline protease (MP,(2) accession no. ACY25898) is produced by a marine bacterium strain isolated from Yellow Sea sediment in China. Previous research has shown that this protease is a cold-adapted enzyme with antioxidant activity that could be used as a detergent additive. Owing to its instability in the liquid state, MP's application in liquid detergents was limited. Therefore, the discovery of reversible MP inhibitors to stabilize the protease was imperative. Here, we used the X-ray structure of MP and recompiled AutoDock 4.2 with refined Zn(2+) characters to screen the free chemical database ZINC. After completing the docking procedure, we applied strategies including the "initial filter", consensus scoring and pharmocophore model to accelerate the process and improve the virtual screening success rate. The "initial filter" was built based on the docking results of boronic acid derivatives validated as reversible inhibitors of MP by our previous studies. Finally, ten compounds were purchased or synthetized to test their binding affinity for MP. Three of the compounds could reversibly inhibit MP with apparent Ki values of 0.8-1.2 mmol. These active compounds and their binding modes provide useful information for understanding the molecular mechanism of reversible MP inhibition. The results may also serve as the foundation for further screening and design of reversible MP inhibitors.

  6. Virtual Screening of Acetylcholinesterase Inhibitors Using the Lipinski’s Rule of Five and ZINC Databank

    Directory of Open Access Journals (Sweden)

    Pablo Andrei Nogara

    2015-01-01

    Full Text Available Alzheimer’s disease (AD is a progressive and neurodegenerative pathology that can affect people over 65 years of age. It causes several complications, such as behavioral changes, language deficits, depression, and memory impairments. One of the methods used to treat AD is the increase of acetylcholine (ACh in the brain by using acetylcholinesterase inhibitors (AChEIs. In this study, we used the ZINC databank and the Lipinski’s rule of five to perform a virtual screening and a molecular docking (using Auto Dock Vina 1.1.1 aiming to select possible compounds that have quaternary ammonium atom able to inhibit acetylcholinesterase (AChE activity. The molecules were obtained by screening and further in vitro assays were performed to analyze the most potent inhibitors through the IC50 value and also to describe the interaction models between inhibitors and enzyme by molecular docking. The results showed that compound D inhibited AChE activity from different vertebrate sources and butyrylcholinesterase (BChE from Equus ferus (EfBChE, with IC50 ranging from 1.69 ± 0.46 to 5.64 ± 2.47 µM. Compound D interacted with the peripheral anionic subsite in both enzymes, blocking substrate entrance to the active site. In contrast, compound C had higher specificity as inhibitor of EfBChE. In conclusion, the screening was effective in finding inhibitors of AChE and BuChE from different organisms.

  7. Discovery of novel and cardioselective diltiazem-like calcium channel blockers via virtual screening.

    Science.gov (United States)

    Carosati, Emanuele; Budriesi, Roberta; Ioan, Pierfranco; Ugenti, Maria P; Frosini, Maria; Fusi, Fabio; Corda, Gaetano; Cosimelli, Barbara; Spinelli, Domenico; Chiarini, Alberto; Cruciani, Gabriele

    2008-09-25

    With the effort to discover new chemotypes blocking L-type calcium channels (LTCCs), ligand-based virtual screening was applied with a specific interest toward the diltiazem binding site. Roughly 50000 commercially available compounds served as a database for screening. The filtering through predicted pharmacokinetic properties and structural requirements reduced the initial database to a few compounds for which the similarity was calculated toward two template molecules, diltiazem and 4-chloro-Ncyclopropyl- N-(4-piperidinyl)benzene-sulfonamide, the most interesting hit of a previous screening experiment. For 18 compounds, inotropic and chronotropic activity as well as the vasorelaxant effect on guinea pig were studied "in vitro", and for the most promising, binding studies to the diltiazem site were carried out. The procedure yielded several hits, confirming in silico techniques to be useful for finding new chemotypes. In particular, N-[2-(dimethylamino)ethyl]-3-hydroxy-2-naphthamide, N,Ndimethyl- N'-(2-pyridin-3-ylquinolin-4-yl)ethane-1,2-diamine, 2-[(4-chlorophenyl)(pyridin-2-yl)methoxy]- N,N-dimethylethanamine (carbinoxamine), and 7-[2-(diethylamino)ethoxy]-2H-chromen-2-one revealed interesting activity and binding to the benzothiazepine site.

  8. Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

    Institute of Scientific and Technical Information of China (English)

    Sugunadevi SAKKIAH; Keun Woo LEE

    2012-01-01

    Aim:To identify the critical chemical features,with reliable geometric constraints,that contributes to the inhibition of butyrylcholinesterase (BChE) function.Methods:Ligand-based pharmacophore modeling was used to identify the critical chemical features of BChE inhibitors.The generated pharmacophore model was validated using various techniques,such as Fischer's randomization method,test set,and decoy set.The best pharmacophore model was used as a query in virtual screening to identify novel scaffolds that inhibit BChE.Compounds selected by the best hypothesis in the virtual screening were tested for drug-like properties,and molecular docking study was applied to determine the optimal orientation of the hit compounds in the BChE active site.To find the reactivity of the hit compounds,frontier orbital analysis was carried out using density functional theory.Results:Based on its correlation coefficient (0.96),root mean square (RMS) deviation (1.01),and total cost (105.72),the quantitative hypothesis Hypo1 consisting of 2 HBA,1 Hy-Ali,and 1 Hy-Ar was selected as the best hypothesis.Thus,Hypo1 was used as a 3D query in virtual screening of the Maybridge and Chembridge databases.The hit compounds were filtered using ADMET,Lipinski's Rule of Five,and molecular docking to reduce the number of false positive results.Finally,33 compounds were selected based on their critical interactions with the significant amino acids in BChE's active site.To confirm the inhibitors' potencies,the orbital energies,such as HOMO and LUMO,of the hit compounds and 7 training set compounds were calculated.Among the 33 hit compounds,10 compounds with the highest HOMO values were selected,and this set was further culled to 5 compounds based on their energy gaps important for stability and energy transfer.From the overall results,5 hit compounds were confirmed to be potential BChE inhibitors that satisfied all the pharmacophoric features in Hypo1.Conclusion:This study pinpoints important chemical

  9. Uroporphyrinogen Decarboxylase as a Potential Target for Specific Components of Traditional Chinese Medicine: A Virtual Screening and Molecular Dynamics Study

    OpenAIRE

    Yung-An Tsou; Kuan-Chung Chen; Hung-Che Lin; Su-Sen Chang; Calvin Yu-Chian Chen

    2012-01-01

    Uroporphyrinogen decarboxylase (UROD) has been suggested as a protectant against radiation for head and neck cancer (HNC). In this study, we employed traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan (http://tcm.cmu.edu.tw/) to screen for drug-like candidates with potential UROD inhibition characteristics using virtual screening techniques. Isopraeroside IV, scopolin, and nodakenin exhibited the highest Dock Scores, and were predicted to have good Absorption, Distribution,...

  10. Sulfonylureas and Glinides as New PPARγ Agonists:. Virtual Screening and Biological Assays

    Science.gov (United States)

    Scarsi, Marco; Podvinec, Michael; Roth, Adrian; Hug, Hubert; Kersten, Sander; Albrecht, Hugo; Schwede, Torsten; Meyer, Urs A.; Rücker, Christoph

    2007-12-01

    This work combines the predictive power of computational drug discovery with experimental validation by means of biological assays. In this way, a new mode of action for type 2 diabetes drugs has been unvealed. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target PPARγ improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides bind to PPARγ and exhibit PPARγ agonistic activity. This result was predicted in silico by virtual screening and confirmed in vitro by three biological assays. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, since it provides evidence that drugs can be designed which target both the sulfonylurea receptor and PPARγ. Targeting both receptors could in principle allow to increase pancreatic insulin secretion, as well as to improve insulin resistance.

  11. Virtual screening studies to identify novel inhibitors for Sigma F protein of Mycobacterium tuberculosis.

    Science.gov (United States)

    Mustyala, Kiran Kumar; Malkhed, Vasavi; Chittireddy, Venkataramana Reddy; Vuruputuri, Uma

    2015-12-01

    Tuberculosis (TB) is one of the oldest threats to public health. TB is caused by the pathogen Mycobacterium tuberculosis (MTB). The Sigma factors are essential for the survival of MTB. The Sigma factor Sigma F (SigF) regulates genes expression under stress conditions. The SigF binds to RNA polymerase and forms a holoenzyme, which initiates the transcription of various genes. The Usfx, an anti-SigF protein, binds to SigF and alters the transcription initiation and gene expression. In the present work, virtual screening studies are taken up to identify the interactions between SigF and small molecular inhibitors which can inhibit the formation of holoenzyme. The studies reveal that ARG 104 and ARG 224 amino acid residues of SigF protein are forming important binding interactions with the ligands. The in silico ADME properties for the ligand data set are calculated to check the druggability of the molecules.

  12. Identification of novel Trypanosoma cruzi prolyl oligopeptidase inhibitors by structure-based virtual screening

    Science.gov (United States)

    de Almeida, Hugo; Leroux, Vincent; Motta, Flávia Nader; Grellier, Philippe; Maigret, Bernard; Santana, Jaime M.; Bastos, Izabela Marques Dourado

    2016-12-01

    We have previously demonstrated that the secreted prolyl oligopeptidase of Trypanosoma cruzi (POPTc80) is involved in the infection process by facilitating parasite migration through the extracellular matrix. We have built a 3D structural model where POPTc80 is formed by a catalytic α/β-hydrolase domain and a β-propeller domain, and in which the substrate docks at the inter-domain interface, suggesting a "jaw opening" gating access mechanism. This preliminary model was refined by molecular dynamics simulations and next used for a virtual screening campaign, whose predictions were tested by standard binding assays. This strategy was successful as all 13 tested molecules suggested from the in silico calculations were found out to be active POPTc80 inhibitors in the micromolar range (lowest K i at 667 nM). This work paves the way for future development of innovative drugs against Chagas disease.

  13. Discovery of Entamoeba histolytica hexokinase 1 inhibitors through homology modeling and virtual screening.

    Science.gov (United States)

    Saucedo-Mendiola, María Leticia; Salas-Pacheco, José Manuel; Nájera, Hugo; Rojo-Domínguez, Arturo; Yépez-Mulia, Lilián; Avitia-Domínguez, Claudia; Téllez-Valencia, Alfredo

    2014-06-01

    Entamoeba histolytica, the parasite which causes amebiasis is responsible for 110,000 deaths a year. Entamoeba histolytica depends on glycolysis to obtain ATP for cellular work. According to metabolic flux studies, hexokinase exerts the highest flux control of this metabolic pathway; therefore, it is an excellent target in the search of new antiamebic drugs. To this end, a tridimensional model of E. histolytica hexokinase 1 (EhHK1) was constructed and validated by homology modeling. After virtual screening of 14,400 small molecules, the 100 with the best docking scores were selected, purchased and assessed in their inhibitory capacity. The results showed that three molecules (compounds 2921, 11275 and 2755) inhibited EhHK1 with an I50 of 48, 91 and 96 µM, respectively. Thus, we found the first inhibitors of EhHK1 that can be used in the search of new chemotherapeutic agents against amebiasis.

  14. Understanding Dermatan Sulfate-Heparin Cofactor II Interaction through Virtual Library Screening.

    Science.gov (United States)

    Raghuraman, Arjun; Mosier, Philip D; Desai, Umesh R

    2010-09-09

    Dermatan sulfate, an important member of the glycosaminoglycan family, interacts with heparin cofactor II, a member of the serpin family of proteins, to modulate antithrombotic response. Yet, the nature of this interaction remains poorly understood at a molecular level. We report the genetic algorithm-based combinatorial virtual library screening study of a natural, high-affinity dermatan sulfate hexasaccharide with heparin cofactor II. Of the 192 topologies possible for the hexasaccharide, only 16 satisfied the "high-specificity" criteria used in computational study. Of these, 13 topologies were predicted to bind in the heparin-binding site of heparin cofactor II at a ∼60° angle to helix D, a novel binding mode. This new binding geometry satisfies all known solution and mutagenesis data and supports thrombin ternary complexation through a template mechanism. The study is expected to facilitate the design of allosteric agonists of heparin cofactor II as antithrombotic agents.

  15. Systemic QSAR and phenotypic virtual screening: chasing butterflies in drug discovery.

    Science.gov (United States)

    Cruz-Monteagudo, Maykel; Schürer, Stephan; Tejera, Eduardo; Pérez-Castillo, Yunierkis; Medina-Franco, José L; Sánchez-Rodríguez, Aminael; Borges, Fernanda

    2017-03-06

    Current advances in systems biology suggest a new change of paradigm reinforcing the holistic nature of the drug discovery process. According to the principles of systems biology, a simple drug perturbing a network of targets can trigger complex reactions. Therefore, it is possible to connect initial events with final outcomes and consequently prioritize those events, leading to a desired effect. Here, we introduce a new concept, 'Systemic Chemogenomics/Quantitative Structure-Activity Relationship (QSAR)'. To elaborate on the concept, relevant information surrounding it is addressed. The concept is challenged by implementing a systemic QSAR approach for phenotypic virtual screening (VS) of candidate ligands acting as neuroprotective agents in Parkinson's disease (PD). The results support the suitability of the approach for the phenotypic prioritization of drug candidates.

  16. BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen

    Energy Technology Data Exchange (ETDEWEB)

    Ayoub, Alex M.; Hawk, Laura M.L.; Herzig, Ryan J.; Jiang, Jiewei; Wisniewski, Andrea J.; Gee, Clifford T.; Zhao, Peiliang; Zhu, Jin-Yi; Berndt, Norbert; Offei-Addo, Nana K.; Scott, Thomas G.; Qi, Jun; Bradner, James E.; Ward, Timothy R.; Schönbrunn, Ernst; Georg, Gunda I.; Pomerantz, William C.K. (Moffitt); (UMM); (Harvard-Med)

    2017-06-06

    Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure–activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure–activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.

  17. DiSCuS: an open platform for (not only) virtual screening results management.

    Science.gov (United States)

    Wójcikowski, Maciej; Zielenkiewicz, Piotr; Siedlecki, Paweł

    2014-01-27

    DiSCuS, a "Database System for Compound Selection", has been developed. The primary goal of DiSCuS is to aid researchers in the steps subsequent to generating high-throughput virtual screening (HTVS) results, such as selection of compounds for further study, purchase, or synthesis. To do so, DiSCuS provides (1) a storage facility for ligand-receptor complexes (generated with external programs), (2) a number of tools for validating these complexes, such as scoring functions, potential energy contributions, and med-chem features with ligand similarity estimates, and (3) powerful searching and filtering options with logical operators. DiSCuS supports multiple receptor targets for a single ligand, so it can be used either to evaluate different variants of an active site or for selectivity studies. DiSCuS documentation, installation instructions, and source code can be found at http://discus.ibb.waw.pl .

  18. Discovery of a Novel 5-HT2A Inhibitor by Pharmacophore-based Virtual Screening

    Institute of Scientific and Technical Information of China (English)

    XIONG Zi-jun; DU Peng; LI Bian; XU Li-li; ZHEN Xue-chu; FU Wei

    2011-01-01

    The serotonin 2A(5-HT2A) receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of schizophrenia and depression.In this study,a potent novel 5-HT2A inhibitor 05245768 with a Ki value of (593.89±34.10) nmol/L was discovered by integrating a set of computational approaches and experiments(protein structure prediction,pharmacophore-based virtual screening,automated molecular docking and pharmacological bioassay).The 5-HT2A receptor showed a negatively charged binding pocket.The binding mode of compound 05245768 with 5-HT2A was obtained by GOLD docking procedure,which revealed the conserved interaction between protonated nitrogen in compound 05245768 and carboxylate group of D3.32 at the active site of 5-HT2A.

  19. BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen.

    Science.gov (United States)

    Ayoub, Alex M; Hawk, Laura M L; Herzig, Ryan J; Jiang, Jiewei; Wisniewski, Andrea J; Gee, Clifford T; Zhao, Peiliang; Zhu, Jin-Yi; Berndt, Norbert; Offei-Addo, Nana K; Scott, Thomas G; Qi, Jun; Bradner, James E; Ward, Timothy R; Schönbrunn, Ernst; Georg, Gunda I; Pomerantz, William C K

    2017-06-22

    Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure-activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.

  20. High-throughput quantum chemistry and virtual screening for OLED material components

    Science.gov (United States)

    Halls, Mathew D.; Giesen, David J.; Hughes, Thomas F.; Goldberg, Alexander; Cao, Yixiang

    2013-09-01

    Computational structure enumeration, analysis using an automated simulation workflow and filtering of large chemical structure libraries to identify lead systems, has become a central paradigm in drug discovery research. Transferring this paradigm to challenges in materials science is now possible due to advances in the speed of computational resources and the efficiency and stability of chemical simulation packages. State-of-the-art software tools that have been developed for drug discovery can be applied to efficiently explore the chemical design space to identify solutions for problems such as organic light-emitting diode material components. In this work, virtual screening for OLED materials based on intrinsic quantum mechanical properties is illustrated. Also, a new approach to more reliably identify candidate systems is introduced that is based on the chemical reaction energetics of defect pathways for OLED materials.

  1. Accessible high-throughput virtual screening molecular docking software for students and educators.

    Directory of Open Access Journals (Sweden)

    Reed B Jacob

    2012-05-01

    Full Text Available We survey low cost high-throughput virtual screening (HTVS computer programs for instructors who wish to demonstrate molecular docking in their courses. Since HTVS programs are a useful adjunct to the time consuming and expensive wet bench experiments necessary to discover new drug therapies, the topic of molecular docking is core to the instruction of biochemistry and molecular biology. The availability of HTVS programs coupled with decreasing costs and advances in computer hardware have made computational approaches to drug discovery possible at institutional and non-profit budgets. This paper focuses on HTVS programs with graphical user interfaces (GUIs that use either DOCK or AutoDock for the prediction of DockoMatic, PyRx, DockingServer, and MOLA since their utility has been proven by the research community, they are free or affordable, and the programs operate on a range of computer platforms.

  2. Virtual screening of selective inhibitors of phosphopantetheine adenylyltransferase from Mycobacterium tuberculosis

    Science.gov (United States)

    Podshivalov, D. D.; Timofeev, V. I.; Sidorov-Biryukov, D. D.; Kuranova, I. P.

    2017-05-01

    Bacterial phosphopantetheine adenylyltransferase from Mycobacterium tuberculosis (PPAT Mt) is a convenient target protein for the directed search for selective inhibitors as potent antituberculosis drugs. Four compounds suitable for the detailed investigation of their interactions with PPAT Mt were found by virtual screening. The active-site region of the enzyme was chosen as the ligand-binding site. The positions of the ligands found by the docking were refined by molecular dynamics simulation. The nearest environment of the ligands, the positions of which in the active site of the enzyme were found in a computational experiment, was analyzed. The compounds under consideration were shown to directly interact with functionally important active-site amino-acid residues and block access of substrates to the active site. Therefore, these compounds can be used for the design of selective inhibitors of PPAT Mt as potent antituberculosis drugs.

  3. Using the Two-Hybrid Screen in the Classroom Laboratory

    OpenAIRE

    Odom, Daniel P.; Grossel, Martha J

    2002-01-01

    The National Science Foundation and others have made compelling arguments that research be incorporated into the learning of undergraduates. In response to these arguments, a two-hybrid research project was incorporated into a molecular biology course that contained both a lecture section and a laboratory section. The course was designed around specific goals for educational outcomes, including introducing research to a wide range of students, teaching students experimental design and data an...

  4. Identification by virtual screening and in vitro testing of human DOPA decarboxylase inhibitors.

    Directory of Open Access Journals (Sweden)

    Frederick Daidone

    Full Text Available Dopa decarboxylase (DDC, a pyridoxal 5'-phosphate (PLP enzyme responsible for the biosynthesis of dopamine and serotonin, is involved in Parkinson's disease (PD. PD is a neurodegenerative disease mainly due to a progressive loss of dopamine-producing cells in the midbrain. Co-administration of L-Dopa with peripheral DDC inhibitors (carbidopa or benserazide is the most effective symptomatic treatment for PD. Although carbidopa and trihydroxybenzylhydrazine (the in vivo hydrolysis product of benserazide are both powerful irreversible DDC inhibitors, they are not selective because they irreversibly bind to free PLP and PLP-enzymes, thus inducing diverse side effects. Therefore, the main goals of this study were (a to use virtual screening to identify potential human DDC inhibitors and (b to evaluate the reliability of our virtual-screening (VS protocol by experimentally testing the "in vitro" activity of selected molecules. Starting from the crystal structure of the DDC-carbidopa complex, a new VS protocol, integrating pharmacophore searches and molecular docking, was developed. Analysis of 15 selected compounds, obtained by filtering the public ZINC database, yielded two molecules that bind to the active site of human DDC and behave as competitive inhibitors with K(i values ≥10 µM. By performing in silico similarity search on the latter compounds followed by a substructure search using the core of the most active compound we identified several competitive inhibitors of human DDC with K(i values in the low micromolar range, unable to bind free PLP, and predicted to not cross the blood-brain barrier. The most potent inhibitor with a K(i value of 500 nM represents a new lead compound, targeting human DDC, that may be the basis for lead optimization in the development of new DDC inhibitors. To our knowledge, a similar approach has not been reported yet in the field of DDC inhibitors discovery.

  5. TSCC: Two-Stage Combinatorial Clustering for virtual screening using protein-ligand interactions and physicochemical features

    Science.gov (United States)

    2010-01-01

    Background The increasing numbers of 3D compounds and protein complexes stored in databases contribute greatly to current advances in biotechnology, being employed in several pharmaceutical and industrial applications. However, screening and retrieving appropriate candidates as well as handling false positives presents a challenge for all post-screening analysis methods employed in retrieving therapeutic and industrial targets. Results Using the TSCC method, virtually screened compounds were clustered based on their protein-ligand interactions, followed by structure clustering employing physicochemical features, to retrieve the final compounds. Based on the protein-ligand interaction profile (first stage), docked compounds can be clustered into groups with distinct binding interactions. Structure clustering (second stage) grouped similar compounds obtained from the first stage into clusters of similar structures; the lowest energy compound from each cluster being selected as a final candidate. Conclusion By representing interactions at the atomic-level and including measures of interaction strength, better descriptions of protein-ligand interactions and a more specific analysis of virtual screening was achieved. The two-stage clustering approach enhanced our post-screening analysis resulting in accurate performances in clustering, mining and visualizing compound candidates, thus, improving virtual screening enrichment. PMID:21143810

  6. Combined Virtual and Experimental Screening for CK1 Inhibitors Identifies a Modulator of p53 and Reveals Important Aspects of in Silico Screening Performance.

    Science.gov (United States)

    Myrianthopoulos, Vassilios; Lozach, Olivier; Zareifi, Danae; Alexopoulos, Leonidas; Meijer, Laurent; Gorgoulis, Vassilis G; Mikros, Emmanuel

    2017-10-06

    A compound collection of pronounced structural diversity was comprehensively screened for inhibitors of the DNA damage-related kinase CK1. The collection was evaluated in vitro. A potent and selective CK1 inhibitor was discovered and its capacity to modulate the endogenous levels of the CK1-regulated tumor suppressor p53 was demonstrated in cancer cell lines. Administration of 10 μM of the compound resulted in significant increase of p53 levels, reaching almost 2-fold in hepatocellular carcinoma cells. In parallel to experimental screening, two representative and orthogonal in silico screening methodologies were implemented for enabling the retrospective assessment of virtual screening performance on a case-specific basis. Results showed that both techniques performed at an acceptable and fairly comparable level, with a slight advantage of the structure-based over the ligand-based approach. However, both approaches demonstrated notable sensitivity upon parameters such as screening template choice and treatment of redundancy in the enumerated compound collection. An effort to combine insight derived by sequential implementation of the two methods afforded poor further improvement of screening performance. Overall, the presented assessment highlights the relation between improper use of enrichment metrics and misleading results, and demonstrates the inherent delicacy of in silico methods, emphasizing the challenging character of virtual screening protocol optimization.

  7. A prospective cross-screening study on G-protein-coupled receptors: lessons learned in virtual compound library design.

    NARCIS (Netherlands)

    Sanders, M.P.A.; Roumen, L.; Horst, E. van der; Lane, J.R.; Vischer, H.F.; Offenbeek, J. van; Vries, H. de; Verhoeven, S.; Chow, K.Y.; Verkaar, F.; Beukers, M.W.; McGuire, R.; Leurs, R.; IJzerman, A.P.; Vlieg, J. de; Esch, I.J. de; Zaman, G.J.; Klomp, J.P.G.; Bender, A.; Graaf, C. de

    2012-01-01

    We present the systematic prospective evaluation of a protein-based and a ligand-based virtual screening platform against a set of three G-protein-coupled receptors (GPCRs): the beta-2 adrenoreceptor (ADRB2), the adenosine A(2A) receptor (AA2AR), and the sphingosine 1-phosphate receptor (S1PR1). Nov

  8. Virtual screening and experimental validation reveal novel small-molecule inhibitors of 14-3-3 protein-protein interactions.

    Science.gov (United States)

    Thiel, Philipp; Röglin, Lars; Meissner, Nicole; Hennig, Sven; Kohlbacher, Oliver; Ottmann, Christian

    2013-10-04

    We report first non-covalent and exclusively extracellular inhibitors of 14-3-3 protein-protein interactions identified by virtual screening. Optimization by crystal structure analysis and in vitro binding assays yielded compounds capable of disrupting the interaction of 14-3-3σ with aminopeptidase N in a cellular assay.

  9. The Role of Affordances in Children's Learning Performance and Efficiency When Using Virtual Manipulative Mathematics Touch-Screen Apps

    Science.gov (United States)

    Moyer-Packenham, Patricia S.; Bullock, Emma K.; Shumway, Jessica F.; Tucker, Stephen I.; Watts, Christina M.; Westenskow, Arla; Anderson-Pence, Katie L.; Maahs-Fladung, Cathy; Boyer-Thurgood, Jennifer; Gulkilik, Hilal; Jordan, Kerry

    2016-01-01

    This paper focuses on understanding the role that affordances played in children's learning performance and efficiency during clinical interviews of their interactions with mathematics apps on touch-screen devices. One hundred children, ages 3 to 8, each used six different virtual manipulative mathematics apps during 30-40-min interviews. The…

  10. The Role of Affordances in Children's Learning Performance and Efficiency When Using Virtual Manipulative Mathematics Touch-Screen Apps

    Science.gov (United States)

    Moyer-Packenham, Patricia S.; Bullock, Emma K.; Shumway, Jessica F.; Tucker, Stephen I.; Watts, Christina M.; Westenskow, Arla; Anderson-Pence, Katie L.; Maahs-Fladung, Cathy; Boyer-Thurgood, Jennifer; Gulkilik, Hilal; Jordan, Kerry

    2016-01-01

    This paper focuses on understanding the role that affordances played in children's learning performance and efficiency during clinical interviews of their interactions with mathematics apps on touch-screen devices. One hundred children, ages 3 to 8, each used six different virtual manipulative mathematics apps during 30-40-min interviews. The…

  11. Identification of a novel NR2B-selective NMDA receptor antagonist using a virtual screening approach.

    Science.gov (United States)

    Mony, Laetitia; Triballeau, Nicolas; Paoletti, Pierre; Acher, Francine C; Bertrand, Hugues-Olivier

    2010-09-15

    We report the identification of a novel NR2B-selective NMDAR antagonist with an original scaffold, LSP10-0500. This compound was identified by a virtual high-throughput screening approach on the basis of a quantitative pharmacophore model of NR2B-specific NMDAR antagonists. A SAR study around LSP10-0500 is also described.

  12. Comparison of Hybrid capture 2 testing at different thresholds with cytology as primary cervical screening test

    OpenAIRE

    Rijkaart, D. C.; Coupé, V M H; Kemenade, van, PM Patricia; Heideman, D A M; Hesselink, A. T.; Verweij, W.; Rozendaal, L; Verheijen, R H; Snijders, P. J. F.; Berkhof, J; Meijer, C J L M

    2010-01-01

    Background: We evaluated the performance of primary high-risk human papillomavirus (hrHPV) testing by hybrid capture 2 (HC2) with different thresholds for positivity, in comparison with conventional cytology. Methods: We used data of 25 871 women (aged 30–60 years) from the intervention group of the VUSA-Screen study (VU University Medical Center and Saltro laboratory population-based cervical screening study), who were screened by cytology and hrHPV. Primary outcome measure was the number of...

  13. One-hybrid screens at the Saccharomyces cerevisiae HMR locus identify novel transcriptional silencing factors.

    Science.gov (United States)

    Andrulis, Erik D; Zappulla, David C; Alexieva-Botcheva, Krassimira; Evangelista, Carlos; Sternglanz, Rolf

    2004-01-01

    In Saccharomyces cerevisiae, genes located at the telomeres and the HM loci are subject to transcriptional silencing. Here, we report results of screening a Gal4 DNA-binding domain hybrid library for proteins that cause silencing when targeted to a silencer-defective HMR locus. PMID:15020450

  14. Large-scale virtual screening for the identification of new Helicobacter pylori urease inhibitor scaffolds.

    Science.gov (United States)

    Azizian, Homa; Nabati, Farzaneh; Sharifi, Amirhossein; Siavoshi, Farideh; Mahdavi, Mohammad; Amanlou, Massoud

    2012-07-01

    Here, we report a structure-based virtual screening of the ZINC database (containing about five million compounds) by computational docking and the analysis of docking energy calculations followed by in vitro screening against H. pylori urease enzyme. One of the compounds selected showed urease inhibition in the low micromolar range. Barbituric acid and compounds 1a, 1d, 1e, 1f, 1g, 1h were found to be more potent urease inhibitors than the standard inhibitor hydroxyurea, yielding IC(50) values of 41.6, 83.3, 66.6, 50, 58.8, and 60 μM, respectively (IC(50) of hydroxyurea = 100 μM). 5-Benzylidene barbituric acid has enhanced biological activities compared to barbituric acid. Furthermore, the results indicated that among the substituted 5-benzylidene barbiturates, those with para substitution have higher urease inhibitor activities. This may be because the barbituric acid moiety is closer to the bimetallic nickel center in unsubstituted or para-substituted than in ortho- or meta-substituted analogs, so it has greater chelating ability.

  15. Toward the discovery of functional transthyretin amyloid inhibitors: application of virtual screening methods.

    Science.gov (United States)

    Simões, Carlos J V; Mukherjee, Trishna; Brito, Rui M M; Jackson, Richard M

    2010-10-25

    Inhibition of amyloid fibril formation by stabilization of the native form of the protein transthyretin (TTR) is a viable approach for the treatment of familial amyloid polyneuropathy that has been gaining momentum in the field of amyloid research. The TTR stabilizer molecules discovered to date have shown efficacy at inhibiting fibrilization in vitro but display impairing issues of solubility, affinity for TTR in the blood plasma and/or adverse effects. In this study we present a benchmark of four protein- and ligand-based virtual screening (VS) methods for identifying novel TTR stabilizers: (i) two-dimensional (2D) similarity searches with chemical hashed, pharmacophore, and UNITY fingerprints, (ii) 3D searches based on shape, chemical, and electrostatic similarity, (iii) LigMatch, a new ligand-based method which uses multiple templates and combines 3D geometric hashing with a 2D preselection process, and (iv) molecular docking to consensus X-ray crystal structures of TTR. We illustrate the potential of the best-performing VS protocols to retrieve promising new leads by ranking a tailored library of 2.3 million commercially available compounds. Our predictions show that the top-scoring molecules possess distinctive features from the known TTR binders, holding better solubility, fraction of halogen atoms, and binding affinity profiles. To the best of our knowledge, this is the first attempt to rationalize the utilization of a large battery of in silico screening techniques toward the identification of a new generation of TTR amyloid inhibitors.

  16. Discovery of Anti-Hypertensive Oligopeptides from Adlay Based on In Silico Proteolysis and Virtual Screening

    Directory of Open Access Journals (Sweden)

    Liansheng Qiao

    2016-12-01

    Full Text Available Adlay (Coix larchryma-jobi L. was the commonly used Traditional Chinese Medicine (TCM with high content of seed storage protein. The hydrolyzed bioactive oligopeptides of adlay have been proven to be anti-hypertensive effective components. However, the structures and anti-hypertensive mechanism of bioactive oligopeptides from adlay were not clear. To discover the definite anti-hypertensive oligopeptides from adlay, in silico proteolysis and virtual screening were implemented to obtain potential oligopeptides, which were further identified by biochemistry assay and molecular dynamics simulation. In this paper, ten sequences of adlay prolamins were collected and in silico hydrolyzed to construct the oligopeptide library with 134 oligopeptides. This library was reverse screened by anti-hypertensive pharmacophore database, which was constructed by our research team and contained ten anti-hypertensive targets. Angiotensin-I converting enzyme (ACE was identified as the main potential target for the anti-hypertensive activity of adlay oligopeptides. Three crystal structures of ACE were utilized for docking studies and 19 oligopeptides were finally identified with potential ACE inhibitory activity. According to mapping features and evaluation indexes of pharmacophore and docking, three oligopeptides were selected for biochemistry assay. An oligopeptide sequence, NPATY (IC50 = 61.88 ± 2.77 µM, was identified as the ACE inhibitor by reverse-phase high performance liquid chromatography (RP-HPLC assay. Molecular dynamics simulation of NPATY was further utilized to analyze interactive bonds and key residues. ALA354 was identified as a key residue of ACE inhibitors. Hydrophobic effect of VAL518 and electrostatic effects of HIS383, HIS387, HIS513 and Zn2+ were also regarded as playing a key role in inhibiting ACE activities. This study provides a research strategy to explore the pharmacological mechanism of Traditional Chinese Medicine (TCM proteins based on

  17. Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches

    Directory of Open Access Journals (Sweden)

    Pathan AAK

    2016-05-01

    Full Text Available Akbar Ali Khan Pathan,1,2,* Bhavana Panthi,3,* Zahid Khan,1 Purushotham Reddy Koppula,4–6 Mohammed Saud Alanazi,1 Sachchidanand,3 Narasimha Reddy Parine,1 Mukesh Chourasia3,* 1Genome Research Chair (GRC, Department of Biochemistry, College of Science, King Saud University, 2Integrated Gulf Biosystems, Riyadh, Kingdom of Saudi Arabia; 3Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Hajipur, India; 4Department of Internal Medicine, School of Medicine, 5Harry S. Truman Memorial Veterans Affairs Hospital, 6Department of Radiology, School of Medicine, Columbia, MO, USA *These authors contributed equally to this work Objective: Kirsten rat sarcoma (K-Ras protein is a member of Ras family belonging to the small guanosine triphosphatases superfamily. The members of this family share a conserved structure and biochemical properties, acting as binary molecular switches. The guanosine triphosphate-bound active K-Ras interacts with a range of effectors, resulting in the stimulation of downstream signaling pathways regulating cell proliferation, differentiation, and apoptosis. Efforts to target K-Ras have been unsuccessful until now, placing it among high-value molecules against which developing a therapy would have an enormous impact. K-Ras transduces signals when it binds to guanosine triphosphate by directly binding to downstream effector proteins, but in case of guanosine diphosphate-bound conformation, these interactions get disrupted. Methods: In the present study, we targeted the nucleotide-binding site in the “on” and “off” state conformations of the K-Ras protein to find out suitable lead compounds. A structure-based virtual screening approach has been used to screen compounds from different databases, followed by a combinatorial fragment-based approach to design the apposite lead for the K-Ras protein. Results: Interestingly, the designed compounds exhibit a binding preference for the

  18. Can a virtual reality cognitive training application fulfill a dual role? Using the virtual supermarket cognitive training application as a screening tool for mild cognitive impairment.

    Science.gov (United States)

    Zygouris, Stelios; Giakoumis, Dimitrios; Votis, Konstantinos; Doumpoulakis, Stefanos; Ntovas, Konstantinos; Segkouli, Sofia; Karagiannidis, Charalampos; Tzovaras, Dimitrios; Tsolaki, Magda

    2015-01-01

    Recent research advocates the potential of virtual reality (VR) applications in assessing cognitive functions highlighting the possibility of using a VR application for mild cognitive impairment (MCI) screening. The aim of this study is to investigate whether a VR cognitive training application, the virtual supermarket (VSM), can be used as a screening tool for MCI. Two groups, one of healthy older adults (n = 21) and one of MCI patients (n = 34), were recruited from day centers for cognitive disorders and administered the VSM and a neuropsychological test battery. The performance of the two groups in the VSM was compared and correlated with performance in established neuropsychological tests. At the same time, the effectiveness of a combination of traditional neuropsychological tests and the VSM was examined. VSM displayed a correct classification rate (CCR) of 87.30% when differentiating between MCI patients and healthy older adults, while it was unable to differentiate between MCI subtypes. At the same time, the VSM correlates with various established neuropsychological tests. A limited number of tests were able to improve the CCR of the VSM when combined with the VSM for screening purposes. VSM appears to be a valid method of screening for MCI in an older adult population though it cannot be used for MCI subtype assessment. VSM's concurrent validity is supported by the large number of correlations between the VSM and established tests. It is considered a robust test on its own as the inclusion of other tests failed to improve its CCR significantly.

  19. Virtual Screening Techniques to Probe the Antimalarial Activity of some Traditionally Used Phytochemicals.

    Science.gov (United States)

    Shibi, Indira G; Aswathy, Lilly; Jisha, Radhakrishnan S; Masand, Vijay H; Gajbhiye, Jayant M

    2016-01-01

    Malaria parasites show resistance to most of the antimalarial drugs and hence developing antimalarials which can act on multitargets rather than a single target will be a promising strategy of drug design. Here we report a new approach by which virtual screening of 292 unique phytochemicals present in 72 traditionally important herbs is used for finding out inhibitors of plasmepsin-2 and falcipain-2 for antimalarial activity against P. falciparum. Initial screenings of the selected molecules by Random Forest algorithm model of Weka using the bioassay datasets AID 504850 and AID 2302 screened 120 out of the total 292 phytochemicals to be active against the targets. Toxtree scan cautioned 21 compounds to be either carcinogenic or mutagenic and were thus removed for further analysis. Out of the remaining 99 compounds, only 46 compounds offered drug-likeness as per the 'rule of five' criteria. Out of ten antimalarial drug targets, only two target proteins such as 3BPF and 3PNR of falcipain-2 and 1PFZ and 2BJU of plasmepsin-2 are selected as targets. The potential binding of the selected 46 compounds to the active sites of these four targets was analyzed using MOE software. The docked conformations and the interactions with the binding pocket residues of the target proteins were understood by 'Ligplot' analysis. It has been found that 8 compounds are dual inhibitors of falcipain-2 and plasmepsin-2, with the best binding energies. Compound 117 (6aR, 12aS)-12a-Hydroxy-9-methoxy-2,3-dimethylenedioxy-8-prenylrotenone (Usaratenoid C) present in the plant Millettia usaramensis showed maximum molecular docking score.

  20. Targeting the Akt1 allosteric site to identify novel scaffolds through virtual screening.

    Science.gov (United States)

    Yilmaz, Oya Gursoy; Olmez, Elif Ozkirimli; Ulgen, Kutlu O

    2014-02-01

    Preclinical data and tumor specimen studies report that AKT kinases are related to many human cancers. Therefore, identification and development of small molecule inhibitors targeting AKT and its signaling pathway can be therapeutic in treatment of cancer. Numerous studies report inhibitors that target the ATP-binding pocket in the kinase domains, but the similarity of this site, within the kinase family makes selectivity a major problem. The sequence identity amongst PH domains is significantly lower than that in kinase domains and developing more selective inhibitors is possible if PH domain is targeted. This in silico screening study is the first time report toward the identification of potential allosteric inhibitors expected to bind the cavity between kinase and PH domains of Akt1. Structural information of Akt1 was used to develop structure-based pharmacophore models comprising hydrophobic, acceptor, donor and ring features. The 3D structural information of previously identified allosteric Akt inhibitors obtained from literature was employed to develop a ligand-based pharmacophore model. Database was generated with drug like subset of ZINC and screening was performed based on 3D similarity to the selected pharmacophore hypotheses. Binding modes and affinities of the ligands were predicted by Glide software. Top scoring hits were further analyzed considering 2D similarity between the compounds, interactions with Akt1, fitness to pharmacophore models, ADME, druglikeness criteria and Induced-Fit docking. Using virtual screening methodologies, derivatives of 3-methyl-xanthine, quinoline-4-carboxamide and 2-[4-(cyclohexa-1,3-dien-1-yl)-1H-pyrazol-3-yl]phenol were proposed as potential leads for allosteric inhibition of Akt1.

  1. Virtual Screening for Potential Allosteric Inhibitors of Cyclin-Dependent Kinase 2 from Traditional Chinese Medicine

    Directory of Open Access Journals (Sweden)

    Fang Lu

    2016-09-01

    Full Text Available Cyclin-dependent kinase 2 (CDK2, a member of Cyclin-dependent kinases (CDKs, plays an important role in cell division and DNA replication. It is regarded as a desired target to treat cancer and tumor by interrupting aberrant cell proliferation. Compared to lower subtype selectivity of CDK2 ATP-competitive inhibitors, CDK2 allosteric inhibitor with higher subtype selectivity has been used to treat CDK2-related diseases. Recently, the first crystal structure of CDK2 with allosteric inhibitor has been reported, which provides new opportunities to design pure allosteric inhibitors of CDK2. The binding site of the ATP-competition inhibitors and the allosteric inhibitors are partially overlapped in space position, so the same compound might interact with the two binding sites. Thus a novel screening strategy was essential for the discovery of pure CDK2 allosteric inhibitors. In this study, pharmacophore and molecular docking were used to screen potential CDK2 allosteric inhibitors and ATP-competition inhibitors from Traditional Chinese Medicine (TCM. In the docking result of the allosteric site, the compounds which can act with the CDK2 ATP site were discarded, and the remaining compounds were regarded as the potential pure allosteric inhibitors. Among the results, prostaglandin E1 and nordihydroguaiaretic acid (NDGA were available and their growth inhibitory effect on human HepG2 cell lines was determined by MTT assay. The two compounds could substantially inhibit the growth of HepG2 cell lines with an estimated IC50 of 41.223 μmol/L and 45.646 μmol/L. This study provides virtual screening strategy of allosteric compounds and a reliable method to discover potential pure CDK2 allosteric inhibitors from TCM. Prostaglandin E1 and NDGA could be regarded as promising candidates for CDK2 allosteric inhibitors.

  2. iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan.

    Science.gov (United States)

    Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

    2011-06-01

    The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

  3. A New Type of Network Security Protocol Using Hybrid Encryption in Virtual Private Networking

    Directory of Open Access Journals (Sweden)

    E. Ramaraj

    2006-01-01

    Full Text Available Today wireless communications is acting as a major role in networks. Through year-end 2006, the employee's ability to install unmanaged access points will result is more than 50% of enterprises exposing sensitive information through the wireless virtual private networks (VPN. It enables you to send the data between two computers across a shared or public network in a manner that emulates the properties of a private link. The basic requirements for VPN are User Authentication, Address Management, Data Compression, Data Encryption and Key Management. The private links are established in VPN using Point-to-Point Tunneling Protocol (PPTP and Layer-Two-Tunneling Protocol (L2TP. These protocols are satisfies VPN requirements in five layers. In user authentication layer, multiple trusted authorities using Extensible Authentication Protocol (EAP do the authentication process. In fourth layer the data encryption part using RC4 called Microsoft-Point-to-Point Encryption (MPPE method. The aim of this paper, instead of multiple trusted authorities we focus single trusted authority using public key cryptography RSA in EAP and also we include AES-Rijndael stream cipher algorithm instead of RC4 for MPPE. We propose new type of hybrid encryption technique using AES-Rijndael for encryption and decryption and RSA used for key management.

  4. Colon cancer screening

    Science.gov (United States)

    Screening for colon cancer; Colonoscopy - screening; Sigmoidoscopy - screening; Virtual colonoscopy - screening; Fecal immunochemical test; Stool DNA test; sDNA test; Colorectal cancer - screening; Rectal ...

  5. REPROVIS-DB: a benchmark system for ligand-based virtual screening derived from reproducible prospective applications.

    Science.gov (United States)

    Ripphausen, Peter; Wassermann, Anne Mai; Bajorath, Jürgen

    2011-10-24

    Benchmark calculations are essential for the evaluation of virtual screening (VS) methods. Typically, classes of known active compounds taken from the medicinal chemistry literature are divided into reference molecules (search templates) and potential hits that are added to background databases assumed to consist of compounds not sharing this activity. Then VS calculations are carried out, and the recall of known active compounds is determined. However, conventional benchmarking is affected by a number of problems that reduce its value for method evaluation. In addition to often insufficient statistical validation and the lack of generally accepted evaluation standards, the artificial nature of typical benchmark settings is often criticized. Retrospective benchmark calculations generally overestimate the potential of VS methods and do not scale with their performance in prospective applications. In order to provide additional opportunities for benchmarking that more closely resemble practical VS conditions, we have designed a publicly available compound database (DB) of reproducible virtual screens (REPROVIS-DB) that organizes information from successful ligand-based VS applications including reference compounds, screening databases, compound selection criteria, and experimentally confirmed hits. Using the currently available 25 hand-selected compound data sets, one can attempt to reproduce successful virtual screens with other than the originally applied methods and assess their potential for practical applications.

  6. Multiple conformational states in retrospective virtual screening - homology models vs. crystal structures: beta-2 adrenergic receptor case study.

    Science.gov (United States)

    Mordalski, Stefan; Witek, Jagna; Smusz, Sabina; Rataj, Krzysztof; Bojarski, Andrzej J

    2015-01-01

    Distinguishing active from inactive compounds is one of the crucial problems of molecular docking, especially in the context of virtual screening experiments. The randomization of poses and the natural flexibility of the protein make this discrimination even harder. Some of the recent approaches to post-docking analysis use an ensemble of receptor models to mimic this naturally occurring conformational diversity. However, the optimal number of receptor conformations is yet to be determined. In this study, we compare the results of a retrospective screening of beta-2 adrenergic receptor ligands performed on both the ensemble of receptor conformations extracted from ten available crystal structures and an equal number of homology models. Additional analysis was also performed for homology models with up to 20 receptor conformations considered. The docking results were encoded into the Structural Interaction Fingerprints and were automatically analyzed by support vector machine. The use of homology models in such virtual screening application was proved to be superior in comparison to crystal structures. Additionally, increasing the number of receptor conformational states led to enhanced effectiveness of active vs. inactive compounds discrimination. For virtual screening purposes, the use of homology models was found to be most beneficial, even in the presence of crystallographic data regarding the conformational space of the receptor. The results also showed that increasing the number of receptors considered improves the effectiveness of identifying active compounds by machine learning methods. Graphical abstractComparison of machine learning results obtained for various number of beta-2 AR homology models and crystal structures.

  7. Acetylcholinesterase inhibitory activity of scopolin and scopoletin discovered by virtual screening of natural products.

    Science.gov (United States)

    Rollinger, Judith M; Hornick, Ariane; Langer, Thierry; Stuppner, Hermann; Prast, Helmut

    2004-12-02

    For the targeting selection of acetylcholinesterase (AChE) inhibitors from natural sources we generated a structure-based pharmacophore model utilizing an in silico filtering experiment for the discovery of promising candidates out of a 3D multiconformational database consisting of more than 110,000 natural products. In our study, scopoletin (1) and its glucoside scopolin (2) emerged as potential AChE inhibitors by the virtual screening procedure. They were isolated by different chromatographic methods from the medicinal plant Scopolia carniolica Jaqc. and tested in an enzyme assay using Ellman's reagent. They showed moderate, but significant, dose-dependent and long-lasting inhibitory activities. In the in vivo experiments (icv application of 2 micromol) 1 and 2 increased the extracellular acetylcholine (ACh) concentration in rat brain to about 170% and 300% compared to basal release, respectively. At the same concentration, the positive control galanthamine increased the ACh concentration to about the same level as 1. These are the first in vivo results indicating an effect of coumarins on brain ACh.

  8. Combinatorial Pharmacophore-Based 3D-QSAR Analysis and Virtual Screening of FGFR1 Inhibitors

    Directory of Open Access Journals (Sweden)

    Nannan Zhou

    2015-06-01

    Full Text Available The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR signaling pathway plays crucial roles in cell proliferation, angiogenesis, migration, and survival. Aberration in FGFRs correlates with several malignancies and disorders. FGFRs have proved to be attractive targets for therapeutic intervention in cancer, and it is of high interest to find FGFR inhibitors with novel scaffolds. In this study, a combinatorial three-dimensional quantitative structure-activity relationship (3D-QSAR model was developed based on previously reported FGFR1 inhibitors with diverse structural skeletons. This model was evaluated for its prediction performance on a diverse test set containing 232 FGFR inhibitors, and it yielded a SD value of 0.75 pIC50 units from measured inhibition affinities and a Pearson’s correlation coefficient R2 of 0.53. This result suggests that the combinatorial 3D-QSAR model could be used to search for new FGFR1 hit structures and predict their potential activity. To further evaluate the performance of the model, a decoy set validation was used to measure the efficiency of the model by calculating EF (enrichment factor. Based on the combinatorial pharmacophore model, a virtual screening against SPECS database was performed. Nineteen novel active compounds were successfully identified, which provide new chemical starting points for further structural optimization of FGFR1 inhibitors.

  9. A Thoroughly Validated Virtual Screening Strategy for Discovery of Novel HDAC3 Inhibitors

    Science.gov (United States)

    Hu, Huabin; Xia, Jie; Wang, Dongmei; Wang, Xiang Simon; Wu, Song

    2017-01-01

    Histone deacetylase 3 (HDAC3) has been recently identified as a potential target for the treatment of cancer and other diseases, such as chronic inflammation, neurodegenerative diseases, and diabetes. Virtual screening (VS) is currently a routine technique for hit identification, but its success depends on rational development of VS strategies. To facilitate this process, we applied our previously released benchmarking dataset, i.e., MUBD-HDAC3 to the evaluation of structure-based VS (SBVS) and ligand-based VS (LBVS) combinatorial approaches. We have identified FRED (Chemgauss4) docking against a structural model of HDAC3, i.e., SAHA-3 generated by a computationally inexpensive “flexible docking”, as the best SBVS approach and a common feature pharmacophore model, i.e., Hypo1 generated by Catalyst/HipHop as the optimal model for LBVS. We then developed a pipeline that was composed of Hypo1, FRED (Chemgauss4), and SAHA-3 sequentially, and demonstrated that it was superior to other combinations in terms of ligand enrichment. In summary, we present the first highly-validated, rationally-designed VS strategy specific to HDAC3 inhibitor discovery. The constructed pipeline is publicly accessible for the scientific community to identify novel HDAC3 inhibitors in a time-efficient and cost-effective way. PMID:28106794

  10. Homology Model-Based Virtual Screening for the Identification of Human Helicase DDX3 Inhibitors.

    Science.gov (United States)

    Fazi, Roberta; Tintori, Cristina; Brai, Annalaura; Botta, Lorenzo; Selvaraj, Manikandan; Garbelli, Anna; Maga, Giovanni; Botta, Maurizio

    2015-11-23

    Targeting cellular cofactors instead of viral enzymes represents a new strategy to combat infectious diseases, which should help to overcome the problem of viral resistance. Recently, it has been revealed that the cellular ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3) is an essential host factor for the replication of several viruses such as HIV, HCV, JEV, Dengue, and West Nile. Accordingly, a drug targeting DDX3 could theoretically inhibit all viruses that are dependent on this host factor. Herein, for the first time, a model of hDDX3 in its closed conformation, which binds the viral RNA was developed by using the homology module of Prime through the Maestro interface of Schrodinger. Next, a structure-based virtual screening protocol was applied to identify DDX3 small molecule inhibitors targeting the RNA binding pocket. As a result, an impressive hit rate of 40% was obtained with the identification of 10 active compounds out of the 25 tested small molecules. The best poses of the active ligands highlighted the crucial residues to be targeted for the inhibition of the helicase activity of DDX3. The obtained results confirm the reliability of the constructed DDX3/RNA model and the proposed computational strategy for investigating novel DDX3 inhibitors.

  11. Vinardo: A Scoring Function Based on Autodock Vina Improves Scoring, Docking, and Virtual Screening.

    Directory of Open Access Journals (Sweden)

    Rodrigo Quiroga

    Full Text Available Autodock Vina is a very popular, and highly cited, open source docking program. Here we present a scoring function which we call Vinardo (Vina RaDii Optimized. Vinardo is based on Vina, and was trained through a novel approach, on state of the art datasets. We show that the traditional approach to train empirical scoring functions, using linear regression to optimize the correlation of predicted and experimental binding affinities, does not result in a function with optimal docking capabilities. On the other hand, a combination of scoring, minimization, and re-docking on carefully curated training datasets allowed us to develop a simplified scoring function with optimum docking performance. This article provides an overview of the development of the Vinardo scoring function, highlights its differences with Vina, and compares the performance of the two scoring functions in scoring, docking and virtual screening applications. Vinardo outperforms Vina in all tests performed, for all datasets analyzed. The Vinardo scoring function is available as an option within Smina, a fork of Vina, which is freely available under the GNU Public License v2.0 from http://smina.sf.net. Precompiled binaries, source code, documentation and a tutorial for using Smina to run the Vinardo scoring function are available at the same address.

  12. Receptor-Based Virtual Screening of EGFR Kinase Inhibitors from the NCI Diversity Database

    Directory of Open Access Journals (Sweden)

    Kiattawee Choowongkomon

    2010-06-01

    Full Text Available Epidermal growth factor receptor (EGFR abnormalities have been associated with several types of human cancer. The crystal structures of its tyrosine kinase domain (EGFR-TK complexed with small molecule inhibitors revealed the kinase inhibition modes, prompting us to search for novel anti-cancer drugs. A total of 1,990 compounds from the National Cancer Institute (NCI diversity set with nonredundant structures have been tested to inhibit cancer cell lines with unknown mechanism. Cancer inhibition through EGFR-TK is one of the mechanisms of these compounds. In this work, we performed receptor-based virtual screening against the NCI diversity database. Using two different docking algorithms, AutoDock and Gold, combined with subsequent post-docking analyses, we found eight candidate compounds with high scoring functions that all bind to the ATP-competitive site of the kinase. None of these compounds belongs to the main group of the currently known EGFR-TK inhibitors. Binding mode analyses revealed that the way these compounds complexed with EGFR-TK differs from quinazoline inhibitor binding and the interaction mainly involves hydrophobic interactions. Also, the common kinase-inhibitor (NH---N and CO---HC hydrogen bonds between the hinge region and the hit compounds are rarely observed. Our results suggest that these molecules could be developed as novel lead compounds in anti-cancer drug design.

  13. Vinardo: A Scoring Function Based on Autodock Vina Improves Scoring, Docking, and Virtual Screening.

    Science.gov (United States)

    Quiroga, Rodrigo; Villarreal, Marcos A

    2016-01-01

    Autodock Vina is a very popular, and highly cited, open source docking program. Here we present a scoring function which we call Vinardo (Vina RaDii Optimized). Vinardo is based on Vina, and was trained through a novel approach, on state of the art datasets. We show that the traditional approach to train empirical scoring functions, using linear regression to optimize the correlation of predicted and experimental binding affinities, does not result in a function with optimal docking capabilities. On the other hand, a combination of scoring, minimization, and re-docking on carefully curated training datasets allowed us to develop a simplified scoring function with optimum docking performance. This article provides an overview of the development of the Vinardo scoring function, highlights its differences with Vina, and compares the performance of the two scoring functions in scoring, docking and virtual screening applications. Vinardo outperforms Vina in all tests performed, for all datasets analyzed. The Vinardo scoring function is available as an option within Smina, a fork of Vina, which is freely available under the GNU Public License v2.0 from http://smina.sf.net. Precompiled binaries, source code, documentation and a tutorial for using Smina to run the Vinardo scoring function are available at the same address.

  14. Open-source platform to benchmark fingerprints for ligand-based virtual screening.

    Science.gov (United States)

    Riniker, Sereina; Landrum, Gregory A

    2013-05-30

    : Similarity-search methods using molecular fingerprints are an important tool for ligand-based virtual screening. A huge variety of fingerprints exist and their performance, usually assessed in retrospective benchmarking studies using data sets with known actives and known or assumed inactives, depends largely on the validation data sets used and the similarity measure used. Comparing new methods to existing ones in any systematic way is rather difficult due to the lack of standard data sets and evaluation procedures. Here, we present a standard platform for the benchmarking of 2D fingerprints. The open-source platform contains all source code, structural data for the actives and inactives used (drawn from three publicly available collections of data sets), and lists of randomly selected query molecules to be used for statistically valid comparisons of methods. This allows the exact reproduction and comparison of results for future studies. The results for 12 standard fingerprints together with two simple baseline fingerprints assessed by seven evaluation methods are shown together with the correlations between methods. High correlations were found between the 12 fingerprints and a careful statistical analysis showed that only the two baseline fingerprints were different from the others in a statistically significant way. High correlations were also found between six of the seven evaluation methods, indicating that despite their seeming differences, many of these methods are similar to each other.

  15. IVSPlat 1.0: an integrated virtual screening platform with a molecular graphical interface.

    Science.gov (United States)

    Sun, Yin Xue; Huang, Yan Xin; Li, Feng Li; Wang, Hong Yan; Fan, Cong; Bao, Yong Li; Sun, Lu Guo; Ma, Zhi Qiang; Kong, Jun; Li, Yu Xin

    2012-01-05

    The virtual screening (VS) of lead compounds using molecular docking and pharmacophore detection is now an important tool in drug discovery. VS tasks typically require a combination of several software tools and a molecular graphics system. Thus, the integration of all the requisite tools in a single operating environment could reduce the complexity of running VS experiments. However, only a few freely available integrated software platforms have been developed. A free open-source platform, IVSPlat 1.0, was developed in this study for the management and automation of VS tasks. We integrated several VS-related programs into a molecular graphics system to provide a comprehensive platform for the solution of VS tasks based on molecular docking, pharmacophore detection, and a combination of both methods. This tool can be used to visualize intermediate and final results of the VS execution, while also providing a clustering tool for the analysis of VS results. A case study was conducted to demonstrate the applicability of this platform. IVSPlat 1.0 provides a plug-in-based solution for the management, automation, and visualization of VS tasks. IVSPlat 1.0 is an open framework that allows the integration of extra software to extend its functionality and modified versions can be freely distributed. The open source code and documentation are available at http://kyc.nenu.edu.cn/IVSPlat/.

  16. Docking-based virtual screening of potential human P2Y12 receptor antagonists

    Institute of Scientific and Technical Information of China (English)

    Hua Chen; Xianchi Dong; Minyun Zhou; Haiming Shi; Xinping Luo

    2011-01-01

    Platelet plays essential roles in hemostasis and its dysregulation can lead to arterial thrombosis. P2Y12 is an important platelet membrane adenosine diphosphate receptor,and its antagonists have been widely developed as anticoagulation agents. The current P2Y12 inhibitors available in clinical practice have not fully achieved saOsfactory antithrombotic effects, leaving room for further improvement To identify new chemical compounds as potential anticoagulation inhibitors, we constructed a three-dimensional structure model of human P2Y12 by homology modeling based on the recently reported G-protein coupled receptor Meleagris gallopavo βl adrenergic receptor. Virtual screening of the modeled P2Y12 against three subsets of small molecules from the ZINC database, namely lead-like, fragment-like, and drug-like, identified a number of compounds tbat might have high binding affinity to P2Y12.Detailed analyses of the top three compounds from each subset with the highest scores indicated that all of these compounds beard a hydrophobic bulk supplemented with a few polar atoms which bound at the ligand binding site via largely hydrophobic interactions with the receptor. This study not only provides a structure model of P2Y12 for rational design of anti-platelet inhibitors, but also identifies some potential chemicals for further development.

  17. Structure-based virtual screening for the discovery of natural inhibitors for human rhinovirus coat protein.

    Science.gov (United States)

    Rollinger, Judith M; Steindl, Theodora M; Schuster, Daniela; Kirchmair, Johannes; Anrain, Kathrin; Ellmerer, Ernst P; Langer, Thierry; Stuppner, Hermann; Wutzler, Peter; Schmidtke, Michaela

    2008-02-28

    Inhibitors of the human rhinovirus (HRV) coat protein are promising candidates to treat and prevent a number of upper respiratory diseases. The aim of this study was to find antiviral compounds from nature, focusing on the HRV coat protein. Through computational structure-based screening of an in-house 3D database containing 9676 individual plant metabolites from ancient herbal medicines, combined with knowledge from traditional use, we selected sesquiterpene coumarins from the gum resin asafetida as promising natural products. Chromatographic separation steps resulted in the isolation of microlobidene (1), farnesiferol C (2), farnesiferol B (3), and kellerin (4). Determination of the inhibition of the HRV-induced cytopathic effect for serotypes 1A, 2, 14, and 16 revealed a dose-dependent and selective antirhinoviral activity against serotype 2 for asafetida (IC50 = 11.0 microg/mL) and its virtually predicted constituents 2 (IC50 = 2.5 microM) and 3 (IC50 = 2.6 microM). Modeling studies helped to rationalize the retrieved results.

  18. A Thoroughly Validated Virtual Screening Strategy for Discovery of Novel HDAC3 Inhibitors

    Directory of Open Access Journals (Sweden)

    Huabin Hu

    2017-01-01

    Full Text Available Histone deacetylase 3 (HDAC3 has been recently identified as a potential target for the treatment of cancer and other diseases, such as chronic inflammation, neurodegenerative diseases, and diabetes. Virtual screening (VS is currently a routine technique for hit identification, but its success depends on rational development of VS strategies. To facilitate this process, we applied our previously released benchmarking dataset, i.e., MUBD-HDAC3 to the evaluation of structure-based VS (SBVS and ligand-based VS (LBVS combinatorial approaches. We have identified FRED (Chemgauss4 docking against a structural model of HDAC3, i.e., SAHA-3 generated by a computationally inexpensive “flexible docking”, as the best SBVS approach and a common feature pharmacophore model, i.e., Hypo1 generated by Catalyst/HipHop as the optimal model for LBVS. We then developed a pipeline that was composed of Hypo1, FRED (Chemgauss4, and SAHA-3 sequentially, and demonstrated that it was superior to other combinations in terms of ligand enrichment. In summary, we present the first highly-validated, rationally-designed VS strategy specific to HDAC3 inhibitor discovery. The constructed pipeline is publicly accessible for the scientific community to identify novel HDAC3 inhibitors in a time-efficient and cost-effective way.

  19. Combined Ligand/Structure-Based Virtual Screening and Molecular Dynamics Simulations of Steroidal Androgen Receptor Antagonists.

    Science.gov (United States)

    Wang, Yuwei; Han, Rui; Zhang, Huimin; Liu, Hongli; Li, Jiazhong; Liu, Huanxiang; Gramatica, Paola

    2017-01-01

    The antiandrogens, such as bicalutamide, targeting the androgen receptor (AR), are the main endocrine therapies for prostate cancer (PCa). But as drug resistance to antiandrogens emerges in advanced PCa, there presents a high medical need for exploitation of novel AR antagonists. In this work, the relationships between the molecular structures and antiandrogenic activities of a series of 7α-substituted dihydrotestosterone derivatives were investigated. The proposed MLR model obtained high predictive ability. The thoroughly validated QSAR model was used to virtually screen new dihydrotestosterones derivatives taken from PubChem, resulting in the finding of novel compounds CID_70128824, CID_70127147, and CID_70126881, whose in silico bioactivities are much higher than the published best one, even higher than bicalutamide. In addition, molecular docking, molecular dynamics (MD) simulations, and MM/GBSA have been employed to analyze and compare the binding modes between the novel compounds and AR. Through the analysis of the binding free energy and residue energy decomposition, we concluded that the newly discovered chemicals can in silico bind to AR with similar position and mechanism to the reported active compound and the van der Waals interaction is the main driving force during the binding process.

  20. Combined Ligand/Structure-Based Virtual Screening and Molecular Dynamics Simulations of Steroidal Androgen Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Yuwei Wang

    2017-01-01

    Full Text Available The antiandrogens, such as bicalutamide, targeting the androgen receptor (AR, are the main endocrine therapies for prostate cancer (PCa. But as drug resistance to antiandrogens emerges in advanced PCa, there presents a high medical need for exploitation of novel AR antagonists. In this work, the relationships between the molecular structures and antiandrogenic activities of a series of 7α-substituted dihydrotestosterone derivatives were investigated. The proposed MLR model obtained high predictive ability. The thoroughly validated QSAR model was used to virtually screen new dihydrotestosterones derivatives taken from PubChem, resulting in the finding of novel compounds CID_70128824, CID_70127147, and CID_70126881, whose in silico bioactivities are much higher than the published best one, even higher than bicalutamide. In addition, molecular docking, molecular dynamics (MD simulations, and MM/GBSA have been employed to analyze and compare the binding modes between the novel compounds and AR. Through the analysis of the binding free energy and residue energy decomposition, we concluded that the newly discovered chemicals can in silico bind to AR with similar position and mechanism to the reported active compound and the van der Waals interaction is the main driving force during the binding process.

  1. Virtual Screening of compounds from Tabernaemontana divaricata for potential anti-bacterial activity

    Science.gov (United States)

    Gogoi, Rashmi Rekha; Gogoi, Dhrubajyoti; Bezbaruah, Rajib Lochan

    2014-01-01

    Virtual Screening and Molecular Docking analysis for Tabernaemontana divaricata derived 66 Law Molecular Weight Compounds (LMW) was conducted and to identified and predicted novel molecules as a inhibitor of Streptococcus pneumonia. The investigation has revealed several compounds with optimum binding towards Penicillin-binding proteins, Sialidases, Aspartate betasemialdehide dehydrogenase cell membrane protein of Streptococcus pneumonia. Docking results were computed in term of binding energy, ligand efficiency and number of hydrogen bonding. Apparicine (-5.14), 5-Hydroxyvoaphylline (-4.78), Voacangine (-4.7), 19-Hydroxycoronaridine (-4.44) and Coronaridine (-4.72) are identified as most suitable to bind with N-acetylglucosamine-1- phosphate uridyltransferase receptor. Ervaticine (-6.33), Ibogamine (-6.15), Methylvoaphylline (-5.74) and Coronaridine hydroxyindolenine (-5.32) has showed novel binding against the penicillin-binding proteins. Ervaticine (-6.42), 5-oxo-11-hydroxy voaphylline (-6.18), Conolobine B (-6.02) has found optimum binding against the active site of NanB sialidase of Streptococcus pneumonia. The compounds 3S-Cyanocoronaridine (-6.71), 19-Epivoacristine (-5.48) and Ervaticine(-5.45) interacting with aspartate beta-semialdehide and found suitable with least docking score. PMID:24748755

  2. Screening methods for linear-scaling short-range hybrid calculations on CPU and GPU architectures

    Science.gov (United States)

    Beuerle, Matthias; Kussmann, Jörg; Ochsenfeld, Christian

    2017-04-01

    We present screening schemes that allow for efficient, linear-scaling short-range exchange calculations employing Gaussian basis sets for both CPU and GPU architectures. They are based on the LinK [C. Ochsenfeld et al., J. Chem. Phys. 109, 1663 (1998)] and PreLinK [J. Kussmann and C. Ochsenfeld, J. Chem. Phys. 138, 134114 (2013)] methods, but account for the decay introduced by the attenuated Coulomb operator in short-range hybrid density functionals. Furthermore, we discuss the implementation of short-range electron repulsion integrals on GPUs. The introduction of our screening methods allows for speedups of up to a factor 7.8 as compared to the underlying linear-scaling algorithm, while retaining full numerical control over the accuracy. With the increasing number of short-range hybrid functionals, our new schemes will allow for significant computational savings on CPU and GPU architectures.

  3. Ligand-based virtual screening and inductive learning for identification of SIRT1 inhibitors in natural products

    Science.gov (United States)

    Sun, Yunan; Zhou, Hui; Zhu, Hongmei; Leung, Siu-Wai

    2016-01-01

    Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase, and its dysregulation can lead to ageing, diabetes, and cancer. From 346 experimentally confirmed SIRT1 inhibitors, an inhibitor structure pattern was generated by inductive logic programming (ILP) with DMax Chemistry Assistant software. The pattern contained amide, amine, and hetero-aromatic five-membered rings, each of which had a hetero-atom and an unsubstituted atom at a distance of 2. According to this pattern, a ligand-based virtual screening of 1 444 880 active compounds from Chinese herbs identified 12 compounds as inhibitors of SIRT1. Three compounds (ZINC08790006, ZINC08792229, and ZINC08792355) had high affinity (-7.3, -7.8, and -8.6 kcal/mol, respectively) for SIRT1 as estimated by molecular docking software AutoDock Vina. This study demonstrated a use of ILP and background knowledge in machine learning to facilitate virtual screening.

  4. Optimizing a Hybrid Energy Storage System for a Virtual Power Plant for Improved Wind Power Generation: A Case Study for Denmark

    DEFF Research Database (Denmark)

    Braun, Philipp; Swierczynski, Maciej Jozef; Diosi, Robert

    2011-01-01

    This paper describes one approach to find two optimum energy storages (ESs) to build a hybrid system which is part of a virtual power plant. Here it means the combination of the hybrid energy storage system and wind power plant (WPP). The discussed approach is applied in a case study on the power...

  5. Inhibitors of Helicobacter pylori Protease HtrA Found by ‘Virtual Ligand’ Screening Combat Bacterial Invasion of Epithelia

    OpenAIRE

    Martin Löwer; Tim Geppert; Petra Schneider; Benjamin Hoy; Silja Wessler; Gisbert Schneider

    2011-01-01

    BACKGROUND: The human pathogen Helicobacter pylori (H. pylori) is a main cause for gastric inflammation and cancer. Increasing bacterial resistance against antibiotics demands for innovative strategies for therapeutic intervention. METHODOLOGY/PRINCIPAL FINDINGS: We present a method for structure-based virtual screening that is based on the comprehensive prediction of ligand binding sites on a protein model and automated construction of a ligand-receptor interaction map. Pharmacophoric featur...

  6. Health benefits and cost-effectiveness of a hybrid screening strategy for colorectal cancer.

    Science.gov (United States)

    Dinh, Tuan; Ladabaum, Uri; Alperin, Peter; Caldwell, Cindy; Smith, Robert; Levin, Theodore R

    2013-09-01

    Colorectal cancer (CRC) screening guidelines recommend screening schedules for each single type of test except for concurrent sigmoidoscopy and fecal occult blood test (FOBT). We investigated the cost-effectiveness of a hybrid screening strategy that was based on a fecal immunological test (FIT) and colonoscopy. We conducted a cost-effectiveness analysis by using the Archimedes Model to evaluate the effects of different CRC screening strategies on health outcomes and costs related to CRC in a population that represents members of Kaiser Permanente Northern California. The Archimedes Model is a large-scale simulation of human physiology, diseases, interventions, and health care systems. The CRC submodel in the Archimedes Model was derived from public databases, published epidemiologic studies, and clinical trials. A hybrid screening strategy led to substantial reductions in CRC incidence and mortality, gains in quality-adjusted life years (QALYs), and reductions in costs, comparable with those of the best single-test strategies. Screening by annual FIT of patients 50-65 years old and then a single colonoscopy when they were 66 years old (FIT/COLOx1) reduced CRC incidence by 72% and gained 110 QALYs for every 1000 people during a period of 30 years, compared with no screening. Compared with annual FIT, FIT/COLOx1 gained 1400 QALYs/100,000 persons at an incremental cost of $9700/QALY gained and required 55% fewer FITs. Compared with FIT/COLOx1, colonoscopy at 10-year intervals gained 500 QALYs/100,000 at an incremental cost of $35,100/QALY gained but required 37% more colonoscopies. Over the ranges of parameters examined, the cost-effectiveness of hybrid screening strategies was slightly more sensitive to the adherence rate with colonoscopy than the adherence rate with yearly FIT. Uncertainties associated with estimates of FIT performance within a program setting and sensitivities for flat and right-sided lesions are expected to have significant impacts on the cost

  7. Calculating an optimal box size for ligand docking and virtual screening against experimental and predicted binding pockets.

    Science.gov (United States)

    Feinstein, Wei P; Brylinski, Michal

    2015-01-01

    Computational approaches have emerged as an instrumental methodology in modern research. For example, virtual screening by molecular docking is routinely used in computer-aided drug discovery. One of the critical parameters for ligand docking is the size of a search space used to identify low-energy binding poses of drug candidates. Currently available docking packages often come with a default protocol for calculating the box size, however, many of these procedures have not been systematically evaluated. In this study, we investigate how the docking accuracy of AutoDock Vina is affected by the selection of a search space. We propose a new procedure for calculating the optimal docking box size that maximizes the accuracy of binding pose prediction against a non-redundant and representative dataset of 3,659 protein-ligand complexes selected from the Protein Data Bank. Subsequently, we use the Directory of Useful Decoys, Enhanced to demonstrate that the optimized docking box size also yields an improved ranking in virtual screening. Binding pockets in both datasets are derived from the experimental complex structures and, additionally, predicted by eFindSite. A systematic analysis of ligand binding poses generated by AutoDock Vina shows that the highest accuracy is achieved when the dimensions of the search space are 2.9 times larger than the radius of gyration of a docking compound. Subsequent virtual screening benchmarks demonstrate that this optimized docking box size also improves compound ranking. For instance, using predicted ligand binding sites, the average enrichment factor calculated for the top 1 % (10 %) of the screening library is 8.20 (3.28) for the optimized protocol, compared to 7.67 (3.19) for the default procedure. Depending on the evaluation metric, the optimal docking box size gives better ranking in virtual screening for about two-thirds of target proteins. This fully automated procedure can be used to optimize docking protocols in order to

  8. Virtual screening for potential inhibitors of Mcl-1 conformations sampled by normal modes, molecular dynamics, and nuclear magnetic resonance

    Directory of Open Access Journals (Sweden)

    Glantz-Gashai Y

    2017-06-01

    Full Text Available Yitav Glantz-Gashai,* Tomer Meirson,* Eli Reuveni, Abraham O Samson Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel *These authors contributed equally to this work Abstract: Myeloid cell leukemia-1 (Mcl-1 is often overexpressed in human cancer and is an important target for developing antineoplastic drugs. In this study, a data set containing 2.3 million lead-like molecules and a data set of all the US Food and Drug Administration (FDA-approved drugs are virtually screened for potential Mcl-1 ligands using Protein Data Bank (PDB ID 2MHS. The potential Mcl-1 ligands are evaluated and computationally docked on to three conformation ensembles generated by normal mode analysis (NMA, molecular dynamics (MD, and nuclear magnetic resonance (NMR, respectively. The evaluated potential Mcl-1 ligands are then compared with their clinical use. Remarkably, half of the top 30 potential drugs are used clinically to treat cancer, thus partially validating our virtual screen. The partial validation also favors the idea that the other half of the top 30 potential drugs could be used in the treatment of cancer. The normal mode-, MD-, and NMR-based conformation greatly expand the conformational sampling used herein for in silico identification of potential Mcl-1 inhibitors. Keywords: virtual screening, Mcl-1, molecular dynamics, NMR, normal modes

  9. Virtual screening-based discovery and mechanistic characterization of the acylthiourea MRT-10 family as smoothened antagonists.

    Science.gov (United States)

    Manetti, Fabrizio; Faure, Helene; Roudaut, Hermine; Gorojankina, Tatiana; Traiffort, Elisabeth; Schoenfelder, Angele; Mann, Andre; Solinas, Antonio; Taddei, Maurizio; Ruat, Martial

    2010-10-01

    The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental data, we generated and validated a pharmacophoric model for Smo inhibitors constituted by three hydrogen bond acceptor groups and three hydrophobic regions. We used this model for the virtual screening of a library of commercially available compounds. Visual and structural criteria allowed the selection of 20 top scoring ligands, and an acylthiourea, N-(3-benzamidophenylcarbamothioyl)-3,4,5-trimethoxybenzamide (MRT-10), was identified and characterized as a Smo antagonist. The corresponding acylurea, N-(3-benzamidophenylcarbamoyl)-3,4,5-trimethoxybenzamide (MRT-14), was synthesized and shown to display, in various Hh assays, an inhibitory potency comparable to or greater than that of reference Smo antagonists cyclopamine and N-((3S,5S)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)-N-(3-methoxybenzyl)-3,3-dimethylbutanamide (Cur61414). Focused virtual screening of the same library further identified five additional related antagonists. MRT-10 and MRT-14 constitute the first members of novel families of Smo antagonists. The described virtual screening approach is aimed at identifying novel modulators of Smo and of other G-protein coupled receptors.

  10. Virtual Screening and Pharmacophore Design for a Novel Theoretical Inhibitor of Macrophage Stimulating Factor as a Metastatic Agent

    Directory of Open Access Journals (Sweden)

    Ibrahim Torktaz

    2013-09-01

    Full Text Available Introduction: Metastasis is a crucial aspect of cancer. Macrophage stimulating protein (MSP is a single chain protein and can be cleaved by serum proteases. MSP has several roles in metastasis. In this in silico study, MSP as a metastatic agent was considered as a drug target. Methods: Crystallographic structure of MSP was retrieved from protein data bank. To find a chemical inhibitor of MSP, a library of KEGG compounds was screened and 1000 shape complemented ligands were retrieved with FindSite algorithm. Molegro Virtual Docker (MVD software was used for docking simulation of shape complemented ligands against MSP. Moldock score was used as scoring function for virtual screening and potential inhibitors with more negative binding energy were obtained. PLANS scoring function was used for revaluation of virtual screening data. Results: The top found chemical had binding affinity of -183.55 based on MolDock score and equal to -66.733 PLANTs score to MSP structure. Conclusion: Based on pharmacophore model of potential inhibitor, this study suggests that the chemical which was found in this research and its derivate can be used for subsequent laboratory studies.

  11. Novel Scaffold Identification of mGlu1 Receptor Negative Allosteric Modulators Using a Hierarchical Virtual Screening Approach.

    Science.gov (United States)

    Jang, Jae Wan; Cho, Nam-Chul; Min, Sun-Joon; Cho, Yong Seo; Park, Ki Duk; Seo, Seon Hee; No, Kyoung Tai; Pae, Ae Nim

    2016-02-01

    Metabotropic glutamate receptor 1 (mGluR1) is considered as an attractive drug target for neuropathic pain treatments. The hierarchical virtual screening approach for identifying novel scaffolds of mGluR1 allosteric modulators was performed using a homology model built with the dopamine D3 crystal structure as template. The mGluR1 mutagenesis data, conserved amino acid sequences across class A and class C GPCRs, and previously reported multiple sequence alignments of class C GPCRs to the rhodopsin template, were employed for the sequence alignment to overcome difficulties of model generation with low sequence identity of mGluR1 and dopamine D3. The structures refined by molecular dynamics simulations were employed for docking of Asinex commercial libraries after hierarchical virtual screening with pharmacophore and naïve Bayesian models. Five of 35 compounds experimentally evaluated using a calcium mobilization assay exhibited micromolar activities (IC50) with chemotype novelty that demonstrated the validity of our methods. A hierarchical structure and ligand-based virtual screening approach with homology model of class C GPCR based on dopamine D3 class A GPCR structure was successfully performed and applied to discover novel negative mGluR1 allosteric modulators.

  12. Free Energy-Based Virtual Screening and Optimization of RNase H Inhibitors of HIV-1 Reverse Transcriptase

    Science.gov (United States)

    2016-01-01

    We report the results of a binding free energy-based virtual screening campaign of a library of 77 α-hydroxytropolone derivatives against the challenging RNase H active site of the reverse transcriptase (RT) enzyme of human immunodeficiency virus-1. Multiple protonation states, rotamer states, and binding modalities of each compound were individually evaluated. The work involved more than 300 individual absolute alchemical binding free energy parallel molecular dynamics calculations and over 1 million CPU hours on national computing clusters and a local campus computational grid. The thermodynamic and structural measures obtained in this work rationalize a series of characteristics of this system useful for guiding future synthetic and biochemical efforts. The free energy model identified key ligand-dependent entropic and conformational reorganization processes difficult to capture using standard docking and scoring approaches. Binding free energy-based optimization of the lead compounds emerging from the virtual screen has yielded four compounds with very favorable binding properties, which will be the subject of further experimental investigations. This work is one of the few reported applications of advanced-binding free energy models to large-scale virtual screening and optimization projects. It further demonstrates that, with suitable algorithms and automation, advanced-binding free energy models can have a useful role in early-stage drug-discovery programs. PMID:27713931

  13. Identification of PPARgamma partial agonists of natural origin (I: development of a virtual screening procedure and in vitro validation.

    Directory of Open Access Journals (Sweden)

    Laura Guasch

    Full Text Available BACKGROUND: Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural products. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPARγ partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPARγ partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPARγ partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPARγ partial agonists: they bind to PPARγ, do not or only moderately stimulate the transactivation activity of PPARγ, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPARγ partial agonists.

  14. New molecular scaffolds for the design of Mycobacterium tuberculosis type II dehydroquinase inhibitors identified using ligand and receptor based virtual screening.

    Science.gov (United States)

    Kumar, Ashutosh; Siddiqi, Mohammad Imran; Miertus, Stanislav

    2010-04-01

    Using ligand and receptor based virtual screening approaches we have identified potential virtual screening hits targeting type II dehydroquinase from Mycobacterium tuberculosis, an effective and validated anti-mycobacterial target. Initially, we applied a virtual screening workflow based on a combination of 2D structural fingerprints, 3D pharmacophore and molecular docking to identify compounds that rigidly match specific aspects of ligand bioactive conformation. Subsequently, the resulting compounds were ranked and prioritized using receptor interaction fingerprint based scoring and quantitative structure activity relationship model developed using already known actives. The virtual screening hits prioritized belong to several classes of molecular scaffolds with several available substitution positions that could allow chemical modification to enhance binding affinity. Finally, identified hits may be useful to a medicinal chemist or combinatorial chemist to pick up the new molecular starting points for medicinal chemistry optimization for the design of novel type II dehydroquinase inhibitors.

  15. Virtual screening of mandelate racemase mutants with enhanced activity based on binding energy in the transition state.

    Science.gov (United States)

    Gu, Jiali; Liu, Min; Guo, Fei; Xie, Wenping; Lu, Wenqiang; Ye, Lidan; Chen, Zhirong; Yuan, Shenfeng; Yu, Hongwei

    2014-02-05

    Mandelate racemase (MR) is a promising candidate for the dynamic kinetic resolution of racemates. However, the poor activity of MR towards most of its non-natural substrates limits its widespread application. In this work, a virtual screening method based on the binding energy in the transition state was established to assist in the screening of MR mutants with enhanced catalytic efficiency. Using R-3-chloromandelic acid as a model substrate, a total of 53 mutants were constructed based on rational design in the two rounds of screening. The number of mutants for experimental validation was brought down to 17 by the virtual screening method, among which 14 variants turned out to possess improved catalytic efficiency. The variant V26I/Y54V showed 5.2-fold higher catalytic efficiency (k(cat)/K(m)) towards R-3-chloromandelic acid than that observed for the wild-type enzyme. Using this strategy, mutants were successfully obtained for two other substrates, R-mandelamide and R-2-naphthylglycolate (V26I and V29L, respectively), both with a 2-fold improvement in catalytic efficiency. These results demonstrated that this method could effectively predict the trend of mutational effects on catalysis. Analysis from the energetic and structural assays indicated that the enhanced interactions between the active sites and the substrate in the transition state led to improved catalytic efficiency. It was concluded that this virtual screening method based on the binding energy in the transition state was beneficial in enzyme rational redesign and helped to better understand the catalytic properties of the enzyme.

  16. Field Emission Properties of the Graphene Double-Walled Carbon Nanotube Hybrid Films Prepared by Vacuum Filtration and Screen Printing

    OpenAIRE

    Jinzhuo Xu; Tao Feng; Yiwei Chen; Zhuo Sun

    2013-01-01

    The graphene double-walled carbon nanotube (DWCNT) hybrid films were prepared by vacuum filtration and screen printing. Their electron field emission properties have been studied systematically. The electron emission properties of the hybrid films are much better than those of pure DWCNT films and pure graphene films. Comparing with the screen printed films, the vacuum filtered films have many advantages, such as lower turn-on field, higher emission current density, better uniformity, better ...

  17. The screening effects of the screened exchange hybrid functional in surface systems: A case study on the CO/Pt(111) problem

    Science.gov (United States)

    Li, H.; Gillen, R.; Robertson, J.

    2016-06-01

    The screened exchange (sX) hybrid functional has been widely used in computational material science. Although it has widely been studied in bulk systems, less is known about its functional behavior in surface systems which are crucial to many technologies such as materials synthesis and nano-electronic devices. Assessing the screening dependent functional behaviors in the surface systems is therefore important for its application in such systems. In this work, we investigate the screening effects of the sX in CO adsorption on Pt(111) surface. The differences between the sX and Heyd-Scuseria-Ernzerhof (HSE06) hybrid functionals, and the effects of screening parameters are studied. The screening has two effects: first, the HOMO-LUMO gap is screening dependent. This affects the site preference most significantly. In this work, atop adsorption of CO/Pt(111) is predicted by the hybrid functionals with screened exchange potential. The sX(1.44) gives the largest HOMO-LUMO gap for the isolated CO molecule. The adsorption energy difference between the atop and fcc site is also the largest by the sX(1.44) which is explained by the reduced metal d states to the CO 2π* state back-donation, with stronger effect for the fcc adsorption than for the atop adsorption; second, the adsorption energy is screening dependent. This can be seen by comparing the sX(2.38) and HSE06 which have different screening strengths. They show similar surface band structures for the CO adsorption but different adsorption energies, which is explained by the stronger CO 5σ state to the metal d states donation or the effectively screened Pauli repulsion. This work underlines the screening strength as a main difference between sX and HSE06, as well as an important hybrid functional parameter for surface calculation.

  18. A pre-breeding screening program for transgenic boars based on fluorescence in situ hybridization assay.

    Science.gov (United States)

    Bou, Gerelchimeg; Sun, Mingju; Lv, Ming; Zhu, Jiang; Li, Hui; Wang, Juan; Li, Lu; Liu, Zhongfeng; Zheng, Zhong; He, Wenteng; Kong, Qingran; Liu, Zhonghua

    2014-08-01

    For efficient transgenic herd expansion, only the transgenic animals that possess the ability to transmit transgene into next generation are considered for breeding. However, for transgenic pig, practically lacking a pre-breeding screening program, time, labor and money is always wasted to maintain non-transgenic pigs, low or null transgenic transmission pigs and the related fruitless gestations. Developing a pre-breeding screening program would make the transgenic herd expansion more economical and efficient. In this technical report, we proposed a three-step pre-breeding screening program for transgenic boars simply through combining the fluorescence in situ hybridization (FISH) assay with the common pre-breeding screening workflow. In the first step of screening, combined with general transgenic phenotype analysis, FISH is used to identify transgenic boars. In the second step of screening, combined with conventional semen test, FISH is used to detect transgenic sperm, thus to identify the individuals producing high quality semen and transgenic sperm. In the third step of screening, FISH is used to assess the in vitro fertilization embryos, thus finally to identify the individuals with the ability to produce transgenic embryos. By this three-step screening, the non-transgenic boars and boars with no ability to produce transgenic sperm or transgenic embryos would be eliminated; therefore only those boars could produce transgenic offspring are maintained and used for breeding and herd expansion. It is the first time a systematic pre-breeding screening program is proposed for transgenic pigs. This program might also be applied in other transgenic large animals, and provide an economical and efficient strategy for herd expansion.

  19. Ecological validity of virtual reality daily living activities screening for early dementia: longitudinal study.

    Science.gov (United States)

    Tarnanas, Ioannis; Schlee, Winfried; Tsolaki, Magda; Müri, René; Mosimann, Urs; Nef, Tobias

    2013-08-06

    Dementia is a multifaceted disorder that impairs cognitive functions, such as memory, language, and executive functions necessary to plan, organize, and prioritize tasks required for goal-directed behaviors. In most cases, individuals with dementia experience difficulties interacting with physical and social environments. The purpose of this study was to establish ecological validity and initial construct validity of a fire evacuation Virtual Reality Day-Out Task (VR-DOT) environment based on performance profiles as a screening tool for early dementia. The objectives were (1) to examine the relationships among the performances of 3 groups of participants in the VR-DOT and traditional neuropsychological tests employed to assess executive functions, and (2) to compare the performance of participants with mild Alzheimer's-type dementia (AD) to those with amnestic single-domain mild cognitive impairment (MCI) and healthy controls in the VR-DOT and traditional neuropsychological tests used to assess executive functions. We hypothesized that the 2 cognitively impaired groups would have distinct performance profiles and show significantly impaired independent functioning in ADL compared to the healthy controls. The study population included 3 groups: 72 healthy control elderly participants, 65 amnestic MCI participants, and 68 mild AD participants. A natural user interface framework based on a fire evacuation VR-DOT environment was used for assessing physical and cognitive abilities of seniors over 3 years. VR-DOT focuses on the subtle errors and patterns in performing everyday activities and has the advantage of not depending on a subjective rating of an individual person. We further assessed functional capacity by both neuropsychological tests (including measures of attention, memory, working memory, executive functions, language, and depression). We also evaluated performance in finger tapping, grip strength, stride length, gait speed, and chair stands separately and

  20. Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening.

    Science.gov (United States)

    Ung, Peter Man-Un; Song, Wenxin; Cheng, Lili; Zhao, Xinbin; Hu, Hailin; Chen, Ligong; Schlessinger, Avner

    2016-07-15

    The human Glucose Transporter 1 (hGLUT1 or SLC2A1) is a facilitative membrane transporter found in the liver, intestines, kidney, and brain, where it transports sugars such as d-glucose and d-galactose. Genetic variations in hGLUT1 are associated with a broad range of diseases and metabolic disorders. For example, hGLUT1 is upregulated in various cancer types (e.g., breast carcinoma) to support the increased anaerobic glycolysis and the Warburg effect. Thus, hGLUT1 is an emerging therapeutic target, which also transports commonly used cancer biomarkers (e.g., (18)F-DG). In this study, we use computational prediction followed by experimental testing, to characterize hGLUT1. We construct homology models of hGLUT1 in a partially occluded outward open ("occluded") conformation based on the X-ray structure of the E. coli xylose transporter, XylE. Comparison of the binding site of the occluded models to experimentally determined hGLUT structures revealed a hydrophobic pocket adjacent to the sugar-binding site, which was tested experimentally via site-directed mutagenesis. Virtual screening of various libraries of purchasable compounds against the occluded models, followed by experimental testing with cellular assays revealed seven previously unknown hGLUT1 ligands with IC50 values ranging from 0.45 μM to 59 μM. These ligands represent three unique chemotypes that are chemically different from any other known hGLUT1 ligands. The newly characterized hydrophobic pocket can potentially be utilized by the new ligands for increased affinity. Furthermore, the previously unknown hGLUT1 ligands can serve as chemical tools to further characterize hGLUT1 function or lead molecules for future drug development.

  1. Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets

    Directory of Open Access Journals (Sweden)

    Renata Rachide Nunes

    Full Text Available The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001 against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol. The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2 and a human cell line (WI-26VA4. Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM and inactive against WI-26VA4 (IC50 > 200 µM. Further ligand optimisation cycles generated new prospects for docking and biological assays.

  2. Virtual Screening of Peptide and Peptidomimetic Fragments Targeted to Inhibit Bacterial Dithiol Oxidase DsbA.

    Directory of Open Access Journals (Sweden)

    Wilko Duprez

    Full Text Available Antibacterial drugs with novel scaffolds and new mechanisms of action are desperately needed to address the growing problem of antibiotic resistance. The periplasmic oxidative folding system in Gram-negative bacteria represents a possible target for anti-virulence antibacterials. By targeting virulence rather than viability, development of resistance and side effects (through killing host native microbiota might be minimized. Here, we undertook the design of peptidomimetic inhibitors targeting the interaction between the two key enzymes of oxidative folding, DsbA and DsbB, with the ultimate goal of preventing virulence factor assembly. Structures of DsbB--or peptides--complexed with DsbA revealed key interactions with the DsbA active site cysteine, and with a hydrophobic groove adjacent to the active site. The present work aimed to discover peptidomimetics that target the hydrophobic groove to generate non-covalent DsbA inhibitors. The previously reported structure of a Proteus mirabilis DsbA active site cysteine mutant, in a non-covalent complex with the heptapeptide PWATCDS, was used as an in silico template for virtual screening of a peptidomimetic fragment library. The highest scoring fragment compound and nine derivatives were synthesized and evaluated for DsbA binding and inhibition. These experiments discovered peptidomimetic fragments with inhibitory activity at millimolar concentrations. Although only weakly potent relative to larger covalent peptide inhibitors that interact through the active site cysteine, these fragments offer new opportunities as templates to build non-covalent inhibitors. The results suggest that non-covalent peptidomimetics may need to interact with sites beyond the hydrophobic groove in order to produce potent DsbA inhibitors.

  3. DockoMatic 2.0: high throughput inverse virtual screening and homology modeling.

    Science.gov (United States)

    Bullock, Casey; Cornia, Nic; Jacob, Reed; Remm, Andrew; Peavey, Thomas; Weekes, Ken; Mallory, Chris; Oxford, Julia T; McDougal, Owen M; Andersen, Timothy L

    2013-08-26

    DockoMatic is a free and open source application that unifies a suite of software programs within a user-friendly graphical user interface (GUI) to facilitate molecular docking experiments. Here we describe the release of DockoMatic 2.0; significant software advances include the ability to (1) conduct high throughput inverse virtual screening (IVS); (2) construct 3D homology models; and (3) customize the user interface. Users can now efficiently setup, start, and manage IVS experiments through the DockoMatic GUI by specifying receptor(s), ligand(s), grid parameter file(s), and docking engine (either AutoDock or AutoDock Vina). DockoMatic automatically generates the needed experiment input files and output directories and allows the user to manage and monitor job progress. Upon job completion, a summary of results is generated by Dockomatic to facilitate interpretation by the user. DockoMatic functionality has also been expanded to facilitate the construction of 3D protein homology models using the Timely Integrated Modeler (TIM) wizard. The wizard TIM provides an interface that accesses the basic local alignment search tool (BLAST) and MODELER programs and guides the user through the necessary steps to easily and efficiently create 3D homology models for biomacromolecular structures. The DockoMatic GUI can be customized by the user, and the software design makes it relatively easy to integrate additional docking engines, scoring functions, or third party programs. DockoMatic is a free comprehensive molecular docking software program for all levels of scientists in both research and education.

  4. Virtual Screening for Potential Inhibitors of NS3 Protein of Zika Virus

    Science.gov (United States)

    Sahoo, Maheswata; Jena, Lingaraja; Daf, Sangeeta

    2016-01-01

    Zika virus (ZIKV) is a mosquito borne pathogen, belongs to Flaviviridae family having a positive-sense single-stranded RNA genome, currently known for causing large epidemics in Brazil. Its infection can cause microcephaly, a serious birth defect during pregnancy. The recent outbreak of ZIKV in February 2016 in Brazil realized it as a major health risk, demands an enhanced surveillance and a need to develop novel drugs against ZIKV. Amodiaquine, prochlorperazine, quinacrine, and berberine are few promising drugs approved by Food and Drug Administration against dengue virus which also belong to Flaviviridae family. In this study, we performed molecular docking analysis of these drugs against nonstructural 3 (NS3) protein of ZIKV. The protease activity of NS3 is necessary for viral replication and its prohibition could be considered as a strategy for treatment of ZIKV infection. Amongst these four drugs, berberine has shown highest binding affinity of –5.8 kcal/mol and it is binding around the active site region of the receptor. Based on the properties of berberine, more similar compounds were retrieved from ZINC database and a structure-based virtual screening was carried out by AutoDock Vina in PyRx 0.8. Best 10 novel drug-like compounds were identified and amongst them ZINC53047591 (2-(benzylsulfanyl)-3-cyclohexyl-3H-spiro[benzo[h]quinazoline-5,1'-cyclopentan]-4(6H)-one) was found to interact with NS3 protein with binding energy of –7.1 kcal/mol and formed H-bonds with Ser135 and Asn152 amino acid residues. Observations made in this study may extend an assuring platform for developing anti-viral competitive inhibitors against ZIKV infection. PMID:27729840

  5. DockoMatic 2.0: High Throughput Inverse Virtual Screening and Homology Modeling

    Science.gov (United States)

    Bullock, Casey; Cornia, Nic; Jacob, Reed; Remm, Andrew; Peavey, Thomas; Weekes, Ken; Mallory, Chris; Oxford, Julia T.; McDougal, Owen M.; Andersen, Timothy L.

    2013-01-01

    DockoMatic is a free and open source application that unifies a suite of software programs within a user-friendly Graphical User Interface (GUI) to facilitate molecular docking experiments. Here we describe the release of DockoMatic 2.0; significant software advances include the ability to: (1) conduct high throughput Inverse Virtual Screening (IVS); (2) construct 3D homology models; and (3) customize the user interface. Users can now efficiently setup, start, and manage IVS experiments through the DockoMatic GUI by specifying a receptor(s), ligand(s), grid parameter file(s), and docking engine (either AutoDock or AutoDock Vina). DockoMatic automatically generates the needed experiment input files and output directories, and allows the user to manage and monitor job progress. Upon job completion, a summary of results is generated by Dockomatic to facilitate interpretation by the user. DockoMatic functionality has also been expanded to facilitate the construction of 3D protein homology models using the Timely Integrated Modeler (TIM) wizard. The wizard TIM provides an interface that accesses the basic local alignment search tool (BLAST) and MODELLER programs, and guides the user through the necessary steps to easily and efficiently create 3D homology models for biomacromolecular structures. The DockoMatic GUI can be customized by the user, and the software design makes it relatively easy to integrate additional docking engines, scoring functions, or third party programs. DockoMatic is a free comprehensive molecular docking software program for all levels of scientists in both research and education. PMID:23808933

  6. Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models.

    Science.gov (United States)

    Leffler, Abba E; Kuryatov, Alexander; Zebroski, Henry A; Powell, Susan R; Filipenko, Petr; Hussein, Adel K; Gorson, Juliette; Heizmann, Anna; Lyskov, Sergey; Tsien, Richard W; Poget, Sébastien F; Nicke, Annette; Lindstrom, Jon; Rudy, Bernardo; Bonneau, Richard; Holford, Mandë

    2017-09-19

    Venom peptide toxins such as conotoxins play a critical role in the characterization of nicotinic acetylcholine receptor (nAChR) structure and function and have potential as nervous system therapeutics as well. However, the lack of solved structures of conotoxins bound to nAChRs and the large size of these peptides are barriers to their computational docking and design. We addressed these challenges in the context of the α4β2 nAChR, a widespread ligand-gated ion channel in the brain and a target for nicotine addiction therapy, and the 19-residue conotoxin α-GID that antagonizes it. We developed a docking algorithm, ToxDock, which used ensemble-docking and extensive conformational sampling to dock α-GID and its analogs to an α4β2 nAChR homology model. Experimental testing demonstrated that a virtual screen with ToxDock correctly identified three bioactive α-GID mutants (α-GID[A10V], α-GID[V13I], and α-GID[V13Y]) and one inactive variant (α-GID[A10Q]). Two mutants, α-GID[A10V] and α-GID[V13Y], had substantially reduced potency at the human α7 nAChR relative to α-GID, a desirable feature for α-GID analogs. The general usefulness of the docking algorithm was highlighted by redocking of peptide toxins to two ion channels and a binding protein in which the peptide toxins successfully reverted back to near-native crystallographic poses after being perturbed. Our results demonstrate that ToxDock can overcome two fundamental challenges of docking large toxin peptides to ion channel homology models, as exemplified by the α-GID:α4β2 nAChR complex, and is extendable to other toxin peptides and ion channels. ToxDock is freely available at rosie.rosettacommons.org/tox_dock.

  7. Human recombinant beta-secretase immobilized enzyme reactor for fast hits' selection and characterization from a virtual screening library.

    Science.gov (United States)

    De Simone, Angela; Mancini, Francesca; Cosconati, Sandro; Marinelli, Luciana; La Pietra, Valeria; Novellino, Ettore; Andrisano, Vincenza

    2013-01-25

    In the present work, a human recombinant BACE1 immobilized enzyme reactor (hrBACE1-IMER) has been applied for the sensitive fast screening of 38 compounds selected through a virtual screening approach. HrBACE1-IMER was inserted into a liquid chromatograph coupled with a fluorescent detector. A fluorogenic peptide substrate (M-2420), containing the β-secretase site of the Swedish mutation of APP, was injected and cleaved in the on-line HPLC-hrBACE1-IMER system, giving rise to the fluorescent product. The compounds of the library were tested for their ability to inhibit BACE1 in the immobilized format and to reduce the area related to the chromatographic peak of the fluorescent enzymatic product. The results were validated in solution by using two different FRET methods. Due to the efficient virtual screening methodology, more than fifty percent of the selected compounds showed a measurable inhibitory activity. One of the most active compound (a bis-indanone derivative) was characterized in terms of IC(50) and K(i) determination on the hrBACE1-IMER. Thus, the hrBACE1-IMER has been confirmed as a valid tool for the throughput screening of different chemical entities with potency lower than 30μM for the fast hits' selection and for mode of action determination.

  8. Hybrid polylingual object model: an efficient and seamless integration of Java and native components on the Dalvik virtual machine.

    Science.gov (United States)

    Huang, Yukun; Chen, Rong; Wei, Jingbo; Pei, Xilong; Cao, Jing; Prakash Jayaraman, Prem; Ranjan, Rajiv

    2014-01-01

    JNI in the Android platform is often observed with low efficiency and high coding complexity. Although many researchers have investigated the JNI mechanism, few of them solve the efficiency and the complexity problems of JNI in the Android platform simultaneously. In this paper, a hybrid polylingual object (HPO) model is proposed to allow a CAR object being accessed as a Java object and as vice in the Dalvik virtual machine. It is an acceptable substitute for JNI to reuse the CAR-compliant components in Android applications in a seamless and efficient way. The metadata injection mechanism is designed to support the automatic mapping and reflection between CAR objects and Java objects. A prototype virtual machine, called HPO-Dalvik, is implemented by extending the Dalvik virtual machine to support the HPO model. Lifespan management, garbage collection, and data type transformation of HPO objects are also handled in the HPO-Dalvik virtual machine automatically. The experimental result shows that the HPO model outweighs the standard JNI in lower overhead on native side, better executing performance with no JNI bridging code being demanded.

  9. Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening

    Directory of Open Access Journals (Sweden)

    Lin SH

    2015-06-01

    Full Text Available Shih-Hung Lin,1 Kao-Jean Huang,1,2 Ching-Feng Weng,1 David Shiuan1 1Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China; 2Development Center of Biotechnology, Taipei, Taiwan, Republic of China Abstract: Cholesterol plays an important role in living cells. However, a very high level of cholesterol may lead to atherosclerosis. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A reductase is the key enzyme in the cholesterol biosynthesis pathway, and the statin-like drugs are inhibitors of human HMG-CoA reductase (hHMGR. The present study aimed to virtually screen for potential hHMGR inhibitors from natural product to discover hypolipidemic drug candidates with fewer side effects and lesser toxicities. We used the 3D structure 1HWK from the PDB (Protein Data Bank database of hHMGR as the target to screen for the strongly bound compounds from the traditional Chinese medicine database. Many interesting molecules including polyphenolic compounds, polisubstituted heterocyclics, and linear lipophilic alcohols were identified and their ADMET (absorption, disrtibution, metabolism, excretion, toxicity properties were predicted. Finally, four compounds were obtained for the in vitro validation experiments. The results indicated that curcumin and salvianolic acid C can effectively inhibit hHMGR, with IC50 (half maximal inhibitory concentration values of 4.3 µM and 8 µM, respectively. The present study also demonstrated the feasibility of discovering new drug candidates through structure-based virtual screening. Keywords: HMG-CoA reductase, virtual screening, curcumin, salvianolic acid C

  10. Identification of a novel inhibitor of dengue virus protease through use of a virtual screening drug discovery Web portal.

    Science.gov (United States)

    Viswanathan, Usha; Tomlinson, Suzanne M; Fonner, John M; Mock, Stephen A; Watowich, Stanley J

    2014-10-27

    We report the discovery of a novel small-molecule inhibitor of the dengue virus (DENV) protease (NS2B-NS3pro) using a newly constructed Web-based portal (DrugDiscovery@TACC) for structure-based virtual screening. Our drug discovery portal, an extension of virtual screening studies performed using IBM's World Community Grid, facilitated access to supercomputer resources managed by the Texas Advanced Computing Center (TACC) and enabled druglike commercially available small-molecule libraries to be rapidly screened against several high-resolution DENV NS2B-NS3pro crystallographic structures. Detailed analysis of virtual screening docking scores and hydrogen-bonding interactions between each docked ligand and the NS2B-NS3pro Ser135 side chain were used to select molecules for experimental validation. Compounds were ordered from established chemical companies, and compounds with established aqueous solubility were tested for their ability to inhibit DENV NS2B-NS3pro cleavage of a model substrate in kinetic studies. As a proof-of-concept, we validated a small-molecule dihydronaphthalenone hit as a single-digit-micromolar mixed noncompetitive inhibitor of the DENV protease. Since the dihydronaphthalenone was predicted to interact with NS2B-NS3pro residues that are largely conserved between DENV and the related West Nile virus (WNV), we tested this inhibitor against WNV NS2B-NS3pro and observed a similar mixed noncompetitive inhibition mechanism. However, the inhibition constants were ∼10-fold larger against the WNV protease relative to the DENV protease. This novel validated lead had no chemical features or pharmacophores associated with adverse toxicity, carcinogenicity, or mutagenicity risks and thus is attractive for additional characterization and optimization.

  11. A Screened Hybrid DFT Study of Actinide Oxides, Nitrides, and Carbides

    Energy Technology Data Exchange (ETDEWEB)

    Wen, Xiaodong; Martin, Richard L.; Scuseria, Gustavo E.; Rudin, Sven P.; Batista, Enrique R.

    2013-06-27

    A systematic study of the structural, electronic, and magnetic properties of actinide oxides, nitrides, and carbides (AnX1–2 with X = C, N, O) is performed using the Heyd–Scuseria–Ernzerhof (HSE) hybrid functional. Our computed results show that the screened hybrid HSE functional gives a good description of the electronic and structural properties of actinide dioxides (strongly correlated insulators) when compared with available experimental data. However, there are still some problems reproducing the electronic properties of actinide nitrides and carbides (strongly correlated metals). In addition, in order to compare with the results by HSE, the structures, electronic, and magnetic properties of these actinide compounds are also investigated in the PBE and PBE+U approximation. Interestingly, the density of states of UN obtained with PBE compares well with the experimental photoemission spectra, in contrast to the hybrid approximation. This is presumably related to the need of additional screening in the Hartree–Fock exchange term of the metallic phases.

  12. Screening of FOXP3-interacted proteins by yeast two-hybrid technique

    Institute of Scientific and Technical Information of China (English)

    Zhou Lina; Wu Jun; Luo Gaoxing; He Weifeng; Chen Xiwei; Bo Ganping; Yuan Shunzong; Zhang Xiaorong; Hu Xiaohong

    2008-01-01

    Objective: To screen the proteins interacting with the Treg specification factor forkhead box protein P3 (FOXP3) by yeast two-hybrid system. Methods: Human FOXP3 gene was amplified by nest RT-PCR from peripheral blood mononuclear cells (PBMC) and inserted into plasmid pGBKT7 to construct the bait vector, then the self-activation and toxicity of the bait vector in host yeast strain AH109 were observed. Thereafter, a human liver cDNA library was screened by the bait vector. The positive clones were selected out by nutrient-deficient culture and back-hybridizing. The sequences from the candidate positive clones were blasted and analyzed by bioinformatics methods. Results: The constructed bait vector encoding FOXP3 was found no self-activation and toxicity in yeast AH109. Three proteins which interacted with FOXP3, including tumor protein D52, splicing factor 3b subunit 1 and hypothetical protein, were identified. Conclusion: Three new candidate proteins interacting with FOXP3 are selected out by this yeast two-hybrid system and library, which may facilitate the further study of FOXP3 in Treg.

  13. Towards an automated virtual slide screening: theoretical considerations and practical experiences of automated tissue-based virtual diagnosis to be implemented in the Internet

    Directory of Open Access Journals (Sweden)

    Bzdyl Piotr

    2006-06-01

    Full Text Available Abstract Aims To develop and implement an automated virtual slide screening system that distinguishes normal histological findings and several tissue – based crude (texture – based diagnoses. Theoretical considerations Virtual slide technology has to handle and transfer images of GB Bytes in size. The performance of tissue based diagnosis can be separated into a a sampling procedure to allocate the slide area containing the most significant diagnostic information, and b the evaluation of the diagnosis obtained from the information present in the selected area. Nyquist's theorem that is broadly applied in acoustics, can also serve for quality assurance in image information analysis, especially to preset the accuracy of sampling. Texture – based diagnosis can be performed with recursive formulas that do not require a detailed segmentation procedure. The obtained results will then be transferred into a "self-learning" discrimination system that adjusts itself to changes of image parameters such as brightness, shading, or contrast. Methods Non-overlapping compartments of the original virtual slide (image will be chosen at random and according to Nyquist's theorem (predefined error-rate. The compartments will be standardized by local filter operations, and are subject for texture analysis. The texture analysis is performed on the basis of a recursive formula that computes the median gray value and the local noise distribution. The computations will be performed at different magnifications that are adjusted to the most frequently used objectives (*2, *4.5, *10, *20, *40. The obtained data are statistically analyzed in a hierarchical sequence, and in relation to the clinical significance of the diagnosis. Results The system has been tested with a total of 896 lung cancer cases that include the diagnoses groups: cohort (1 normal lung – cancer; cancer subdivided: cohort (2 small cell lung cancer – non small cell lung cancer; non small cell lung

  14. An integrated hybrid microfluidic device for oviposition-based chemical screening of adult Drosophila melanogaster.

    Science.gov (United States)

    Leung, Jacob C K; Hilliker, Arthur J; Rezai, Pouya

    2016-02-21

    Chemical screening using Drosophila melanogaster (the fruit fly) is vital in drug discovery, agricultural, and toxicological applications. Oviposition (egg laying) on chemically-doped agar plates is an important read-out metric used to quantitatively assess the biological fitness and behavioral responses of Drosophila. Current oviposition-based chemical screening studies are inaccurate, labor-intensive, time-consuming, and inflexible due to the manual chemical doping of agar. In this paper, we have developed a novel hybrid agar-polydimethylsiloxane (PDMS) microfluidic device for single- and multi-concentration chemical dosing and on-chip oviposition screening of free-flying adult stage Drosophila. To achieve this, we have devised a novel technique to integrate agar with PDMS channels using ice as a sacrificial layer. Subsequently, we have conducted single-chemical toxicity and multiple choice chemical preference assays on adult Drosophila melanogaster using zinc and acetic acid at various concentrations. Our device has enabled us to 1) demonstrate that Drosophila is capable of sensing the concentration of different chemicals on a PDMS-agar microfluidic device, which plays significant roles in determining oviposition site selection and 2) investigate whether oviposition preference differs between single- and multi-concentration chemical environments. This device may be used to study fundamental and applied biological questions in Drosophila and other egg laying insects. It can also be extended in design to develop sophisticated and dynamic chemical dosing and high-throughput screening platforms in the future that are not easily achievable with the existing oviposition screening techniques.

  15. Passive hybrid force-position control for tele-operation based on real-time simulation of a virtual mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Joly, L.; Andriot, C.

    1995-12-31

    Hybrid force-position control aims at controlling position and force in separate directions. It is particularly useful to perform certain robotic tasks. In tele-operation context, passivity is important because it ensures stability when the system interacts with any passive environment. In this paper, we propose an original approach to hybrid force-position control of a force reflecting tele-robot system. It is based on real-time simulation of a virtual mechanism corresponding to the task. the resulting control law is passive. Experiments on a 6 degrees of freedom tele-operation system consisting in following a bent pipe under several control modes validate the approach. (authors). 12 refs., 6 figs.

  16. Screened exchange hybrid density functional for accurate and efficient structures and interaction energies.

    Science.gov (United States)

    Brandenburg, Jan Gerit; Caldeweyher, Eike; Grimme, Stefan

    2016-06-21

    We extend the recently introduced PBEh-3c global hybrid density functional [S. Grimme et al., J. Chem. Phys., 2015, 143, 054107] by a screened Fock exchange variant based on the Henderson-Janesko-Scuseria exchange hole model. While the excellent performance of the global hybrid is maintained for small covalently bound molecules, its performance for computed condensed phase mass densities is further improved. Most importantly, a speed up of 30 to 50% can be achieved and especially for small orbital energy gap cases, the method is numerically much more robust. The latter point is important for many applications, e.g., for metal-organic frameworks, organic semiconductors, or protein structures. This enables an accurate density functional based electronic structure calculation of a full DNA helix structure on a single core desktop computer which is presented as an example in addition to comprehensive benchmark results.

  17. Structure based virtual screening to identify inhibitors against MurE Enzyme of Mycobacterium tuberculosis using AutoDock Vina.

    Science.gov (United States)

    Singh, Shilpi; Bajpai, Urmi; Lynn, Andrew Michael

    2014-01-01

    The Mur E enzyme of Mur pathway of Mycobacterium tuberculosis is an attractive drug target as it is unique to bacteria and is absent in mammalian cells. The virtual screening of large libraries of drug like molecules against a protein target is a common strategy used to identify novel inhibitors. However, the method has a large number of pitfalls, with large variations in accuracy caused in part by inaccurate protocols, use of improper standards and libraries, and system dependencies such as the potential for nonspecific docking from large active-site cavities. The screening of drug-like small molecules from diversity sets can, however, be used to short-list potential fragments as building blocks to generate leads with improved specificity. We describe a protocol to implement this strategy, which involves an analysis of the active site and known inhibitors to identify orthospecific determinants, virtual screening of a drug-like diversity library to identify potential drug primitives, and inspection of the potential docked fragments for both binding potential and toxicity. The protocol is implemented on the M.tb Mur E protein which has a large active site with poor enrichment of known positives and a set of drug-like molecules that meets this criteria is presented for further analysis. MTB - Mycobacterium tuberculosis, NCI - National Cancer Institute, PDB - Protein Databank.

  18. Stereoselective virtual screening of the ZINC database using atom pair 3D-fingerprints.

    Science.gov (United States)

    Awale, Mahendra; Jin, Xian; Reymond, Jean-Louis

    2015-01-01

    Tools to explore large compound databases in search for analogs of query molecules provide a strategically important support in drug discovery to help identify available analogs of any given reference or hit compound by ligand based virtual screening (LBVS). We recently showed that large databases can be formatted for very fast searching with various 2D-fingerprints using the city-block distance as similarity measure, in particular a 2D-atom pair fingerprint (APfp) and the related category extended atom pair fingerprint (Xfp) which efficiently encode molecular shape and pharmacophores, but do not perceive stereochemistry. Here we investigated related 3D-atom pair fingerprints to enable rapid stereoselective searches in the ZINC database (23.2 million 3D structures). Molecular fingerprints counting atom pairs at increasing through-space distance intervals were designed using either all atoms (16-bit 3DAPfp) or different atom categories (80-bit 3DXfp). These 3D-fingerprints retrieved molecular shape and pharmacophore analogs (defined by OpenEye ROCS scoring functions) of 110,000 compounds from the Cambridge Structural Database with equal or better accuracy than the 2D-fingerprints APfp and Xfp, and showed comparable performance in recovering actives from decoys in the DUD database. LBVS by 3DXfp or 3DAPfp similarity was stereoselective and gave very different analogs when starting from different diastereomers of the same chiral drug. Results were also different from LBVS with the parent 2D-fingerprints Xfp or APfp. 3D- and 2D-fingerprints also gave very different results in LBVS of folded molecules where through-space distances between atom pairs are much shorter than topological distances. 3DAPfp and 3DXfp are suitable for stereoselective searches for shape and pharmacophore analogs of query molecules in large databases. Web-browsers for searching ZINC by 3DAPfp and 3DXfp similarity are accessible at www.gdb.unibe.ch and should provide useful assistance to drug

  19. G-centers in irradiated silicon revisited: A screened hybrid density functional theory approach

    KAUST Repository

    Wang, H.

    2014-05-13

    Electronic structure calculations employing screened hybrid density functional theory are used to gain fundamental insight into the interaction of carbon interstitial (Ci) and substitutional (Cs) atoms forming the CiCs defect known as G-center in silicon (Si). The G-center is one of the most important radiation related defects in Czochralski grown Si. We systematically investigate the density of states and formation energy for different types of CiCs defects with respect to the Fermi energy for all possible charge states. Prevalence of the neutral state for the C-type defect is established.

  20. New agents with potential leishmanicidal activity identified by virtual screening of chemical databases: New agents with potential leishmanicidal activity

    Directory of Open Access Journals (Sweden)

    Juan Rebollo

    2013-04-01

    Full Text Available Introduction and Objectives: Leishmaniosis, a disease caused by a protozoan parasite, remains a serious public health problem threatening about 350 million people around the world, of which 12 million are believed to be currently infected (WHO 2010. To date, there are no vaccines against the species of parasites and the treatment is based only on chemotherapy with toxic-, expensive- and inefficient- drugs. There is an urgent need for better drugs against Leishmania, the etiological agent of the disease. The main anti-leishmanial drug used in Colombia is meglumineantimoniate [chemical name according to the International Union of Pure and Applied Chemistry (IUPAC: Hydroxy-dioxostiborane; (2R,3R,4R,5S- 6-methylaminohexane-1,2,3,4,5-pentol, (C7H17NO5], which is not efficient in the treatment of infections caused by Leishmania braziliensis, the most prevalent specie in the Caribbean coast of Colombia. Methods: We performed an in silico virtual screening of several datasets including ChemBridge and Pubchem. We virtually screened a total of 28.755 compounds against a 3D model of 6-phosphoglucono -lactonase (6-PGL from Leishmania braziliensis to identify novel inhibitors.Molecular docking of databases was performed using the software Sybyl 8.0 and AutoDockVina. Results: The initial virtual screening using a structure-based method identified 10 compounds, which were later tested with AutodockVina and classified according to their docking scores. Conclusions: These novel and potential inhibitors constitute new drug candidates that must be biologically tested to define their value as an alternative chemotherapeutic agent in the treatment of these protozoan infections. Salud UIS 2013; 45 (1: 33-40

  1. An unbiased method to build benchmarking sets for ligand-based virtual screening and its application to GPCRs.

    Science.gov (United States)

    Xia, Jie; Jin, Hongwei; Liu, Zhenming; Zhang, Liangren; Wang, Xiang Simon

    2014-05-27

    Benchmarking data sets have become common in recent years for the purpose of virtual screening, though the main focus had been placed on the structure-based virtual screening (SBVS) approaches. Due to the lack of crystal structures, there is great need for unbiased benchmarking sets to evaluate various ligand-based virtual screening (LBVS) methods for important drug targets such as G protein-coupled receptors (GPCRs). To date these ready-to-apply data sets for LBVS are fairly limited, and the direct usage of benchmarking sets designed for SBVS could bring the biases to the evaluation of LBVS. Herein, we propose an unbiased method to build benchmarking sets for LBVS and validate it on a multitude of GPCRs targets. To be more specific, our methods can (1) ensure chemical diversity of ligands, (2) maintain the physicochemical similarity between ligands and decoys, (3) make the decoys dissimilar in chemical topology to all ligands to avoid false negatives, and (4) maximize spatial random distribution of ligands and decoys. We evaluated the quality of our Unbiased Ligand Set (ULS) and Unbiased Decoy Set (UDS) using three common LBVS approaches, with Leave-One-Out (LOO) Cross-Validation (CV) and a metric of average AUC of the ROC curves. Our method has greatly reduced the "artificial enrichment" and "analogue bias" of a published GPCRs benchmarking set, i.e., GPCR Ligand Library (GLL)/GPCR Decoy Database (GDD). In addition, we addressed an important issue about the ratio of decoys per ligand and found that for a range of 30 to 100 it does not affect the quality of the benchmarking set, so we kept the original ratio of 39 from the GLL/GDD.

  2. Categorical, Narrative, and Hybrid Behavior Generation in the GENIE Environment for Interactive Narrative Virtual Worlds

    NARCIS (Netherlands)

    Lindley, C.A.; Nack, F.-M.

    2001-01-01

    The GEneric Narrative Interaction Environment (GENIE) is a conceptual architecture for the exploration of interactive narrative generation in virtual worlds. Specific research demonstrators implement different aspects of the GENIE architecture, with the longer term goal of implementing the full syst

  3. EMOTION INTERACTION WITH VIRTUAL REALITY USING HYBRID EMOTION CLASSIFICATION TECHNIQUE TOWARD BRAIN SIGNALS

    National Research Council Canada - National Science Library

    Faris A. Abuhashish; Jamal Zraqou; Wesam Alkhodour; Mohd S. Sunar; Hoshang Kolivand

    2015-01-01

    .... Last decade many researchers focused on emotion classification in order to employ emotion in interaction with virtual reality, the classification will be done based on Electroencephalogram (EEG) brain signals...

  4. A Bayesian Approach to Calibrating High-Throughput Virtual Screening Results and Application to Organic Photovoltaic Materials

    CERN Document Server

    Pyzer-Knapp, Edward O; Aspuru-Guzik, Alan

    2015-01-01

    A novel approach for calibrating quantum-chemical properties determined as part of a high-throughput virtual screen to experimental analogs is presented. Information on the molecular graph is extracted through the use of extended connectivity fingerprints, and exploited using a Gaussian process to calibrate both electronic properties such as frontier orbital energies, and optical gaps and device properties such as short circuit current density, open circuit voltage and power conversion efficiency. The Bayesian nature of this process affords a value for uncertainty in addition to each calibrated value. This allows the researcher to gain intuition about the model as well as the ability to respect its bounds.

  5. Virtual screening using ligand-based pharmacophores for inhibitors of human tyrosyl-DNA phospodiesterase (hTdp1)

    Science.gov (United States)

    Weidlich, Iwona E.; Dexheimer, Thomas; Marchand, Christophe; Antony, Smitha; Pommier, Yves; Nicklaus, Marc C.

    2012-01-01

    Human tyrosyl-DNA phosphodiesterase (hTdp1) inhibitors have become a major area of drug research and structure-based design since they have been shown to work synergistically with camptothecin (CPT) and selectively in cancer cells. The pharmacophore features of 14 hTdp1 inhibitors were used as a filter to screen the ChemNavigator iResearch Library of about 27 million purchasable samples. Docking of the inhibitors and hits obtained from virtual screening was performed into a structural model of hTdp1 based on a high resolution X-ray crystal structure of human Tdp1 in complex with vanadate, DNA and a human topoisomerase I (TopI)-derived peptide (PDB code: 1NOP). We present and discuss in some detail 46 compounds matching the three-dimensional arrangement of the pharmacophoric features. The presented novel chemotypes may provide new scaffolds for developing inhibitors of Tdp1. PMID:19963390

  6. Virtual screening and repositioning of inconclusive molecules of beta-lactamase Bioassays-A data mining approach.

    Science.gov (United States)

    Gad, Akshata; Manuel, Andrew Titus; K R, Jinuraj; John, Lijo; R, Sajeev; V G, Shanmuga Priya; U C, Abdul Jaleel

    2017-07-29

    This study focuses on the best possible way forward in utilizing inconclusive molecules of PubChem bioassays AID 1332, AID 434987 and AID 434955, which are related to beta-lactamase inhibitors of Mycobacterium tuberculosis (Mtb). The inadequacy in the experimental methods that were observed during the invitro screening resulted in an inconclusive dataset. This could be due to certain moieties present within the molecules. In order to reconsider such molecules, insilico methods can be suggested in place of invitro methods For instance, datamining and medicinal chemistry methods: have been adopted to prioritise the inconclusive dataset into active or inactive molecules. These include the Random Forest algorithm for dataminning, Lilly MedChem rules for virtually screening out the promiscuity, and Self Organizing Maps (SOM) for clustering the active molecules and enlisting them for repositioning through the use of artificial neural networks. These repositioned molecules could then be prioritized for downstream drug discovery analysis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Design of efficient molecular organic light-emitting diodes by a high-throughput virtual screening and experimental approach

    Science.gov (United States)

    Gómez-Bombarelli, Rafael; Aguilera-Iparraguirre, Jorge; Hirzel, Timothy D.; Duvenaud, David; MacLaurin, Dougal; Blood-Forsythe, Martin A.; Chae, Hyun Sik; Einzinger, Markus; Ha, Dong-Gwang; Wu, Tony; Markopoulos, Georgios; Jeon, Soonok; Kang, Hosuk; Miyazaki, Hiroshi; Numata, Masaki; Kim, Sunghan; Huang, Wenliang; Hong, Seong Ik; Baldo, Marc; Adams, Ryan P.; Aspuru-Guzik, Alán

    2016-10-01

    Virtual screening is becoming a ground-breaking tool for molecular discovery due to the exponential growth of available computer time and constant improvement of simulation and machine learning techniques. We report an integrated organic functional material design process that incorporates theoretical insight, quantum chemistry, cheminformatics, machine learning, industrial expertise, organic synthesis, molecular characterization, device fabrication and optoelectronic testing. After exploring a search space of 1.6 million molecules and screening over 400,000 of them using time-dependent density functional theory, we identified thousands of promising novel organic light-emitting diode molecules across the visible spectrum. Our team collaboratively selected the best candidates from this set. The experimentally determined external quantum efficiencies for these synthesized candidates were as large as 22%.

  8. A Teach-Discover-Treat Application of ZincPharmer: An Online Interactive Pharmacophore Modeling and Virtual Screening Tool.

    Directory of Open Access Journals (Sweden)

    David Ryan Koes

    Full Text Available The 2012 Teach-Discover-Treat (TDT community-wide experiment provided a unique opportunity to test prospective virtual screening protocols targeting the anti-malarial target dihydroorotate dehydrogenase (DHODH. Facilitated by ZincPharmer, an open access online interactive pharmacophore search of the ZINC database, the experience resulted in the development of a novel classification scheme that successfully predicted the bound structure of a non-triazolopyrimidine inhibitor, as well as an overall hit rate of 27% of tested active compounds from multiple novel chemical scaffolds. The general approach entailed exhaustively building and screening sparse pharmacophore models comprising of a minimum of three features for each bound ligand in all available DHODH co-crystals and iteratively adding features that increased the number of known binders returned by the query. Collectively, the TDT experiment provided a unique opportunity to teach computational methods of drug discovery, develop innovative methodologies and prospectively discover new compounds active against DHODH.

  9. Integrated virtual screening for the identification of novel and selective peroxisome proliferator-activated receptor (PPAR) scaffolds.

    Science.gov (United States)

    Nevin, Daniel K; Peters, Martin B; Carta, Giorgio; Fayne, Darren; Lloyd, David G

    2012-06-14

    We describe a fully customizable and integrated target-specific "tiered" virtual screening approach tailored to identifying and characterizing novel peroxisome proliferator activated receptor γ (PPARγ) scaffolds. Built on structure- and ligand-based computational techniques, a consensus protocol was developed for use in the virtual screening of chemical databases, focused toward retrieval of novel bioactive chemical scaffolds for PPARγ. Consequent from application, three novel PPAR scaffolds displaying distinct chemotypes have been identified, namely, 5-(4-(benzyloxy)-3-chlorobenzylidene)dihydro-2-thioxopyrimidine-4,6(1H,5H)-dione (MDG 548), 3-((4-bromophenoxy)methyl)-N-(4-nitro-1H-pyrazol-1-yl)benzamide (MDG 559), and ethyl 2-[3-hydroxy-5-(5-methyl-2-furyl)-2-oxo-4-(2-thienylcarbonyl)-2,5-dihydro-1H-pyrrol-1-yl]-4-methyl-1,3-thiazole-5-carboxylate (MDG 582). Fluorescence polarization(FP) and time resolved fluorescence resonance energy transfer (TR-FRET) show that these compounds display high affinity competitive binding to the PPARγ-LBD (EC(50) of 215 nM to 5.45 μM). Consequent characterization by a TR-FRET activation reporter assay demonstrated agonism of PPARγ by all three compounds (EC(50) of 467-594 nM). Additionally, differential PPAR isotype specificity was demonstrated through assay against PPARα and PPARδ subtypes. This work showcases the ability of target specific "tiered screen" protocols to successfully identify novel scaffolds of individual receptor subtypes with greater efficacy than isolated screening methods.

  10. The role of affordances in children's learning performance and efficiency when using virtual manipulative mathematics touch-screen apps

    Science.gov (United States)

    Moyer-Packenham, Patricia S.; Bullock, Emma K.; Shumway, Jessica F.; Tucker, Stephen I.; Watts, Christina M.; Westenskow, Arla; Anderson-Pence, Katie L.; Maahs-Fladung, Cathy; Boyer-Thurgood, Jennifer; Gulkilik, Hilal; Jordan, Kerry

    2016-03-01

    This paper focuses on understanding the role that affordances played in children's learning performance and efficiency during clinical interviews of their interactions with mathematics apps on touch-screen devices. One hundred children, ages 3 to 8, each used six different virtual manipulative mathematics apps during 30-40-min interviews. The study used a convergent mixed methods design, in which quantitative and qualitative data were collected concurrently to answer the research questions (Creswell and Plano Clark 2011). Videos were used to capture each child's interactions with the virtual manipulative mathematics apps, document learning performance and efficiency, and record children's interactions with the affordances within the apps. Quantitized video data answered the research question on differences in children's learning performance and efficiency between pre- and post-assessments. A Wilcoxon matched pairs signed-rank test was used to explore these data. Qualitative video data was used to identify affordance access by children when using each app, identifying 95 potential helping and hindering affordances among the 18 apps. The results showed that there were changes in children's learning performance and efficiency when children accessed a helping or a hindering affordance. Helping affordances were more likely to be accessed by children who progressed between the pre- and post-assessments, and the same affordances had helping and hindering effects for different children. These results have important implications for the design of virtual manipulative mathematics learning apps.

  11. Improved genome-scale multi-target virtual screening via a novel collaborative filtering approach to cold-start problem

    Science.gov (United States)

    Lim, Hansaim; Gray, Paul; Xie, Lei; Poleksic, Aleksandar

    2016-12-01

    Conventional one-drug-one-gene approach has been of limited success in modern drug discovery. Polypharmacology, which focuses on searching for multi-targeted drugs to perturb disease-causing networks instead of designing selective ligands to target individual proteins, has emerged as a new drug discovery paradigm. Although many methods for single-target virtual screening have been developed to improve the efficiency of drug discovery, few of these algorithms are designed for polypharmacology. Here, we present a novel theoretical framework and a corresponding algorithm for genome-scale multi-target virtual screening based on the one-class collaborative filtering technique. Our method overcomes the sparseness of the protein-chemical interaction data by means of interaction matrix weighting and dual regularization from both chemicals and proteins. While the statistical foundation behind our method is general enough to encompass genome-wide drug off-target prediction, the program is specifically tailored to find protein targets for new chemicals with little to no available interaction data. We extensively evaluate our method using a number of the most widely accepted gene-specific and cross-gene family benchmarks and demonstrate that our method outperforms other state-of-the-art algorithms for predicting the interaction of new chemicals with multiple proteins. Thus, the proposed algorithm may provide a powerful tool for multi-target drug design.

  12. Development and validation of a docking-based virtual screening platform for the identification of new lactate dehydrogenase inhibitors.

    Science.gov (United States)

    Granchi, Carlotta; Capecchi, Alice; Del Frate, Gianluca; Martinelli, Adriano; Macchia, Marco; Minutolo, Filippo; Tuccinardi, Tiziano

    2015-05-15

    The human muscle isoform of lactate dehydrogenase (hLDH5) is one of the key enzymes of the glycolytic process. It is overexpressed in metastatic cancer cells and is linked to the vitality of tumors in hypoxic conditions. With the aim of identifying new hLDH5 inhibitors, a fully automated docking-based virtual screening platform was developed by considering different protein conformations and the consensus docking strategy. In order to verify the reliability of the reported platform, a small database of about 10,000 compounds was filtered by using this method, and the top-ranked compounds were tested for their hLDH5 inhibition activity. Enzymatic assays revealed that, among the ten selected compounds, two proved to efficiently inhibit enzyme activity with IC50 values in the micromolar range. These results demonstrate the validity of the methodologies we followed, encouraging the application of larger virtual screening studies and further refinements of the platform. Furthermore, the two active compounds herein described may be considered as interesting leads for the development of new and more efficient LDH inhibitors.

  13. Development and Validation of a Docking-Based Virtual Screening Platform for the Identification of New Lactate Dehydrogenase Inhibitors

    Directory of Open Access Journals (Sweden)

    Carlotta Granchi

    2015-05-01

    Full Text Available The human muscle isoform of lactate dehydrogenase (hLDH5 is one of the key enzymes of the glycolytic process. It is overexpressed in metastatic cancer cells and is linked to the vitality of tumors in hypoxic conditions. With the aim of identifying new hLDH5 inhibitors, a fully automated docking-based virtual screening platform was developed by considering different protein conformations and the consensus docking strategy. In order to verify the reliability of the reported platform, a small database of about 10,000 compounds was filtered by using this method, and the top-ranked compounds were tested for their hLDH5 inhibition activity. Enzymatic assays revealed that, among the ten selected compounds, two proved to efficiently inhibit enzyme activity with IC50 values in the micromolar range. These results demonstrate the validity of the methodologies we followed, encouraging the application of larger virtual screening studies and further refinements of the platform. Furthermore, the two active compounds herein described may be considered as interesting leads for the development of new and more efficient LDH inhibitors.

  14. Identification of potent inhibitors for -secretase through structure based virtual screening and molecular dynamics simulations

    Directory of Open Access Journals (Sweden)

    A. Mobeen

    2013-07-01

    Full Text Available Background: Alzheimer's disease (AD is a neurodegenerative disorder in elderly persons aged above 65 years. The cleavage of amyloid precursor protein (APP by -secretase generates peptide fragment A42, the main cause of memory and cognitive defects in AD. Therefore, elevated level of -secretase results in accumulation of insoluble form of A peptides (senile plaques representing the protein as an attractive drug target of AD. Methods: Five recently reported -secretase antagonist (thiazolidinediones, rosiglitazone, pioglitazone, SC7 and tartaric acid structural analogs were searched from ligand info database and prepared using LigPrep. The crystal structure of -secretase was optimized using Maestro v9.2 protein preparation wizard applying optimized potential for liquid simulations (OPLS-2005 force field. Structure based virtual screening was performed for -secretase from prepared ligands using virtual screening workflow of Maestro v9.2 and was ranked based on XP Gscore. Results: Eight lead molecules were identified to have better binding affinity (lower XP Gscore compared to five existing -secretase antagonists and appear to have good pharmacological properties. Binding orientations of the lead molecules were in well agreement with existing inhibitors. Lead1 showed lowest XP Gscore (-10.72 Kcal/mol. Molecular dynamics (MD simulations of -secretase-lead1 complex was stable in all trajectories. Conclusion: Lead1 is proposed as potent inhibitor of -secretase and thus could be considered for rational drug design against AD.

  15. Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling

    Directory of Open Access Journals (Sweden)

    Ly Le

    2011-12-01

    Full Text Available The M2 channel protein on the influenza A virus membrane has become the main target of the anti-flu drugs amantadine and rimantadine. The structure of the M2 channel proteins of the H3N2 (PDB code 2RLF and 2009-H1N1 (Genbank accession number GQ385383 viruses may help researchers to solve the drug-resistant problem of these two adamantane-based drugs and develop more powerful new drugs against influenza A virus. In the present study, we searched for new M2 channel inhibitors through a combination of different computational methodologies, including virtual screening with docking and pharmacophore modeling. Virtual screening was performed to calculate the free energies of binding between receptor M2 channel proteins and 200 new designed ligands. After that, pharmacophore analysis was used to identify the important M2 protein-inhibitor interactions and common features of top binding compounds with M2 channel proteins. Finally, the two most potential compounds were determined as novel leads to inhibit M2 channel proteins in both H3N2 and 2009-H1N1 influenza A virus.

  16. Discovery of potential M2 channel inhibitors based on the amantadine scaffold via virtual screening and pharmacophore modeling.

    Science.gov (United States)

    Tran, Linh; Choi, Sy Bing; Al-Najjar, Belal O; Yusuf, Muhammad; Wahab, Habibah A; Le, Ly

    2011-12-08

    The M2 channel protein on the influenza A virus membrane has become the main target of the anti-flu drugs amantadine and rimantadine. The structure of the M2 channel proteins of the H3N2 (PDB code 2RLF) and 2009-H1N1 (Genbank accession number GQ385383) viruses may help researchers to solve the drug-resistant problem of these two adamantane-based drugs and develop more powerful new drugs against influenza A virus. In the present study, we searched for new M2 channel inhibitors through a combination of different computational methodologies, including virtual screening with docking and pharmacophore modeling. Virtual screening was performed to calculate the free energies of binding between receptor M2 channel proteins and 200 new designed ligands. After that, pharmacophore analysis was used to identify the important M2 protein-inhibitor interactions and common features of top binding compounds with M2 channel proteins. Finally, the two most potential compounds were determined as novel leads to inhibit M2 channel proteins in both H3N2 and 2009-H1N1 influenza A virus.

  17. Target specific proteochemometric model development for BACE1 - protein flexibility and structural water are critical in virtual screening.

    Science.gov (United States)

    Manoharan, Prabu; Chennoju, Kiranmai; Ghoshal, Nanda

    2015-07-01

    BACE1 is an attractive target in Alzheimer's disease (AD) treatment. A rational drug design effort for the inhibition of BACE1 is actively pursued by researchers in both academic and pharmaceutical industries. This continued effort led to the steady accumulation of BACE1 crystal structures, co-complexed with different classes of inhibitors. This wealth of information is used in this study to develop target specific proteochemometric models and these models are exploited for predicting the prospective BACE1 inhibitors. The models developed in this study have performed excellently in predicting the computationally generated poses, separately obtained from single and ensemble docking approaches. The simple protein-ligand contact (SPLC) model outperforms other sophisticated high end models, in virtual screening performance, developed during this study. In an attempt to account for BACE1 protein active site flexibility information in predictive models, we included the change in the area of solvent accessible surface and the change in the volume of solvent accessible surface in our models. The ensemble and single receptor docking results obtained from this study indicate that the structural water mediated interactions improve the virtual screening results. Also, these waters are essential for recapitulating bioactive conformation during docking study. The proteochemometric models developed in this study can be used for the prediction of BACE1 inhibitors, during the early stage of AD drug discovery.

  18. A screen for F1 hybrid male rescue reveals no major-effect hybrid lethality loci in the Drosophila melanogaster autosomal genome.

    Science.gov (United States)

    Cuykendall, Tawny N; Satyaki, P; Ji, Shuqing; Clay, Derek M; Edelman, Nathaniel B; Kimchy, Alexandra; Li, Ling-Hei; Nuzzo, Erin A; Parekh, Neil; Park, Suna; Barbash, Daniel A

    2014-10-27

    Hybrid sons between Drosophila melanogaster females and D. simulans males die as 3rd instar larvae. Two genes, D. melanogaster Hybrid male rescue (Hmr) on the X chromosome, and D. simulans Lethal hybrid rescue (Lhr) on chromosome II, interact to cause this lethality. Loss-of-function mutations in either gene suppress lethality, but several pieces of evidence suggest that additional factors are required for hybrid lethality. Here we screen the D. melanogaster autosomal genome by using the Bloomington Stock Center Deficiency kit to search for additional regions that can rescue hybrid male lethality. Our screen is designed to identify putative hybrid incompatibility (HI) genes similar to Hmr and Lhr which, when removed, are dominant suppressors of lethality. After screening 89% of the autosomal genome, we found no regions that rescue males to the adult stage. We did, however, identify several regions that rescue up to 13% of males to the pharate adult stage. This weak rescue suggests the presence of multiple minor-effect HI loci, but we were unable to map these loci to high resolution, presumably because weak rescue can be masked by genetic background effects. We attempted to test one candidate, the dosage compensation gene male specific lethal-3 (msl-3), by using RNA interference with short hairpin microRNA constructs targeted specifically against D. simulans msl-3 but failed to achieve knockdown, in part due to off-target effects. We conclude that the D. melanogaster autosomal genome likely does not contain additional major-effect HI loci. We also show that Hmr is insufficient to fully account for the lethality associated with the D. melanogaster X chromosome, suggesting that additional X-linked genes contribute to hybrid lethality. Copyright © 2014 Cuykendall et al.

  19. Screening for metronidazole-resistance associated gene fragments of H pylori by suppression subtractive hybridization

    Institute of Scientific and Technical Information of China (English)

    Ai-Qing Li; Ning Dai; Jie Yan; Yong-Liang Zhu

    2007-01-01

    AIM:To screen for metronidazole (MTZ)-resistance associated gene fragments of H pylori by suppression subtractive hybridization (SSH).METHODS:Five MTZ-resistant (tester,T) and 1 MTZ-susceptible (driver,D) clinical H pylori isolates were selected. Genomic DMAs were prepared and submitted to Rsa I digestion. Then two different adaptors were ligated respectively to the 5'-end of two aliquots of the tester DNA fragments and SSH was made between the tester and driver DNAs. The specific inserts of tester strains were screened and MTZ-resistance related gene fragments were identified by dot blotting.RESULTS:Among the randomly selected 120 subtractive colonies,37 DNA fragments had a different number of DNA copies (≥2 times) in resistant and susceptible strains and 17 of them had a significantly different number of DNA copies (≥3 times). Among the sequences obtained from the 17 DNA fragments,new sequences were found in 10 DNA fragments and duplicated sequences in 7 DNA fragments,representing respectively the sequences of depeptide ABC transporter periplasmic dipeptide-binding protein (dppA),permease protein (dppB),ribosomal protein S4 (rps4),ribonuclease in (rnc),protease (pqqE),diaminopimelate epimerase (dapF),acetatekinase (ackA),H pylori plasmid pHPSl and H pylori gene 1334.CONCLUSION:Gene fragments specific to MTZ-resistant H pylori strains can be screened by SSH and may be associated with MTZ-resistant H pylori.

  20. Special Section: New Ways to Detect Colon Cancer 3-D virtual screening now being used

    Science.gov (United States)

    ... organ, like the colon—and view it in virtual reality." Later, he and his team used it with anatomically detailed, three-dimensional representations of a cadaver (dead body) from the National Library of Medicine's Visible Human project (www.nlm.nih.gov). By ...

  1. Better Models for Agile Virtual Enterprises - the Enterprise and its Constituents as Hybrid Agents

    DEFF Research Database (Denmark)

    Bernus, Peter; Baltrusch, Rob; Tølle, Martin

    2003-01-01

    The article proposes a way to improve reference models for the management of virtual enterprises. The pattern of management roles is based on enveloping each decision centre into an agent wrapper, using the same tools and algorithms. Using this approach enterprises (organization, networks, virtua...

  2. Better Models for Agile Virtual Enterprises - the Enterprise and its Constituents as Hybrid Agents

    DEFF Research Database (Denmark)

    Bernus, Peter; Baltrusch, Rob; Tølle, Martin

    2003-01-01

    The article proposes a way to improve reference models for the management of virtual enterprises. The pattern of management roles is based on enveloping each decision centre into an agent wrapper, using the same tools and algorithms. Using this approach enterprises (organization, networks, virtua...

  3. Identification of a Selective G1-Phase Benzimidazolone Inhibitor by a Senescence-Targeted Virtual Screen Using Artificial Neural Networks

    Directory of Open Access Journals (Sweden)

    Alan E. Bilsland

    2015-09-01

    Full Text Available Cellular senescence is a barrier to tumorigenesis in normal cells, and tumor cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning–based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. One hundred and forty-seven virtual hits were acquired for validation in growth inhibition and senescence-associated β-galactosidase assays. Among the found hits, a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced senescence-associated β-galactosidase activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1, and CDC25C. In addition, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long-term treatments. Preliminary structure-activity and structure clustering analyses are reported, and expression analysis of CB-20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT-inhibitor–like profile in normal cells, with different pathways affected in cancer cells.

  4. Pharmacophore-based virtual screening, biological evaluation and binding mode analysis of a novel protease-activated receptor 2 antagonist

    Science.gov (United States)

    Cho, Nam-Chul; Seo, Seoung-Hwan; Kim, Dohee; Shin, Ji-Sun; Ju, Jeongmin; Seong, Jihye; Seo, Seon Hee; Lee, Iiyoun; Lee, Kyung-Tae; Kim, Yun Kyung; No, Kyoung Tai; Pae, Ae Nim

    2016-08-01

    Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library. The initial virtual screening yielded a total number of 47 hits, and additional biological activity tests including PAR2 antagonism and anti-inflammatory effects resulted in a promising candidate, compound 43, which demonstrated an IC50 value of 8.22 µM against PAR2. In next step, a PAR2 homology model was constructed using the crystal structure of the PAR1 as a template to explore the binding mode of the identified ligands. A molecular docking method was optimized by comparing the binding modes of a known PAR2 agonist GB110 and antagonist GB83, and applied to predict the binding mode of our hit compound 43. In-depth docking analyses revealed that the hydrophobic interaction with Phe2435.39 is crucial for PAR2 ligands to exert antagonistic activity. MD simulation results supported the predicted docking poses that PAR2 antagonist blocked a conformational rearrangement of Na+ allosteric site in contrast to PAR2 agonist that showed Na+ relocation upon GPCR activation. In conclusion, we identified new a PAR2 antagonist together with its binding mode, which provides useful insights for the design and development of PAR2 ligands.

  5. Pharmacophore-based virtual screening, biological evaluation and binding mode analysis of a novel protease-activated receptor 2 antagonist.

    Science.gov (United States)

    Cho, Nam-Chul; Seo, Seoung-Hwan; Kim, Dohee; Shin, Ji-Sun; Ju, Jeongmin; Seong, Jihye; Seo, Seon Hee; Lee, Iiyoun; Lee, Kyung-Tae; Kim, Yun Kyung; No, Kyoung Tai; Pae, Ae Nim

    2016-08-01

    Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library. The initial virtual screening yielded a total number of 47 hits, and additional biological activity tests including PAR2 antagonism and anti-inflammatory effects resulted in a promising candidate, compound 43, which demonstrated an IC50 value of 8.22 µM against PAR2. In next step, a PAR2 homology model was constructed using the crystal structure of the PAR1 as a template to explore the binding mode of the identified ligands. A molecular docking method was optimized by comparing the binding modes of a known PAR2 agonist GB110 and antagonist GB83, and applied to predict the binding mode of our hit compound 43. In-depth docking analyses revealed that the hydrophobic interaction with Phe243(5.39) is crucial for PAR2 ligands to exert antagonistic activity. MD simulation results supported the predicted docking poses that PAR2 antagonist blocked a conformational rearrangement of Na(+) allosteric site in contrast to PAR2 agonist that showed Na(+) relocation upon GPCR activation. In conclusion, we identified new a PAR2 antagonist together with its binding mode, which provides useful insights for the design and development of PAR2 ligands.

  6. A 3D model of SARS_CoV 3CL proteinase and its inhibitors design by virtual screening

    Institute of Scientific and Technical Information of China (English)

    LUOCheng; CHENJing; LUOHai-Bin; CHENLi-Li; LIGuo-Wei; SUNTao; YUChang-Ying; YUELi-Duo; SHENJian-Hua; JIANGHua-Liang; XIONGBin; GUIChun-Shan; XUXiao-Ying; DUANWen-Hu; SHENJing-Kang; QINLei; SHITi-Liu; LIYi-Xue; CHENKai-Xian; LUOXiao-Min; SHENXu

    2003-01-01

    AIM:To constructed a three-dimensional (3D) model for the 3C like (3CL) proteinase of SARS coronavirus (SARS_CoV), and to design inhibitors of the 3CL proteinase based on the 3D model. METHODS: Bioinformatics analyses were performed to search the homologous proteins of the SARS_CoV 3CL proteinase from the GenBank and PDB database. A 3D model of the proteinase was constructed by using homology modeling technique. Targeting to the 3D model and its X-ray crystal structure of the main proteinase (Mpro) of transmissible gastroenteritis virus(TGEV), virtual screening was performed employing molecular docking method to identify possible 3CL proteinase inhibitors from small molecular databases. RESULTS:Sequence alignment indicated that the SARS_CoV 3CL proteinase was extremely homologous to TGEV Mpro, especially the substrate-binding pocket (active site). Accordingly, a 3D model for the SARS_CoV 3CL proteinase was constructed based on the crystal structure of TGEV Mpro. The 3D model adopts a similar fold of the TGEV mpro, its structure and binding pocket feature are almost as same as that of TGEV Mpro. The tested virtual screening indicated that 73 available proteinase inhibitors in the MDDR database might dock into both the binding pockets of the TGEV Mpro and the SARS_CoV 3CL proteinase. CONCLUSIONS:Either the 3D model of the SARS_CoV 3CL proteinase or the X-ray crystal stucture of the TGEV Mpro may be used as a starting point for design anti-SARS drugs. Screening the known proteinase inhibitors may be an appreciated shortcut to discover anti-SARS drugs.

  7. Application of consensus scoring and principal component analysis for virtual screening against β-secretase (BACE-1.

    Directory of Open Access Journals (Sweden)

    Shu Liu

    Full Text Available BACKGROUND: In order to identify novel chemical classes of β-secretase (BACE-1 inhibitors, an alternative scoring protocol, Principal Component Analysis (PCA, was proposed to summarize most of the information from the original scoring functions and re-rank the results from the virtual screening against BACE-1. METHOD: Given a training set (50 BACE-1 inhibitors and 9950 inactive diverse compounds, three rank-based virtual screening methods, individual scoring, conventional consensus scoring and PCA, were judged by the hit number in the top 1% of the ranked list. The docking poses were generated by Surflex, five scoring functions (Surflex_Score, D_Score, G_Score, ChemScore, and PMF_Score were used for pose extraction. For each pose group, twelve scoring functions (Surflex_Score, D_Score, G_Score, ChemScore, PMF_Score, LigScore1, LigScore2, PLP1, PLP2, jain, Ludi_1, and Ludi_2 were used for the pose rank. For a test set, 113,228 chemical compounds (Sigma-Aldrich® corporate chemical directory were docked by Surflex, then ranked by the same three ranking methods motioned above to select the potential active compounds for experimental test. RESULTS: For the training set, the PCA approach yielded consistently superior rankings compared to conventional consensus scoring and single scoring. For the test set, the top 20 compounds according to conventional consensus scoring were experimentally tested, no inhibitor was found. Then, we relied on PCA scoring protocol to test another different top 20 compounds and two low micromolar inhibitors (S450588 and 276065 were emerged through the BACE-1 fluorescence resonance energy transfer (FRET assay. CONCLUSION: The PCA method extends the conventional consensus scoring in a quantitative statistical manner and would appear to have considerable potential for chemical screening applications.

  8. Hybrid Design Tools in a Social Virtual Reality Using Networked Oculus Rift: A Feasibility Study in Remote Real-Time Interaction

    NARCIS (Netherlands)

    Wendrich, Robert E.; Chambers, Kris-Howard; Al-Halabi, Wadee; Seibel, Eric J.; Grevenstuk, Olaf; Ullman, David; Hoffman, Hunter G.

    2016-01-01

    Hybrid Design Tool Environments (HDTE) allow designers and engineers to use real tangible tools and physical objects and/or artifacts to make and create real-time virtual representations and presentations on-the-fly. Manipulations of the real tangible objects (e.g., real wire mesh, clay, sketches, e

  9. Hybrid Design Tools in a Social Virtual Reality Using Networked Oculus Rift: A Feasibility Study in Remote Real-Time Interaction

    NARCIS (Netherlands)

    Wendrich, Robert E.; Chambers, Kris-Howard; Al-Halabi, Wadee; Seibel, Eric J.; Grevenstuk, Olaf; Ullman, David; Hoffman, Hunter G.

    2016-01-01

    Hybrid Design Tool Environments (HDTE) allow designers and engineers to use real tangible tools and physical objects and/or artifacts to make and create real-time virtual representations and presentations on-the-fly. Manipulations of the real tangible objects (e.g., real wire mesh, clay, sketches,

  10. The interactome of soybean GmWRKY53 using yeast 2-hybrid library screening to saturation.

    Science.gov (United States)

    Tripathi, Prateek; Rabara, Roel C; Choudhary, Mani Kant; Miller, Marissa A; Huang, Ying-Sheng; Shen, Qingxi J; Blachon, Stéphanie; Rushton, Paul J

    2015-01-01

    Soybean GmWRKY53 functions in both biotic and abiotic stress signaling. Using GmWRKY53 as a bait yeast 2-hybrid library screening to saturation isolated multiple independent fragments for many interacting proteins, enabling delineation of minimal interacting domains and computation of a confidence score. Multiple independent clones coding for the LATE ELONGATED HYPOCOTYL clock protein GmLCL2 (MYB114) were isolated and the binding site for GmWRKY53 was mapped to 90 amino acids separate from the MYB domain. This suggests a direct input from the clock on GmWRKY53 activity. The GmWRKY53-interacting proteins also included 3 water stress-inducible AP2/ERF transcription factors. One of these (Glyma03g26310) is one of the most strongly water stress induced genes in soybean roots, suggesting that GmWRKY53/ERF complexes regulate water stress responses.

  11. G-centers in irradiated silicon revisited: A screened hybrid density functional theory approach

    Energy Technology Data Exchange (ETDEWEB)

    Wang, H.; Schwingenschlögl, U., E-mail: Udo.Schwingenschlogl@kaust.edu.sa [PSE Division, KAUST, Thuwal 23955-6900 (Saudi Arabia); Chroneos, A., E-mail: Alex.Chroneos@open.ac.uk [Engineering and Innovation, The Open University, Milton Keynes MK7 6AA (United Kingdom); Department of Materials, Imperial College, London SW7 2AZ (United Kingdom); Londos, C. A.; Sgourou, E. N. [University of Athens, Solid State Physics Section, Panepistimiopolis Zografos, Athens 157 84 (Greece)

    2014-05-14

    Electronic structure calculations employing screened hybrid density functional theory are used to gain fundamental insight into the interaction of carbon interstitial (C{sub i}) and substitutional (C{sub s}) atoms forming the C{sub i}C{sub s} defect known as G-center in silicon (Si). The G-center is one of the most important radiation related defects in Czochralski grown Si. We systematically investigate the density of states and formation energy for different types of C{sub i}C{sub s} defects with respect to the Fermi energy for all possible charge states. Prevalence of the neutral state for the C-type defect is established.

  12. Inhibitors of human tyrosyl-DNA phospodiesterase (hTdp1) developed by virtual screening using ligand-based pharmacophores.

    Science.gov (United States)

    Weidlich, Iwona E; Dexheimer, Thomas; Marchand, Christophe; Antony, Smitha; Pommier, Yves; Nicklaus, Marc C

    2010-01-01

    Human tyrosyl-DNA phosphodiesterase (hTdp1) inhibitors have become a major area of drug research and structure-based design since they have been shown to work synergistically with camptothecin (CPT) and selectively in cancer cells. The pharmacophore features of 14 hTdp1 inhibitors were used as a filter to screen the ChemNavigator iResearch Library of about 27 million purchasable samples. Docking of the inhibitors and hits obtained from virtual screening was performed into a structural model of hTdp1 based on a high resolution X-ray crystal structure of human Tdp1 in complex with vanadate, DNA and a human topoisomerase I (TopI)-derived peptide (PDB code: 1NOP). A total of 46 compounds matching the three-dimensional arrangement of the pharmacophoric features were assayed. Using a high-throughput screening assay, we have identified an 1H-indol-3-yl-acetic acid derivative as a potent Tdp1 inhibitor with an IC(50) value of 7.94 microM. The obtained novel chemotype may provide a new scaffold for developing inhibitors of Tdp1. Copyright (c) 2009. Published by Elsevier Ltd.

  13. Molecular modeling on pyruvate phosphate dikinase of Entamoeba histolytica and in silico virtual screening for novel inhibitors

    Science.gov (United States)

    Stephen, Preyesh; Vijayan, Ramachandran; Bhat, Audesh; Subbarao, N.; Bamezai, R. N. K.

    2008-09-01

    Pyruvate phosphate dikinase (PPDK) is the key enzyme essential for the glycolytic pathway in most common and perilous parasite Entamoeba histolytica. Inhibiting the function of this enzyme could control the wide spread of intestinal infections caused by Entamoeba histolytica in humans. With this objective, we modeled the three dimensional structure of the PPDK protein. We used templates with 51% identity and 67% similarity to employ homology-modeling approach. Stereo chemical quality of protein structure was validated by protein structure validation program PROCHECK and VERIFY3D. Experimental proof available in literature along with the in silico studies indicated Lys21, Arg91, Asp323, Glu325 and Gln337 to be the probable active sites in the target protein. Virtual screening was carried out using the genetic docking algorithm GOLD and a consensus scoring function X-Score to substantiate the prediction. The small molecule libraries (ChemDivision database, Diversity dataset, Kinase inhibitor database) were used for screening process. Along with the high scoring results, the interaction studies provided promising ligands for future experimental screening to inhibit the function of PPDK in Entamoeba histolytica. Further, the phylogeny study was carried out to assess the possibility of using the proposed ligands as inhibitors in related pathogens.

  14. A novel anti-tumor inhibitor identified by virtual screen with PLK1 structure and zebrafish assay.

    Directory of Open Access Journals (Sweden)

    Jing Lu

    Full Text Available Polo-like kinase 1 (PLK1, one of the key regulators of mitosis, is a target for cancer therapy due to its abnormally high activity in several tumors. Plk1 is highly conserved and shares a nearly identical 3-D structure between zebrafish and humans. The initial 10 mitoses of zebrafish embryonic cleavages occur every∼30 minutes, and therefore provide a rapid assay to evaluate mitosis inhibitors including those targeting Plk1. To increase efficiency and specificity, we first performed a computational virtual screen of∼60000 compounds against the human Plk1 3-D structure docked to both its kinase and Polo box domain. 370 candidates with the top free-energy scores were subjected to zebrafish assay and 3 were shown to inhibit cell division. Compared to general screen for compounds inhibiting zebrafish embryonic cleavage, computation increased the efficiency by 11 folds. One of the 3 compounds, named I2, was further demonstrated to effectively inhibit multiple tumor cell proliferation in vitro and PC3 prostate cancer growth in Xenograft mouse model in vivo. Furthermore, I2 inhibited Plk1 enzyme activity in a dose dependent manner. The IC50 values of I2 in these assays are compatible to those of ON-01910, a Plk1 inhibitor currently in Phase III clinic trials. Our studies demonstrate that zebrafish assays coupled with computational screening significantly improves the efficiency of identifying specific regulators of biological targets. The PLK1 inhibitor I2, and its analogs, may have potential in cancer therapeutics.

  15. Developing a Virtual Group Decision Support System Based on Fuzzy Hybrid MCDM Approach

    Directory of Open Access Journals (Sweden)

    Bahram Izadi

    2013-01-01

    Full Text Available Organizational decisions involve with unusually vague and conflicting criteria. This controversy increases empirical uncertainties, disputes, and the resulting consequences of these decisions. One possible method in subduing this problem is to apply quantitative approaches to provide a transparent process for resolute conclusions which enables decision makers to formulate accurate and decisive on time decisions. Although numerous methods are presented in the literature, the majority of them aim to develop theoretical models. However, this article aims to develop and implement an integrated fuzzy virtual MCDM model based on fuzzy AHP and fuzzy TOPSIS as a decision support system (DDS. Preventing disadvantageous face-to-face decision-making by achieving positive benefit from virtual decision making causes the proposed DDS to be suitable for making crucial decisions such as supplier selection, employee selection, employee appraisal, R&D project selection, etc. The proposed DDS has been implemented in an optical company in Iran.

  16. Identification of novel human dipeptidyl peptidase-IV inhibitors of natural origin (part I: virtual screening and activity assays.

    Directory of Open Access Journals (Sweden)

    Laura Guasch

    Full Text Available BACKGROUND: There has been great interest in determining whether natural products show biological activity toward protein targets of pharmacological relevance. One target of particular interest is DPP-IV whose most important substrates are incretins that, among other beneficial effects, stimulates insulin biosynthesis and secretion. Incretins have very short half-lives because of their rapid degradation by DPP-IV and, therefore, inhibiting this enzyme improves glucose homeostasis. As a result, DPP-IV inhibitors are of considerable interest to the pharmaceutical industry. The main goals of this study were (a to develop a virtual screening process to identify potential DPP-IV inhibitors of natural origin; (b to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits; and (c to use the most active hit for predicting derivatives with higher binding affinities for the DPP-IV binding site. METHODOLOGY/PRINCIPAL FINDINGS: We predicted that 446 out of the 89,165 molecules present in the natural products subset of the ZINC database would inhibit DPP-IV with good ADMET properties. Notably, when these 446 molecules were merged with 2,342 known DPP-IV inhibitors and the resulting set was classified into 50 clusters according to chemical similarity, there were 12 clusters that contained only natural products for which no DPP-IV inhibitory activity has been previously reported. Nine molecules from 7 of these 12 clusters were then selected for in vitro activity testing and 7 out of the 9 molecules were shown to inhibit DPP-IV (where the remaining two molecules could not be solubilized, preventing the evaluation of their DPP-IV inhibitory activity. Then, the hit with the highest activity was used as a lead compound in the prediction of more potent derivatives. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that our virtual-screening protocol was successful in identifying novel

  17. Virtual colonoscopy.

    Science.gov (United States)

    Vining, D J

    1997-04-01

    A new method for colon examination, virtual colonoscopy, has been created by combining spiral computed tomography and virtual reality computer technology. If virtual colonoscopy proves equal to or superior to traditional colonoscopy in sensitivity and specificity for cancer screening, it would yield significant clinical and public health benefits because of its potential for increased acceptance among patients as well as its considerably lower cost and risks.

  18. Identification of promising DNA GyrB inhibitors for Tuberculosis using pharmacophore-based virtual screening, molecular docking and molecular dynamics studies.

    Science.gov (United States)

    Islam, Md Ataul; Pillay, Tahir S

    2017-01-21

    In this study, we searched for potential DNA GyrB inhibitors using pharmacophore-based virtual screening followed by molecular docking and molecular dynamics simulation approaches. For this purpose, a set of 248 DNA GyrB inhibitors was collected from the literature and a well-validated pharmacophore model was generated. The best pharmacophore model explained that two each of hydrogen bond acceptors and hydrophobicity regions were critical for inhibition of DNA GyrB. Good statistical results of the pharmacophore model indicated that the model was robust in nature. Virtual screening of molecular databases revealed three molecules as potential antimycobacterial agents. The final screened promising compounds were evaluated in molecular docking and molecular dynamics simulation studies. In the molecular dynamics studies, RMSD and RMSF values undoubtedly explained that the screened compounds formed stable complexes with DNA GyrB. Therefore, it can be concluded that the compounds identified may have potential for the treatment of TB.

  19. Hybrid simulations : combining atomistic and coarse-grained force fields using virtual sites

    NARCIS (Netherlands)

    Rzepiela, Andrzej J.; Louhivuori, Martti; Peter, Christine; Marrink, Siewert J.

    2011-01-01

    Hybrid simulations, in which part of the system is represented at atomic resolution and the remaining part at a reduced, coarse-grained, level offer a powerful way to combine the accuracy associated with the atomistic force fields to the sampling speed obtained with coarse-grained (CG) potentials. I

  20. Virtual screening using MTiOpenScreen and PyRx 0,8 revealed ZINC95486216 as a human acetylcholinesterase inhibitor candidate

    Science.gov (United States)

    Sulistyo Dwi K., P.; Arindra Trisna, W.; Vindri Catur P., W.; Wijayanti, Erna; Ichsan, Mochammad

    2016-03-01

    One of the efforts to prevent Alzheimer's disease becomes more severe is by inhibiting the activity of Human acetylcholinesterase enzyme (PDB ID: 4BDT). In this study, virtual screening againts 885 natural compounds from AfroDB has been done using MTIOpenScreen and this step has been successful in identifying ZINC15121024 (-12,9) and ZINC95486216 (-12,7) as the top rank compounds. This data then strengthened by the results of second docking step using Autodock software that has been integrated in PyRx 0.8 software. From this stage, ZINC95486216 (-11,3 kcal/mol) is a compound with the most negative binding affinity compared with four Alzheimer's drugs that have been officially used to date including Rivastigmine (-6,3 Kcal/mol), Donepenzil (-7.9 kcal/mol), Galantamine (-8.4 kcal/mol), and Huprine W (-7.3 kcal/mol). In addition, based on the results of the 2D and 3D visualization using LigPlus and PyMol softwares, respectively, known that the five compounds above are equally capable of binding to several amino acids (Trp 286, Phe295, and Tyr341) located in the active site of Human Acetylcholinesterase enzyme.

  1. Making tangible the intangible: Hybridization of the real and the virtual to enhance learning of abstract phenomena

    Directory of Open Access Journals (Sweden)

    Stephanie FLECK

    2016-12-01

    Full Text Available Interactive systems based on Augmented Reality (AR and Tangible User Interfaces (TUI hold great promise for enhancing the learning and understanding of abstract phenomena. In particular, they enable to take advantage of numerical simulation and pedagogical supports, while keeping the learner involved in true physical experimentations. In this paper, we present three examples based on AR and TUI, where the concepts to be learnt are difficult to perceive. The first one, Helios, targets K-12 learners in the field of astronomy. The second one, Hobit is dedicated to experiments in wave optics. Finally, the third one, Teegi, allows one to get to know more about brain activity. These three hybrid interfaces have emerged from a common basis that jointly combines research and development work in the fields of Instructional Design and Human-Computer Interaction, from theoretical to practical aspects. On the basis of investigations carried out in real context of use and on the grounding works in education and HCI which corroborate the design choices that were made, we formalize how and why the hybridization of the real and the virtual enables to leverage the way learners understand intangible phenomena in Sciences education.

  2. Screening of BRD7 interacting proteins by yeast two-hybrid system

    Institute of Scientific and Technical Information of China (English)

    余鹰; 朱诗国; 张必成; 周鸣; 李小玲; 李桂源

    2002-01-01

    BRD7 gene is low or undetectably expressed in nasopharyngeal carcinoma tissue (NPC) and can obviously suppress the growth of NPC cell line HNE1. In this study, the proteins that interacted with BRD7 coding protein were screened by yeast two-hybrid system. The complete reading frame of BRD7 gene was subcloned into pAS2 vector (BRD7-BD). Then the human embryo brain cDNA library was screened by BRD7-BD bait. Eleven positive clones were obtained from 4.8×106 transformed clones. By sequencing directly, 6 interacting proteins of BRD7 coding protein were isolated (Bromodomain-containing 3 protein (BRD3), Bromodomain-containing 2 protein (BRD2), IκB kinase-beta, KIAA1375 protein, interleukin 7 and adaptor-related protein complex 3δ-1 subunit). These results suggest BRD7 protein might form heterogenous dimer or triplex polymer with BRD2 and/or BRD3 to participate in transcriptional regulation.

  3. Field Emission Properties of the Graphene Double-Walled Carbon Nanotube Hybrid Films Prepared by Vacuum Filtration and Screen Printing

    Directory of Open Access Journals (Sweden)

    Jinzhuo Xu

    2013-01-01

    Full Text Available The graphene double-walled carbon nanotube (DWCNT hybrid films were prepared by vacuum filtration and screen printing. Their electron field emission properties have been studied systematically. The electron emission properties of the hybrid films are much better than those of pure DWCNT films and pure graphene films. Comparing with the screen printed films, the vacuum filtered films have many advantages, such as lower turn-on field, higher emission current density, better uniformity, better long-term stability, and stronger adhesive strength with conductive substrates. The optimized hybrid films with 20% weight ratio of graphene, which were fabricated by vacuum filtration, show the best electron emission performances with a low turn-on field of 0.50 Vμm−1 (at 1 μAcm−2 and a high field enhancement factor β of 27000.

  4. Virtual Screening of Natural Products, Molecular Docking and Dynamics Simulations on M.tuberculosis S-adenosyl-L-homocysteine Hydrolase

    Directory of Open Access Journals (Sweden)

    Abdul-Rashid B. Sampaco Iii

    2015-12-01

    Full Text Available The activated methyl cycle of Mycobacterium tuberculosis(Mtbis responsible for the regeneration of S-adenosyl methionine (SAM from S-adenosyl-L-homocysteine (SAH. Inhibition of the key enzymes in this transformation may lead to accumulation of SAH and depletion of SAM in the Mtb cell. This has detrimental effects onthe bacterium’s cellular processes. Virtual screening of natural products from the Philippines and those in Ambinter database against S-adenosyl-L-homocysteine hydrolase (SAHH yielded the tautomer of the molecule, methyl 4-({2-[(4-hydroxy-2-oxo-1,2-dihydro-3-quinolinylcarbonyl]hydrazino}sulfonylphenylcarbamate, which displays better binding energy (-307.64 kcal/mol than the substrate, SAH (-270.601 kcal/mol. Molecular dynamics simulations at body temperature indicated that the hit-SAHH complex is more stable than the enzyme-substrate complex.

  5. Chromene-3-carboxamide derivatives discovered from virtual screening as potent inhibitors of the tumour maker, AKR1B10.

    Science.gov (United States)

    Endo, Satoshi; Matsunaga, Toshiyuki; Kuwata, Kazuo; Zhao, Hai-Tao; El-Kabbani, Ossama; Kitade, Yukio; Hara, Akira

    2010-04-01

    A human aldose reductase-like protein, AKR1B10 in the aldo-keto reductase (AKR) superfamily, was recently identified as a therapeutic target in the treatment of several types of cancer. In order to identify potential leads for new inhibitors of AKR1B10, we adopted the virtual screening approach using the automated program icm, which resulted in the discovery of several chromene-3-carboxamide derivatives as potent competitive inhibitors. The most potent (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide inhibited the reductase activity of AKR1B10 with a K(i) value of 2.7nM, and the metabolism of farnesal and 4-hydroxynonenal in the AKR1B10-overexpressed cells from 0.1microM with an IC(50) value equal to 0.8microM. Copyright 2010 Elsevier Ltd. All rights reserved.

  6. Structure-based virtual screening and discovery of New PPARδ/γ dual agonist and PPARδ and γ agonists.

    Directory of Open Access Journals (Sweden)

    Vinicius G Maltarollo

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are involved in the control of carbohydrate and lipid metabolism and are considered important targets to treat diabetes mellitus and metabolic syndrome. The available PPAR ligands have several side effects leading to health risks justifying the search for new bioactive ligands to activate the PPAR subtypes, in special PPARδ, the less studied PPAR isoform. Here, we used a structure-based virtual screening protocol in order to find out new PPAR ligands. From a lead-like subset of purchasable compounds, we identified 5 compounds with potential PPAR affinity and, from preliminary in vitro assays, 4 of them showed promising biological activity. Therefore, from our in silico and in vitro protocols, new PPAR ligands are potential candidates to treat metabolic diseases.

  7. Structure-Based Virtual Screening and Discovery of New PPARδ/γ Dual Agonist and PPARδ and γ Agonists

    Science.gov (United States)

    Maltarollo, Vinicius G.; Togashi, Marie; Nascimento, Alessandro S.; Honorio, Kathia M.

    2015-01-01

    Peroxisome proliferator-activated receptors (PPARs) are involved in the control of carbohydrate and lipid metabolism and are considered important targets to treat diabetes mellitus and metabolic syndrome. The available PPAR ligands have several side effects leading to health risks justifying the search for new bioactive ligands to activate the PPAR subtypes, in special PPARδ, the less studied PPAR isoform. Here, we used a structure-based virtual screening protocol in order to find out new PPAR ligands. From a lead-like subset of purchasable compounds, we identified 5 compounds with potential PPAR affinity and, from preliminary in vitro assays, 4 of them showed promising biological activity. Therefore, from our in silico and in vitro protocols, new PPAR ligands are potential candidates to treat metabolic diseases. PMID:25767888

  8. Exploring the readthrough of nonsense mutations by non-acidic Ataluren analogues selected by ligand-based virtual screening.

    Science.gov (United States)

    Pibiri, Ivana; Lentini, Laura; Tutone, Marco; Melfi, Raffaella; Pace, Andrea; Di Leonardo, Aldo

    2016-10-21

    Ataluren, also known as PTC124, is a 5-(fluorophenyl)-1,2,4-oxadiazolyl-benzoic acid suggested to suppress nonsense mutations by readthrough of premature stop codons in the mRNA. Potential interaction of PTC124 with mRNA has been recently studied by molecular dynamics simulations highlighting the importance of H-bonding and stacking π-π interactions. A series of non-acidic analogues of PTC124 were selected from a large database via a ligand-based virtual screening approach. Eight of them were synthesized and tested for their readthrough activity using the Fluc reporter harboring the UGA premature stop codon. The most active compound was further tested for suppression of the UGA nonsense mutation in the bronchial epithelial IB3.1 cell line carrying the W1282X mutation in the CFTR gene. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. Human rhinovirus 3C protease: generation of pharmacophore models for peptidic and nonpeptidic inhibitors and their application in virtual screening.

    Science.gov (United States)

    Steindl, Theodora; Laggner, Christian; Langer, Thierry

    2005-01-01

    Three-dimensional pharmacophore models for peptidic and small organic nonpeptidic inhibitors of the human rhinovirus 3C protease were generated in a structure-based as well as in a ligand-based approach, using the software package Catalyst. The inhibitors possess an electrophilic moiety, often a Michael acceptor function, which covalently binds to a cysteine in the active site of the enzyme. Since this process presents the key step for virus inactivation, the creation of a new function in Catalyst was required in order to include this decisive functionality into the pharmacophore models. In the present study we focus on this feature definition process because it presents an innovative strategy to expand the pharmacophore description ability of the Catalyst software to also include covalent bonds between ligand and binding site. The resulting hypotheses were then used for virtual screening of 3D databases in order to verify their quality and to search for structurally diverse, possible new lead substances.

  10. Hsp90 inhibitors, part 1: definition of 3-D QSAutogrid/R models as a tool for virtual screening.

    Science.gov (United States)

    Ballante, Flavio; Caroli, Antonia; Wickersham, Richard B; Ragno, Rino

    2014-03-24

    The multichaperone heat shock protein (Hsp) 90 complex mediates the maturation and stability of a variety of oncogenic signaling proteins. For this reason, Hsp90 has emerged as a promising target for anticancer drug development. Herein, we describe a complete computational procedure for building several 3-D QSAR models used as a ligand-based (LB) component of a comprehensive ligand-based (LB) and structure-based (SB) virtual screening (VS) protocol to identify novel molecular scaffolds of Hsp90 inhibitors. By the application of the 3-D QSAutogrid/R method, eight SB PLS 3-D QSAR models were generated, leading to a final multiprobe (MP) 3-D QSAR pharmacophoric model capable of recognizing the most significant chemical features for Hsp90 inhibition. Both the monoprobe and multiprobe models were optimized, cross-validated, and tested against an external test set. The obtained statistical results confirmed the models as robust and predictive to be used in a subsequent VS.

  11. A virtual clinical trial using projection-based nodule insertion to determine radiologist reader performance in lung cancer screening CT

    Science.gov (United States)

    Yu, Lifeng; Hu, Qiyuan; Koo, Chi Wan; Takahashi, Edwin A.; Levin, David L.; Johnson, Tucker F.; Hora, Megan J.; Dirks, Shane; Chen, Baiyu; McMillan, Kyle; Leng, Shuai; Fletcher, J. G.; McCollough, Cynthia H.

    2017-03-01

    Task-based image quality assessment using model observers is promising to provide an efficient, quantitative, and objective approach to CT dose optimization. Before this approach can be reliably used in practice, its correlation with radiologist performance for the same clinical task needs to be established. Determining human observer performance for a well-defined clinical task, however, has always been a challenge due to the tremendous amount of efforts needed to collect a large number of positive cases. To overcome this challenge, we developed an accurate projection-based insertion technique. In this study, we present a virtual clinical trial using this tool and a low-dose simulation tool to determine radiologist performance on lung-nodule detection as a function of radiation dose, nodule type, nodule size, and reconstruction methods. The lesion insertion and low-dose simulation tools together were demonstrated to provide flexibility to generate realistically-appearing clinical cases under well-defined conditions. The reader performance data obtained in this virtual clinical trial can be used as the basis to develop model observers for lung nodule detection, as well as for dose and protocol optimization in lung cancer screening CT.

  12. Identification of putative estrogen receptor-mediated endocrine disrupting chemicals using QSAR- and structure-based virtual screening approaches

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Liying; Sedykh, Alexander; Tripathi, Ashutosh [Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC (United States); Zhu, Hao [The Rutgers Center for Computational and Integrative Biology, Rutgers University, Camden, NJ (United States); Department of Chemistry, Rutgers University, Camden, NJ (United States); Afantitis, Antreas; Mouchlis, Varnavas D.; Melagraki, Georgia [NovaMechanics Ltd., Nicosia (Cyprus); Rusyn, Ivan, E-mail: iir@unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC (United States); Tropsha, Alexander, E-mail: alex_tropsha@unc.edu [Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC (United States)

    2013-10-01

    Identification of endocrine disrupting chemicals is one of the important goals of environmental chemical hazard screening. We report on the development of validated in silico predictors of chemicals likely to cause estrogen receptor (ER)-mediated endocrine disruption to facilitate their prioritization for future screening. A database of relative binding affinity of a large number of ERα and/or ERβ ligands was assembled (546 for ERα and 137 for ERβ). Both single-task learning (STL) and multi-task learning (MTL) continuous quantitative structure–activity relationship (QSAR) models were developed for predicting ligand binding affinity to ERα or ERβ. High predictive accuracy was achieved for ERα binding affinity (MTL R{sup 2} = 0.71, STL R{sup 2} = 0.73). For ERβ binding affinity, MTL models were significantly more predictive (R{sup 2} = 0.53, p < 0.05) than STL models. In addition, docking studies were performed on a set of ER agonists/antagonists (67 agonists and 39 antagonists for ERα, 48 agonists and 32 antagonists for ERβ, supplemented by putative decoys/non-binders) using the following ER structures (in complexes with respective ligands) retrieved from the Protein Data Bank: ERα agonist (PDB ID: 1L2I), ERα antagonist (PDB ID: 3DT3), ERβ agonist (PDB ID: 2NV7), and ERβ antagonist (PDB ID: 1L2J). We found that all four ER conformations discriminated their corresponding ligands from presumed non-binders. Finally, both QSAR models and ER structures were employed in parallel to virtually screen several large libraries of environmental chemicals to derive a ligand- and structure-based prioritized list of putative estrogenic compounds to be used for in vitro and in vivo experimental validation. - Highlights: • This is the largest curated dataset inclusive of ERα and β (the latter is unique). • New methodology that for the first time affords acceptable ERβ models. • A combination of QSAR and docking enables prediction of affinity and function.

  13. 4D Flexible Atom-Pairs: An efficient probabilistic conformational space comparison for ligand-based virtual screening

    Directory of Open Access Journals (Sweden)

    Jahn Andreas

    2011-07-01

    Full Text Available Abstract Background The performance of 3D-based virtual screening similarity functions is affected by the applied conformations of compounds. Therefore, the results of 3D approaches are often less robust than 2D approaches. The application of 3D methods on multiple conformer data sets normally reduces this weakness, but entails a significant computational overhead. Therefore, we developed a special conformational space encoding by means of Gaussian mixture models and a similarity function that operates on these models. The application of a model-based encoding allows an efficient comparison of the conformational space of compounds. Results Comparisons of our 4D flexible atom-pair approach with over 15 state-of-the-art 2D- and 3D-based virtual screening similarity functions on the 40 data sets of the Directory of Useful Decoys show a robust performance of our approach. Even 3D-based approaches that operate on multiple conformers yield inferior results. The 4D flexible atom-pair method achieves an averaged AUC value of 0.78 on the filtered Directory of Useful Decoys data sets. The best 2D- and 3D-based approaches of this study yield an AUC value of 0.74 and 0.72, respectively. As a result, the 4D flexible atom-pair approach achieves an average rank of 1.25 with respect to 15 other state-of-the-art similarity functions and four different evaluation metrics. Conclusions Our 4D method yields a robust performance on 40 pharmaceutically relevant targets. The conformational space encoding enables an efficient comparison of the conformational space. Therefore, the weakness of the 3D-based approaches on single conformations is circumvented. With over 100,000 similarity calculations on a single desktop CPU, the utilization of the 4D flexible atom-pair in real-world applications is feasible.

  14. 4D Flexible Atom-Pairs: An efficient probabilistic conformational space comparison for ligand-based virtual screening

    Science.gov (United States)

    2011-01-01

    Background The performance of 3D-based virtual screening similarity functions is affected by the applied conformations of compounds. Therefore, the results of 3D approaches are often less robust than 2D approaches. The application of 3D methods on multiple conformer data sets normally reduces this weakness, but entails a significant computational overhead. Therefore, we developed a special conformational space encoding by means of Gaussian mixture models and a similarity function that operates on these models. The application of a model-based encoding allows an efficient comparison of the conformational space of compounds. Results Comparisons of our 4D flexible atom-pair approach with over 15 state-of-the-art 2D- and 3D-based virtual screening similarity functions on the 40 data sets of the Directory of Useful Decoys show a robust performance of our approach. Even 3D-based approaches that operate on multiple conformers yield inferior results. The 4D flexible atom-pair method achieves an averaged AUC value of 0.78 on the filtered Directory of Useful Decoys data sets. The best 2D- and 3D-based approaches of this study yield an AUC value of 0.74 and 0.72, respectively. As a result, the 4D flexible atom-pair approach achieves an average rank of 1.25 with respect to 15 other state-of-the-art similarity functions and four different evaluation metrics. Conclusions Our 4D method yields a robust performance on 40 pharmaceutically relevant targets. The conformational space encoding enables an efficient comparison of the conformational space. Therefore, the weakness of the 3D-based approaches on single conformations is circumvented. With over 100,000 similarity calculations on a single desktop CPU, the utilization of the 4D flexible atom-pair in real-world applications is feasible. PMID:21733172

  15. GPCRs from fusarium graminearum detection, modeling and virtual screening - the search for new routes to control head blight disease.

    Science.gov (United States)

    Bresso, Emmanuel; Togawa, Roberto; Hammond-Kosack, Kim; Urban, Martin; Maigret, Bernard; Martins, Natalia Florencio

    2016-12-15

    Fusarium graminearum (FG) is one of the major cereal infecting pathogens causing high economic losses worldwide and resulting in adverse effects on human and animal health. Therefore, the development of new fungicides against FG is an important issue to reduce cereal infection and economic impact. In the strategy for developing new fungicides, a critical step is the identification of new targets against which innovative chemicals weapons can be designed. As several G-protein coupled receptors (GPCRs) are implicated in signaling pathways critical for the fungi development and survival, such proteins could be valuable efficient targets to reduce Fusarium growth and therefore to prevent food contamination. In this study, GPCRs were predicted in the FG proteome using a manually curated pipeline dedicated to the identification of GPCRs. Based on several successive filters, the most appropriate GPCR candidate target for developing new fungicides was selected. Searching for new compounds blocking this particular target requires the knowledge of its 3D-structure. As no experimental X-Ray structure of the selected protein was available, a 3D model was built by homology modeling. The model quality and stability was checked by 100 ns of molecular dynamics simulations. Two stable conformations representative of the conformational families of the protein were extracted from the 100 ns simulation and were used for an ensemble docking campaign. The model quality and stability was checked by 100 ns of molecular dynamics simulations previously to the virtual screening step. The virtual screening step comprised the exploration of a chemical library with 11,000 compounds that were docked to the GPCR model. Among these compounds, we selected the ten top-ranked nontoxic molecules proposed to be experimentally tested to validate the in silico simulation. This study provides an integrated process merging genomics, structural bioinformatics and drug design for proposing innovative

  16. Virtual-screening targeting Human Immunodeficiency Virus type 1 integrase-lens epithelium-derived growth factor/p75 interaction for drug development.

    Science.gov (United States)

    Gu, Wan-Gang; Liu, Bai-Nan; Yuan, Jun-Fa

    2015-02-01

    Three integrase (IN) inhibitors have been approved by FDA for clinical treatment of Human Immunodeficiency Virus (HIV) infection. This stimulates more researchers to focus their studies on this target for anti-HIV drug development. Three steps regarding of IN activity have been validated for inhibitor discovery: strand transfer, 3'-terminal processing, and IN-lens epithelium-derived growth factor (LEDGF)/p75 interaction. Among them, IN-LEDGF/p75 interaction is a new target validated in recent years. Emergence of drug-resistant virus strains makes this target appealing to pharmacologists. Compared with the traditional screening methods such as AlphaScreen and cell-based screening developed for IN inhibitor discovery, virtual screening is a powerful technique in modern drug discovery. Here we summarized the recent advances of virtual-screening targeting IN-LEDFG/p75 interaction. The combined application of virtual screening and experiments in drug discovery against IN-LEDFG/p75 interaction sheds light on anti-HIV research and drug discovery.

  17. USABILITY TESTING OF VIRTUAL KEYBOARD IN TOUCH SCREEN WITH QUESTIONNAIRE METHOD

    Directory of Open Access Journals (Sweden)

    Harijanto Pangetsu

    2014-05-01

    Full Text Available A system consists of input, process, and output. User interface is a place for users to interact in the system where one of the functions is as input facility of the system. One of the input tools is keyboard. With the development of touchscreen, then virtual keyboard is required. A good interface must be able to be used easily especially for novice users. The usability testing is required to know the usability level of the interface. A good usability has characteristics of effective to use (effectiveness, efficient to use (efficiency, safe to use (safety, having good utility (utility, easy to learn (learnability and easy to remember how to use (memorability. Usability testing is an evaluation approach involving users. With usability testing, it is expected that it can give positive inputs in designing an interface especially virtual keyboard interface mainly with the characteristics of easy to learn (learnability, and easy to remember how to use (memorability so that the resulted design can have good usability level

  18. [Performance by cytology and hybrid capture II in screening for high-grade squamous intraepithelial lesions in women with HIV].

    Science.gov (United States)

    Raposo, Letícia Martins; Velasque, Luciane; Luz, Paula Mendes; Friedman, Ruth Khalili; Cytryn, Andrea; Andrade, Angela Cristina Vasconcelos de; Vanni, Tazio; Brasil, Pedro E A A; Russomano, Fabio; Veloso, Valdiléa Gonçalves; Grinsztejn, Beatriz; Struchiner, Claudio José

    2011-07-01

    HIV-infected women are at increased risk of developing high-grade squamous intraepithelial lesions (HSIL), the precursor lesions for cervical cancer. This study estimated and compared the performance of cytology and hybrid capture II in screening for precursor lesions of cervical cancer among HIV-infected women. The study population consisted of women from the open prospective cohort at the Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation (IPEC/Fiocruz). Colposcopy and histology were considered jointly in defining the gold standard. Cytology showed 31.8% sensitivity and 95.5% specificity, while hybrid capture II showed higher sensitivity (100%) and lower specificity (52%). The positive likelihood ratio was 7.1 for cytology and 2.1 for hybrid capture II, while the negative likelihood ratio was 0.7 for cytology and 0.0 for hybrid capture II.

  19. Uroporphyrinogen decarboxylase as a potential target for specific components of traditional Chinese medicine: a virtual screening and molecular dynamics study.

    Science.gov (United States)

    Tsou, Yung-An; Chen, Kuan-Chung; Lin, Hung-Che; Chang, Su-Sen; Chen, Calvin Yu-Chian

    2012-01-01

    Uroporphyrinogen decarboxylase (UROD) has been suggested as a protectant against radiation for head and neck cancer (HNC). In this study, we employed traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan (http://tcm.cmu.edu.tw/) to screen for drug-like candidates with potential UROD inhibition characteristics using virtual screening techniques. Isopraeroside IV, scopolin, and nodakenin exhibited the highest Dock Scores, and were predicted to have good Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. Two common moieties, 2H-chromen-2-one and glucoside, were observed among the top TCM candidates. Cross comparison of the docking poses indicated that candidates formed stable interactions with key binding and catalytic residues of UROD through these two moieties. The 2H-chromen-2-one moiety enabled pi-cation interactions with Arg37 and H-bonds with Tyr164. The glucoside moiety was involved in forming H-bonds with Arg37 and Asp86. From our computational results, we propose isopraeroside IV, scopolin, and nodakenin as ligands that might exhibit drug-like inhibitory effects on UROD. The glucoside and 2H-chromen-2-one moieties may potentially be used for designing inhibitors of UROD.

  20. Virtual screening studies of Chinese medicine Coptidis Rhizoma as alpha7 nicotinic acetylcholine receptor agonists for treatment of Alzheimer's disease

    Science.gov (United States)

    Xiang, Li; Xu, Youdong; Zhang, Yan; Meng, Xianli; Wang, Ping

    2015-04-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease. Extensive in vitro and in vivo experiments have proved that the decreased activity of the cholinergic neuron is responsible for the memory and cognition deterioration. The alpha7 nicotinic acetylcholine receptor (α7-nAChR) is proposed to a drug target of AD, and compounds which acting as α7-nAChR agonists are considered as candidates in AD treatment. Chinese medicine CoptidisRhizoma and its compounds are reported in various anti-AD effects. In this study, virtual screening, docking approaches and hydrogen bond analyses were applied to screen potential α7-nAChR agonists from CoptidisRhizome. The 3D structure of the protein was obtained from PDB database. 87 reported compounds were included in this research and their structures were accessed by NCBI Pubchem. Docking analysis of the compounds was performed using AutoDock 4.2 and AutoDock Vina. The images of the binding modes hydrogen bonds and the hydrophobic interaction were rendered with PyMOL1.5.0.4. and LigPlot+ respectively. Finally, N-tran-feruloyltyramine, isolariciresinol, flavanone, secoisolariciresinol, (+)-lariciresinol and dihydrochalcone, exhibited the lowest docking energy of protein-ligand complex. The results indicate these 6 compounds are potential α7 nAChR agonists, and expected to be effective in AD treatment.

  1. MS-DOCK: accurate multiple conformation generator and rigid docking protocol for multi-step virtual ligand screening.

    Science.gov (United States)

    Sauton, Nicolas; Lagorce, David; Villoutreix, Bruno O; Miteva, Maria A

    2008-04-10

    The number of protein targets with a known or predicted tri-dimensional structure and of drug-like chemical compounds is growing rapidly and so is the need for new therapeutic compounds or chemical probes. Performing flexible structure-based virtual screening computations on thousands of targets with millions of molecules is intractable to most laboratories nor indeed desirable. Since shape complementarity is of primary importance for most protein-ligand interactions, we have developed a tool/protocol based on rigid-body docking to select compounds that fit well into binding sites. Here we present an efficient multiple conformation rigid-body docking approach, MS-DOCK, which is based on the program DOCK. This approach can be used as the first step of a multi-stage docking/scoring protocol. First, we developed and validated the Multiconf-DOCK tool that generates several conformers per input ligand. Then, each generated conformer (bioactives and 37970 decoys) was docked rigidly using DOCK6 with our optimized protocol into seven different receptor-binding sites. MS-DOCK was able to significantly reduce the size of the initial input library for all seven targets, thereby facilitating subsequent more CPU demanding flexible docking procedures. MS-DOCK can be easily used for the generation of multi-conformer libraries and for shape-based filtering within a multi-step structure-based screening protocol in order to shorten computation times.

  2. Uroporphyrinogen decarboxylase as a potential target for specific components of traditional Chinese medicine: a virtual screening and molecular dynamics study.

    Directory of Open Access Journals (Sweden)

    Yung-An Tsou

    Full Text Available Uroporphyrinogen decarboxylase (UROD has been suggested as a protectant against radiation for head and neck cancer (HNC. In this study, we employed traditional Chinese medicine (TCM compounds from TCM Database@Taiwan (http://tcm.cmu.edu.tw/ to screen for drug-like candidates with potential UROD inhibition characteristics using virtual screening techniques. Isopraeroside IV, scopolin, and nodakenin exhibited the highest Dock Scores, and were predicted to have good Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET properties. Two common moieties, 2H-chromen-2-one and glucoside, were observed among the top TCM candidates. Cross comparison of the docking poses indicated that candidates formed stable interactions with key binding and catalytic residues of UROD through these two moieties. The 2H-chromen-2-one moiety enabled pi-cation interactions with Arg37 and H-bonds with Tyr164. The glucoside moiety was involved in forming H-bonds with Arg37 and Asp86. From our computational results, we propose isopraeroside IV, scopolin, and nodakenin as ligands that might exhibit drug-like inhibitory effects on UROD. The glucoside and 2H-chromen-2-one moieties may potentially be used for designing inhibitors of UROD.

  3. Virtual screening of phytochemicals to novel targets in Haemophilus ducreyi towards the treatment of Chancroid.

    Science.gov (United States)

    Tripathi, Pranav; Chaudhary, Ritu; Singh, Ajeet

    2014-01-01

    Conventionally, drugs are discovered by testing chemically synthesized compounds against a battery of in vivo biological screens. Information technology and Omic science enabled us for high throughput screening of compound libraries against biological targets and hits are then tested for efficacy in cells or animals. Chancroid, caused by Haemophilus ducreyi is a public health problem and has been recognized as a cofactor for Human Immunodeficiency Virus (HIV) transmission. It facilitates HIV transmission by providing an accessible portal entry, promoting viral shedding, and recruiting macrophages as well as CD4 cells to the skin. So, there is a requirement to develop an efficient drug to combat Chancroid that can also diminish HIV infection. In-silico screening of potential inhibitors against the target may facilitate in detection of the novel lead compounds for developing an effective chemo preventive strategy against Haemophilus ducreyi. The present study has investigated the effects of approximately 1100 natural compounds that inhibit three vital enzymes viz. Phosphoenolpyruvate phosphotransferase, Acetyl-coenzyme A carboxylase and Fructose 1, 6-bisphosphatase of Haemophilus ducreyi in reference to a commercial drug Rifabutin. Results reveal that the lead compound uses less energy to bind to target. The lead compound parillin has also been predicted as less immunogenic in comparison to Rifabutin. Further, better molecular dynamics, pharmacokinetics, pharmacodynamics and ADME-T properties establish it as an efficient chancroid preventer.

  4. Dual Binding Site and Selective Acetylcholinesterase Inhibitors Derived from Integrated Pharmacophore Models and Sequential Virtual Screening

    Directory of Open Access Journals (Sweden)

    Shikhar Gupta

    2014-01-01

    Full Text Available In this study, we have employed in silico methodology combining double pharmacophore based screening, molecular docking, and ADME/T filtering to identify dual binding site acetylcholinesterase inhibitors that can preferentially inhibit acetylcholinesterase and simultaneously inhibit the butyrylcholinesterase also but in the lesser extent than acetylcholinesterase. 3D-pharmacophore models of AChE and BuChE enzyme inhibitors have been developed from xanthostigmine derivatives through HypoGen and validated using test set, Fischer’s randomization technique. The best acetylcholinesterase and butyrylcholinesterase inhibitors pharmacophore hypotheses Hypo1_A and Hypo1_B, with high correlation coefficient of 0.96 and 0.94, respectively, were used as 3D query for screening the Zinc database. The screened hits were then subjected to the ADME/T and molecular docking study to prioritise the compounds. Finally, 18 compounds were identified as potential leads against AChE enzyme, showing good predicted activities and promising ADME/T properties.

  5. Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening

    Science.gov (United States)

    Kalid, Ori; Mense, Martin; Fischman, Sharon; Shitrit, Alina; Bihler, Hermann; Ben-Zeev, Efrat; Schutz, Nili; Pedemonte, Nicoletta; Thomas, Philip J.; Bridges, Robert J.; Wetmore, Diana R.; Marantz, Yael; Senderowitz, Hanoch

    2010-12-01

    Folding correctors of F508del-CFTR were discovered by in silico structure-based screening utilizing homology models of CFTR. The intracellular segment of CFTR was modeled and three cavities were identified at inter-domain interfaces: (1) Interface between the two Nucleotide Binding Domains (NBDs); (2) Interface between NBD1 and Intracellular Loop (ICL) 4, in the region of the F508 deletion; (3) multi-domain interface between NBD1:2:ICL1:2:4. We hypothesized that compounds binding at these interfaces may improve the stability of the protein, potentially affecting the folding yield or surface stability. In silico structure-based screening was performed at the putative binding-sites and a total of 496 candidate compounds from all three sites were tested in functional assays. A total of 15 compounds, representing diverse chemotypes, were identified as F508del folding correctors. This corresponds to a 3% hit rate, tenfold higher than hit rates obtained in corresponding high-throughput screening campaigns. The same binding sites also yielded potentiators and, most notably, compounds with a dual corrector-potentiator activity (dual-acting). Compounds harboring both activity types may prove to be better leads for the development of CF therapeutics than either pure correctors or pure potentiators. To the best of our knowledge this is the first report of structure-based discovery of CFTR modulators.

  6. A hybrid mortar virtual element method for discrete fracture network simulations

    Science.gov (United States)

    Benedetto, Matías Fernando; Berrone, Stefano; Borio, Andrea; Pieraccini, Sandra; Scialò, Stefano

    2016-02-01

    The most challenging issue in performing underground flow simulations in Discrete Fracture Networks (DFN) is to effectively tackle the geometrical difficulties of the problem. In this work we put forward a new application of the Virtual Element Method combined with the Mortar method for domain decomposition: we exploit the flexibility of the VEM in handling polygonal meshes in order to easily construct meshes conforming to the traces on each fracture, and we resort to the mortar approach in order to "weakly" impose continuity of the solution on intersecting fractures. The resulting method replaces the need for matching grids between fractures, so that the meshing process can be performed independently for each fracture. Numerical results show optimal convergence and robustness in handling very complex geometries.

  7. Integrating sampling techniques and inverse virtual screening: toward the discovery of artificial peptide-based receptors for ligands.

    Science.gov (United States)

    Pérez, Germán M; Salomón, Luis A; Montero-Cabrera, Luis A; de la Vega, José M García; Mascini, Marcello

    2016-05-01

    A novel heuristic using an iterative select-and-purge strategy is proposed. It combines statistical techniques for sampling and classification by rigid molecular docking through an inverse virtual screening scheme. This approach aims to the de novo discovery of short peptides that may act as docking receptors for small target molecules when there are no data available about known association complexes between them. The algorithm performs an unbiased stochastic exploration of the sample space, acting as a binary classifier when analyzing the entire peptides population. It uses a novel and effective criterion for weighting the likelihood of a given peptide to form an association complex with a particular ligand molecule based on amino acid sequences. The exploratory analysis relies on chemical information of peptides composition, sequence patterns, and association free energies (docking scores) in order to converge to those peptides forming the association complexes with higher affinities. Statistical estimations support these results providing an association probability by improving predictions accuracy even in cases where only a fraction of all possible combinations are sampled. False positives/false negatives ratio was also improved with this method. A simple rigid-body docking approach together with the proper information about amino acid sequences was used. The methodology was applied in a retrospective docking study to all 8000 possible tripeptide combinations using the 20 natural amino acids, screened against a training set of 77 different ligands with diverse functional groups. Afterward, all tripeptides were screened against a test set of 82 ligands, also containing different functional groups. Results show that our integrated methodology is capable of finding a representative group of the top-scoring tripeptides. The associated probability of identifying the best receptor or a group of the top-ranked receptors is more than double and about 10 times higher

  8. High-throughput virtual screening with e-pharmacophore and molecular simulations study in the designing of pancreatic lipase inhibitors

    Directory of Open Access Journals (Sweden)

    Veeramachaneni GK

    2015-08-01

    Full Text Available Ganesh Kumar Veeramachaneni, K Kranthi Raj, Leela Madhuri Chalasani, Jayakumar Singh Bondili, Venkateswara Rao Talluri Department of Biotechnology, K L University, Guntur, India Background: Obesity is a progressive metabolic disorder in the current world population, and is characterized by the excess deposition of fat in the adipose tissue. Pancreatic lipase is one of the key enzymes in the hydrolysis of triglycerides into monoglycerides and free fatty acids, and is thus considered a promising target for the treatment of obesity. The present drugs used for treating obesity do not give satisfactory results, and on prolonged usage result in severe side effects. In view of the drastic increase in the obese population day-to-day, there is a greater need to discover new drugs with lesser side effects.Materials and methods: High-throughput virtual screening combined with e-pharmacophore screening and ADME (absorption, distribution, metabolism, and excretion and PAINS (pan-assay interference compounds filters were applied to screen out the ligand molecules from the ZINC natural molecule database. The screened molecules were subjected to Glide XP docking to study the molecular interactions broadly. Further, molecular dynamic simulations were used to validate the stability of the enzyme–ligand complexes. Finally, the molecules with better results were optimized for in vitro testing.Results: The screening protocols identified eight hits from the natural molecule database, which were further filtered through pharmacological filters. The final four hits were subjected to extra precision docking, and the complexes were finally studied with molecular dynamic simulations. The results pointed to the zinc 85893731 molecule as the most stable in the binding pocket, producing consistent H-bond interaction with Ser152 (G=-7.18. The optimized lead molecule exhibited good docking score, better fit, and improved ADME profile.Conclusion: The present study specifies

  9. A Privacy-aware Virtual Machine Migration Framework on Hybrid Clouds

    Directory of Open Access Journals (Sweden)

    Hongli Zhang

    2014-05-01

    Full Text Available With the proliferation of hybrid clouds in both cost-saving and effectiveness, a growing number of users are building their own private cloud. However, private cloud can only provide limited resource, and always resorts to public cloud in order to meet elastic service requirements. Generally, public cloud is operated by commercial service providers (CSPs who are not completely honest with users to some extent. So, existing hybrid clouds service models are hampered by privacy concerns, and one of the main reasons is that a majority of users’ workloads involves sensitive contents and therefore can’t be directly outsourced to public cloud without proper protection. In this paper, we present a novel framework that makes such privacy-aware VM migration effectively. At First, all the users’ workloads are uploading and running in private cloud VMs then labeling the sensitive and non-sensitive VMs. Then, we design an effective way focusing on how to get VM migration queue without introducing heavy inter-cloud communication traffic after migration. Finally, non-sensitive VMs are migrated to public cloud with utmost effort by live migration premised on minimal service level agreement (SLA disruption. Experiment results illustrate that our proposed framework is effective while occurring an acceptable communication overhead

  10. Development of Drugs for Epstein - Barr virus using High-Throughput in silico Virtual Screening

    Science.gov (United States)

    Li, Ning; Thompson, Scott; Jiang, Hualiang; Lieberman, Paul M.; Luo, Cheng

    2010-01-01

    Importance of the field Epstein-Barr virus (EBV) is a ubiquitious human herpesvirus that is causally associated with endemic forms of Burkitt’s lymphoma (BL), nasopharyngeal carcinoma, and lymphoproliferative disease in immunosuppressed individuals. On a global scale, EBV infects over 90% of the adult population and is responsible for ~1% of all human cancers. To date, there is no efficacious drug or therapy for the treatment of EBV infection and EBV-related diseases. Areas covered in this review In this review, we discuss the existing anti-EBV inhibitors and those under development. We discuss the value of different molecular targets, including EBV lytic DNA replication enzymes, as well as proteins that are expressed exclusively during latent infection, like EBNA1 and LMP1. Since the atomic structure of the EBNA1 DNA binding domain has been described, it is an attractive target for in silico methods of drug design and small molecule screening. We discuss the use of computational methods that can greatly facilitate the development of novel inhibitors and how in silico screening methods can be applied to target proteins with known structures, like EBNA1, to treat EBV infection and disease. What the reader will gain The reader will be familiarized with the problems in targeting of EBV for inhibition by small molecules and how computational methods can greatly facilitate this process. Take home message Despite the impressive efficacy of nucleoside analogues for the treatment of herpesvirus lytic infection, there remain few effective treatments for latent infections. Since EBV-latent infection persists within and contributes to the formation of EBV-associated cancers, targeting EBV latent proteins is an unmet medical need. High throughput in silico screening can accelerate the process of drug discovery for novel and selective agents that inhibit EBV latent infection and associated disease. PMID:22822721

  11. Structure-Based Virtual Ligand Screening on the XRCC4/DNA Ligase IV Interface

    Science.gov (United States)

    Menchon, Grégory; Bombarde, Oriane; Trivedi, Mansi; Négrel, Aurélie; Inard, Cyril; Giudetti, Brigitte; Baltas, Michel; Milon, Alain; Modesti, Mauro; Czaplicki, Georges; Calsou, Patrick

    2016-03-01

    The association of DNA Ligase IV (Lig4) with XRCC4 is essential for repair of DNA double-strand breaks (DSBs) by Non-homologous end-joining (NHEJ) in humans. DSBs cytotoxicity is largely exploited in anticancer therapy. Thus, NHEJ is an attractive target for strategies aimed at increasing the sensitivity of tumors to clastogenic anticancer treatments. However the high affinity of the XRCC4/Lig4 interaction and the extended protein-protein interface make drug screening on this target particularly challenging. Here, we conducted a pioneering study aimed at interfering with XRCC4/Lig4 assembly. By Molecular Dynamics simulation using the crystal structure of the complex, we first delineated the Lig4 clamp domain as a limited suitable target. Then, we performed in silico screening of ~95,000 filtered molecules on this Lig4 subdomain. Hits were evaluated by Differential Scanning Fluorimetry, Saturation Transfer Difference - NMR spectroscopy and interaction assays with purified recombinant proteins. In this way we identified the first molecule able to prevent Lig4 binding to XRCC4 in vitro. This compound has a unique tripartite interaction with the Lig4 clamp domain that suggests a starting chemotype for rational design of analogous molecules with improved affinity.

  12. High-throughput virtual screening using quantum mechanical probes: discovery of selective kinase inhibitors.

    Science.gov (United States)

    Zhou, Ting; Caflisch, Amedeo

    2010-07-05

    A procedure based on semi-empirical quantum mechanical (QM) calculations of interaction energy is proposed for the rapid screening of compound poses generated by high-throughput docking. Small molecules (consisting of 2-10 atoms and termed "probes") are overlapped with polar groups in the binding site of the protein target. The interaction energy values between each compound pose and the probes, calculated by a semi-empirical Hamiltonian, are used as filters. The QM probe method does not require fixed partial charges and takes into account polarization and charge-transfer effects which are not captured by conventional force fields. The procedure is applied to screen approximately 100 million poses (of 2.7 million commercially available compounds) obtained by high-throughput docking in the ATP binding site of the tyrosine kinase erythropoietin-producing human hepatocellular carcinoma receptor B4 (EphB4). Three QM probes on the hinge region and one at the entrance pocket are employed to select for binding affinity, while a QM probe on the side chain of the so-called gatekeeper residue (a hypervariable residue in the kinome) is used to enforce selectivity. The poses with favorable interactions with the five QM probes are filtered further for hydrophobic matching and low ligand strain. In this way, a single-digit micromolar inhibitor of EphB4 with a relatively good selectivity profile is identified in a multimillion-compound library upon experimental tests of only 23 molecules.

  13. Benchmarking Ligand-Based Virtual High-Throughput Screening with the PubChem Database

    Directory of Open Access Journals (Sweden)

    Mariusz Butkiewicz

    2013-01-01

    Full Text Available With the rapidly increasing availability of High-Throughput Screening (HTS data in the public domain, such as the PubChem database, methods for ligand-based computer-aided drug discovery (LB-CADD have the potential to accelerate and reduce the cost of probe development and drug discovery efforts in academia. We assemble nine data sets from realistic HTS campaigns representing major families of drug target proteins for benchmarking LB-CADD methods. Each data set is public domain through PubChem and carefully collated through confirmation screens validating active compounds. These data sets provide the foundation for benchmarking a new cheminformatics framework BCL::ChemInfo, which is freely available for non-commercial use. Quantitative structure activity relationship (QSAR models are built using Artificial Neural Networks (ANNs, Support Vector Machines (SVMs, Decision Trees (DTs, and Kohonen networks (KNs. Problem-specific descriptor optimization protocols are assessed including Sequential Feature Forward Selection (SFFS and various information content measures. Measures of predictive power and confidence are evaluated through cross-validation, and a consensus prediction scheme is tested that combines orthogonal machine learning algorithms into a single predictor. Enrichments ranging from 15 to 101 for a TPR cutoff of 25% are observed.

  14. Pharmacophore modeling improves virtual screening for novel peroxisome proliferator-activated receptor-gamma ligands

    Science.gov (United States)

    Lewis, Stephanie N.; Garcia, Zulma; Hontecillas, Raquel; Bassaganya-Riera, Josep; Bevan, David R.

    2015-05-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear hormone receptor involved in regulating various metabolic and immune processes. The PPAR family of receptors possesses a large binding cavity that imparts promiscuity of ligand binding not common to other nuclear receptors. This feature increases the challenge of using computational methods to identify PPAR ligands that will dock favorably into a structural model. Utilizing both ligand- and structure-based pharmacophore methods, we sought to improve agonist prediction by grouping ligands according to pharmacophore features, and pairing models derived from these features with receptor structures for docking. For 22 of the 33 receptor structures evaluated we observed an increase in true positive rate (TPR) when screening was restricted to compounds sharing molecular features found in rosiglitazone. A combination of structure models used for docking resulted in a higher TPR (40 %) when compared to docking with a single structure model (PPARγ ligands using multiple structure models, ligand-based pharmacophore data, evaluation of protein-ligand interactions, and comparison of docking datasets. The unique combination of methods presented here holds potential for more efficient screening of compounds with unknown affinity for PPARγ that could serve as candidates for therapeutic development.

  15. Screening for cardiac HERG potassium channel interacting proteins using the yeast two-hybrid technique.

    Science.gov (United States)

    Ma, Qingyan; Yu, Hong; Lin, Jijin; Sun, Yifan; Shen, Xinyuan; Ren, Li

    2014-02-01

    The human ERG protein (HERG or Kv 11.1) encoded by the human ether-a-go-go-related gene (herg) is the pore-forming subunit of the cardiac delayed rectifier potassium current (IKr) responsible for action potential (AP) repolarization. Mutations in HERG lead to long-QT syndrome, a major cause of arrhythmias. Protein-protein interactions are fundamental for ion channel trafficking, membrane localization, and functional modulation. To identify proteins involved in the regulation of the HERG channel, we conducted a yeast two-hybrid screen of a human heart cDNA library using the C-terminus or N-terminus of HERG as bait. Fifteen proteins were identified as HERG amino terminal (HERG-NT)-interacting proteins, including Caveolin-1 (a membrane scaffold protein with multiple interacting partners, including G-proteins, kinases and NOS), the zinc finger protein, FHL2 and PTPN12 (a non-receptor tyrosine phosphatase). Eight HERG carboxylic terminal (HERG-CT)-interacting proteins were also identified, including the NF-κB-interacting protein myotrophin, We have identified multiple potential interacting proteins that may regulate cardiac IKr through cytoskeletal interactions, G-protein modulation, phosphorylation and downstream second messenger and transcription cascades. These findings provide further insight into dynamic modulation of HERG under physiological conditions and arrhythmogenesis.

  16. New classes of mind bomb-interacting proteins identified from yeast two-hybrid screens.

    Science.gov (United States)

    Tseng, Li-Chuan; Zhang, Chengjin; Cheng, Chun-Mei; Xu, Haoying; Hsu, Chia-Hao; Jiang, Yun-Jin

    2014-01-01

    Notch signaling pathway defines an evolutionarily conserved mechanism in cell-fate determination in a broad spectrum of developmental processes through local cell interactions. mind bomb (mib) encodes an E3 ubiquitin ligase that is involved in Notch activation through Delta ubiquitylation and internalization. To further dissect the function of Mib, two yeast two-hybrid screens for zebrafish Mib/Mib2-binding proteins with different strategies have been performed. 81 putative interesting proteins were discovered and classified into six groups: ubiquitin proteasome pathway, cytoskeleton, trafficking, replication/transcription/translation factors, cell signaling and others. Confirmed by coimmunoprecipitation (Co-IP), Mib interacted with four tested proteins: ubiquitin specific protease 1 (Usp1), ubiquitin specific protease 9 (Usp9), tumor-necrosis-factor-receptor-associated factor (TRAF)-binding domain (Trabid)/zinc finger, RAN-binding domain containing 1 (Zranb1) and hypoxia-inducible factor 1, alpha subunit inhibitor (Hif1an)/factor inhibiting HIF 1 (Fih-1). Usp1, Usp9, Trabid and Fih-1 also bound to zebrafish Mib2, a Mib homolog with similar structural domains and functions. Both Mib and Mib2 can ubiquitylate Trabid and Fih-1, indicating a potential regulating role of Mib and Mib2 on Trabid and Fih-1 and, furthermore, the possible involvement of Notch signaling in hypoxia-regulated differentiation, tumorigenesis and NF-κB pathway. Finally, functions of confirmed Mib/Mib2-interacting proteins are collated, summarized and hypothesized, which depicts a regulating network beyond Notch signaling.

  17. Microsatellite-Aided Screening for Fertility Restoration Genes (Rf Facilitates Hybrid Improvement

    Directory of Open Access Journals (Sweden)

    Raafat El-Namaky

    2016-05-01

    Full Text Available DNA markers enabled to determine the chromosomal locations of the two Rf genes (Rf3 and Rf4 in the wild-abortive cytoplasmic male sterility (WA-CMS system. Four simple sequence repeats (SSRs RM171, RM258, RM315 and RM443 were used to detect the allelic status with respect to the fertility restoration genes (Rf3 and Rf4 in 300 rice cultivars or breeding lines. The results revealed that out of 300 lines, 90 lines screened had Rf3, 65 lines had Rf4, and 45 lines had Rf3 and Rf4 alleles. Furthermore, 45 lines selected using SSR markers were mated with a CMS line (IR58025A to analyze their restoring ability. Offspring of all the test lines except HHZ8-SAL9DT1-Y1, HHZ5-SAL9-Y3-1 and IDSA77 exhibited higher pollen and spikelet fertility (> 80%, thus confirming they bear the Rf alleles. The hybrid offspring of ARH12-6-1-1-B-3-1, IR32307-10-3-2-1 and Sahel 329 had the highest pollen fertility (97.39%, 98.30% and 97.10%, respectively and spikelet fertility (95.10%, 97.07% and 96.10%, respectively.

  18. Microsatellite-Aided Screening for Fertility Restoration Genes (Rf) Facilitates Hybrid Improvement

    Institute of Scientific and Technical Information of China (English)

    RAAFAT El-Namaky; SABER Sedeek; YONNELLE Dea Moukoumbi; RODOMIRO Ortiz; BABOUCARR Manneh

    2016-01-01

    DNA markers enabled to determine the chromosomal locations of the twoRf genes (Rf3 andRf4) in the wild-abortive cytoplasmic male sterility (WA-CMS) system. Four simple sequence repeats (SSRs) RM171, RM258, RM315 and RM443 were used to detect the alelic status with respect to the fertility restoration genes (Rf3and Rf4) in 300 rice cultivars or breeding lines. The results revealed that out of 300 lines, 90 lines screened hadRf3, 65 lines hadRf4, and 45 lines hadRf3 andRf4 aleles. Furthermore, 45 lines selected using SSR markers were mated with a CMS line (IR58025A) to analyze their restoring ability. Offspring of al the test lines except HHZ8-SAL9DT1-Y1, HHZ5-SAL9-Y3-1 and IDSA77 exhibited higher polen and spikelet fertility (> 80%), thus confirming they bear theRfaleles. The hybrid offspring of ARH12-6-1-1-B-3-1, IR32307-10-3-2-1 and Sahel 329 had the highest polen fertility (97.39%, 98.30% and 97.10%, respectively) and spikelet fertility (95.10%, 97.07% and 96.10%, respectively).

  19. A screened hybrid density functional study on energetic complexes: cobalt, nickel and copper carbohydrazide perchlorates.

    Science.gov (United States)

    Huang, Huisheng; Zhang, Tonglai; Zhang, Jianguo; Wang, Liqiong

    2010-07-15

    The molecular geometry, electronic structure, infrared spectra and thermochemical properties of cobalt and nickel tris(carbohydrazide) perchlorates (CoCP and NiCP) as well as copper bis(carbohydrazide) perchlorate (CuCP) were investigated using the Heyd-Scuseria-Ernzerhof (HSE) screened hybrid density functional. The results show that both perchlorate ions coordinate with the copper atom, and the interactions between copper and perchlorate are ionic, whereas all the metal-carbohydrazide interactions are covalent. Due to the delocalization from the sigma(N-H) bond orbital to the n*(M) antibond orbital, the amino stretching vibrations of these complexes show considerable red-shift compared with those of free carbohydrazide ligand. The calculated heats of reaction and formation indicate that the formations of these complexes are exothermic, and the order of their thermal stability is NiCP>CoCP>CuCP. These agree well with the experimental results. Finally, we find that there is a relationship between the energy gap and impact sensitivity.

  20. New Tools for Embryo Selection: Comprehensive Chromosome Screening by Array Comparative Genomic Hybridization

    Directory of Open Access Journals (Sweden)

    Lorena Rodrigo

    2014-01-01

    Full Text Available The objective of this study was to evaluate the usefulness of comprehensive chromosome screening (CCS using array comparative genomic hybridization (aCGH. The study included 1420 CCS cycles for recurrent miscarriage (n=203; repetitive implantation failure (n=188; severe male factor (n=116; previous trisomic pregnancy (n=33; and advanced maternal age (n=880. CCS was performed in cycles with fresh oocytes and embryos (n=774; mixed cycles with fresh and vitrified oocytes (n=320; mixed cycles with fresh and vitrified day-2 embryos (n=235; and mixed cycles with fresh and vitrified day-3 embryos (n=91. Day-3 embryo biopsy was performed and analyzed by aCGH followed by day-5 embryo transfer. Consistent implantation (range: 40.5–54.2% and pregnancy rates per transfer (range: 46.0–62.9% were obtained for all the indications and independently of the origin of the oocytes or embryos. However, a lower delivery rate per cycle was achieved in women aged over 40 years (18.1% due to the higher percentage of aneuploid embryos (85.3% and lower number of cycles with at least one euploid embryo available per transfer (40.3%. We concluded that aneuploidy is one of the major factors which affect embryo implantation.

  1. Calculation of point defects in rutile TiO2 by the Screened Exchange Hybrid Functional

    CERN Document Server

    Lee, Hsin-Yi; Robertson, John

    2012-01-01

    The formation energies of the oxygen vacancy and titanium interstitial in rutile TiO2 were calculated by the screened exchange (sX) hybrid density functional method, which gives a band gap of 3.1 eV, close to the experimental value. The O vacancy gives rise to a gap state lying 0.7 eV below the conduction band edge, whose charge density is localised around the two of three Ti atoms next to the vacancy. The Ti interstitial generates four defect states in the gap, whose unpaired electrons lie on the interstitial and the adjacent Ti 3d orbitals. The formation energy for the neutral O vacancy is 1.9 eV for the O-poor chemical potential, and similar to that of the neutral Ti interstitial, and has a lower formation energy for Ti interstitial under O-rich conditions. This indicates that both the O vacancy and Ti interstitial are relevant for oxygen deficiency in rutile TiO2 but the O vacancy will dominate under O-rich conditions. This resolves the questions about defect localisation and defect predominance in the li...

  2. The hybrid doctor-patient relationship in the age of technology - Telepsychiatry consultations and the use of virtual space.

    Science.gov (United States)

    Yellowlees, Peter; Richard Chan, Steven; Burke Parish, Michelle

    2015-01-01

    The doctor-patient relationship is evolving and changing through the impact of many technological, social and environmental factors. These factors will be examined, especially the impact of changing attitudes among younger generations of physicians and patients who live in an information-driven networked world. Telepsychiatry is already over 50 years old and has a strong evidence base which suggests that it is a better form of practice compared with the traditional in-person consultation for certain patient groups. In particular, telepsychiatry encourages intimacy in relationships through the use of the 'virtual space' in the consultation, better collaboration between psychiatrists and primary care physicians, and improved patient satisfaction. The practice of psychiatry will change through the use of mobile devices, asynchronous consultations, and the opportunities that automated interpretation and translation bring to work across cultures. The future will likely bring many psychiatrists working increasingly in a hybrid model, both in-person, and online, using the strengths of both approaches to improve patient care.

  3. Virtual Laboratories and Virtual Worlds

    CERN Document Server

    Hut, Piet

    2007-01-01

    Since we cannot put stars in a laboratory, astrophysicists had to wait till the invention of computers before becoming laboratory scientists. For half a century now, we have been conducting experiments in our virtual laboratories. However, we ourselves have remained behind the keyboard, with the screen of the monitor separating us from the world we are simulating. Recently, 3D on-line technology, developed first for games but now deployed in virtual worlds like Second Life, is beginning to make it possible for astrophysicists to enter their virtual labs themselves, in virtual form as avatars. This has several advantages, from new possibilities to explore the results of the simulations to a shared presence in a virtual lab with remote collaborators on different continents. I will report my experiences with the use of Qwaq Forums, a virtual world developed by a new company (see http://www.qwaq.com)

  4. Screening of proteins that interact with human thrombopoietin receptor c-Mpl using yeast two-hybrid system

    Institute of Scientific and Technical Information of China (English)

    赵新燕[1; 冯丽冰[2; 周伟国[3; 戴卫列[4; 李昌本[5; 赵寿元[6

    2000-01-01

    Thrombopoietin (TPO) is the major cytokine involved in platelet production and exerts its effects via the receptor c-Mpl. The yeast two-hybrid system has been used to screen the proteins interacting with c-Mpl. First, the cDNA fragment of c-Mpl intracellular domain was cloned into two-hybrid vector pAS2, and the resulting plasmid is designated as pASMM. Then a human placenta cDNA library was screened using the pASMM as a target plasmid. Seven positive clones were isolated from 150 000 independent transformants. Sequence analysis of one of the positive clones demonstrates that a part of coding sequence of vimentin from 611 bp to 3’ end and flanking non-translation region was obtained. Therefore, there is an interaction between vimentin and TPO receptor. The results suggest that cytoskeletal protein may play an important role in TPO signal transduction pathway.

  5. Screening of proteins that interact with human thrombopoietin receptor c-Mpl using yeast two-hybrid system

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Thrombopoietin(TPO) is the major cytokine involved in platelet production and exerts its effects via the receptor c-Mpl.The yeast two-hybrid system has been used to screen the proteins interacting with c-Mpl.First,the cDNA fragment of c-Mpl intracellular domain was cloned into two-hybrid vector pAS2,and the resulting plasmid is designated as pASMM.Then a human placenta cDNA library was screened using the pASMM as a target plasmid.Seven positive clones were isolated from 150 000 independent transformants.Sequence analysis of one of the positive clones demonstrates that a part of coding sequence of vimentin from 611 bp to 3'end and flanking non-translation region was obtained.Therefore,there is an interaction between vimentin and TPO receptor.The results suggest that cytoskeletal protein may play an important role in TPO signal transduction pathway.

  6. Prediction of Quinolone Activity against Mycobacterium avium by Molecular Topology and Virtual Computational Screening

    Science.gov (United States)

    Gozalbes, Rafael; Brun-Pascaud, Monique; García-Domenech, Ramon; Gálvez, Jorge; Girard, Pierre-Marie; Doucet, Jean-Pierre; Derouin, Francis

    2000-01-01

    We conducted a quantitative structure-activity relationship study using a database of 158 quinolones previously tested against Mycobacterium avium-M. intracellulare complex in order to develop a model capable of predicting the activity of new quinolones against the M. avium-M. intracellulare complex in vitro. Topological indices were used as structural descriptors and were related to anti-M. avium-M. intracellulare complex activity by using the linear discriminant analysis (LDA) statistical technique. The discriminant equation thus obtained correctly classified 137 of the 158 quinolones, including 37 of a test group of 44 randomly chosen compounds. This model was then applied to 24 quinolones, including recently developed fluoroquinolones, whose MICs were subsequently determined in vitro by using the Alamar blue microplate assay; the biological results confirmed the model's predictions. The MICs of these 24 quinolones were then treated by multilinear regression (MLR) to establish a model capable of classifying them according to their in vitro activities. Using this model, a good correlation between measured and predicted MICs was found (r2 = 0.88; r2cv [cross-validation correlation] = 0.82). Moxifloxacin, sparfloxacin, and gatifloxacin were the most potent against the M. avium- M. intracellulare complex, with MICs of 0.2, 0.4, and 0.9 μg/ml, respectively. Finally, virtual modifications of these three drugs were evaluated in LDA and MLR models in order to determine the importance of different substituents in their activity. We conclude that the combination of molecular-topology methods, LDA, and MLR provides an excellent tool for the design of new quinolone structures with enhanced activity. PMID:10991858

  7. Identification of novel drug scaffolds for inhibition of SARS-CoV 3-Chymotrypsin-like protease using virtual and high-throughput screenings.

    Science.gov (United States)

    Lee, Hyun; Mittal, Anuradha; Patel, Kavankumar; Gatuz, Joseph L; Truong, Lena; Torres, Jaime; Mulhearn, Debbie C; Johnson, Michael E

    2014-01-01

    We have used a combination of virtual screening (VS) and high-throughput screening (HTS) techniques to identify novel, non-peptidic small molecule inhibitors against human SARS-CoV 3CLpro. A structure-based VS approach integrating docking and pharmacophore based methods was employed to computationally screen 621,000 compounds from the ZINC library. The screening protocol was validated using known 3CLpro inhibitors and was optimized for speed, improved selectivity, and for accommodating receptor flexibility. Subsequently, a fluorescence-based enzymatic HTS assay was developed and optimized to experimentally screen approximately 41,000 compounds from four structurally diverse libraries chosen mainly based on the VS results. False positives from initial HTS hits were eliminated by a secondary orthogonal binding analysis using surface plasmon resonance (SPR). The campaign identified a reversible small molecule inhibitor exhibiting mixed-type inhibition with a K(i) value of 11.1 μM. Together, these results validate our protocols as suitable approaches to screen virtual and chemical libraries, and the newly identified compound reported in our study represents a promising structural scaffold to pursue for further SARS-CoV 3CLpro inhibitor development. Copyright © 2013. Published by Elsevier Ltd.

  8. Virtual screening for SARS-CoV protease based on KZ7088 pharmacophore points.

    Science.gov (United States)

    Sirois, Suzanne; Wei, Dong-Qing; Du, Qishi; Chou, Kuo-Chen

    2004-01-01

    Pharmacophore modeling can provide valuable insight into ligand-receptor interactions. It can also be used in 3D (dimensional) database searching for potentially finding biologically active compounds and providing new research ideas and directions for drug-discovery projects. To stimulate the structure-based drug design against SARS (severe acute respiratory syndrome), a pharmacophore search was conducted over 3.6 millions of compounds based on the atomic coordinates of the complex obtained by docking KZ7088 (a derivative of AG7088) to SARS CoV M(pro) (coronavirus main proteinase), as reportedly recently (Chou, K. C.; Wei, D. Q.; Zhong, W. Z. Biochem. Biophys. Res. Commun. 2003, 308, 148-151). It has been found that, of the 3.6 millions of compounds screened, 0.07% are with the score satisfying five of the six pharmacophore points. Moreover, each of the hit compounds has been evaluated for druggability according to 13 metrics based on physical, chemical, and structural properties. Of the 0.07% compounds thus retrieved, 17% have a perfect score of 1.0; while 23% with one druggable rule violation, 13% two violations, and 47% more than two violations. If the criterion for druggability is set at a maximum allowance of two rule violations, we obtain that only about 0.03% of the compounds screened are worthy of further tests by experiments. These findings will significantly narrow down the search scope for potential compounds, saving substantial time and money. Finally, the featured templates derived from the current study will also be very useful for guiding the design and synthesis of effective drugs for SARS therapy.

  9. Drug search for leishmaniasis: a virtual screening approach by grid computing

    Science.gov (United States)

    Ochoa, Rodrigo; Watowich, Stanley J.; Flórez, Andrés; Mesa, Carol V.; Robledo, Sara M.; Muskus, Carlos

    2016-07-01

    The trypanosomatid protozoa Leishmania is endemic in 100 countries, with infections causing 2 million new cases of leishmaniasis annually. Disease symptoms can include severe skin and mucosal ulcers, fever, anemia, splenomegaly, and death. Unfortunately, therapeutics approved to treat leishmaniasis are associated with potentially severe side effects, including death. Furthermore, drug-resistant Leishmania parasites have developed in most endemic countries. To address an urgent need for new, safe and inexpensive anti-leishmanial drugs, we utilized the IBM World Community Grid to complete computer-based drug discovery screens (Drug Search for Leishmaniasis) using unique leishmanial proteins and a database of 600,000 drug-like small molecules. Protein structures from different Leishmania species were selected for molecular dynamics (MD) simulations, and a series of conformational "snapshots" were chosen from each MD trajectory to simulate the protein's flexibility. A Relaxed Complex Scheme methodology was used to screen 2000 MD conformations against the small molecule database, producing >1 billion protein-ligand structures. For each protein target, a binding spectrum was calculated to identify compounds predicted to bind with highest average affinity to all protein conformations. Significantly, four different Leishmania protein targets were predicted to strongly bind small molecules, with the strongest binding interactions predicted to occur for dihydroorotate dehydrogenase (LmDHODH; PDB:3MJY). A number of predicted tight-binding LmDHODH inhibitors were tested in vitro and potent selective inhibitors of Leishmania panamensis were identified. These promising small molecules are suitable for further development using iterative structure-based optimization and in vitro/in vivo validation assays.

  10. The Ascaris suum nicotinic receptor, ACR-16, as a drug target: Four novel negative allosteric modulators from virtual screening

    Directory of Open Access Journals (Sweden)

    Fudan Zheng

    2016-04-01

    Full Text Available Soil-transmitted helminth infections in humans and livestock cause significant debility, reduced productivity and economic losses globally. There are a limited number of effective anthelmintic drugs available for treating helminths infections, and their frequent use has led to the development of resistance in many parasite species. There is an urgent need for novel therapeutic drugs for treating these parasites. We have chosen the ACR-16 nicotinic acetylcholine receptor of Ascaris suum (Asu-ACR-16, as a drug target and have developed three-dimensional models of this transmembrane protein receptor to facilitate the search for new bioactive compounds. Using the human α7 nAChR chimeras and Torpedo marmorata nAChR for homology modeling, we defined orthosteric and allosteric binding sites on the Asu-ACR-16 receptor for virtual screening. We identified four ligands that bind to sites on Asu-ACR-16 and tested their activity using electrophysiological recording from Asu-ACR-16 receptors expressed in Xenopus oocytes. The four ligands were acetylcholine inhibitors (SB-277011-A, IC50, 3.12 ± 1.29 μM; (+-butaclamol Cl, IC50, 9.85 ± 2.37 μM; fmoc-1, IC50, 10.00 ± 1.38 μM; fmoc-2, IC50, 16.67 ± 1.95 μM that behaved like negative allosteric modulators. Our work illustrates a structure-based in silico screening method for seeking anthelmintic hits, which can then be tested electrophysiologically for further characterization.

  11. Discovery of Novel Inhibitors for Nek6 Protein through Homology Model Assisted Structure Based Virtual Screening and Molecular Docking Approaches

    Directory of Open Access Journals (Sweden)

    P. Srinivasan

    2014-01-01

    Full Text Available Nek6 is a member of the NIMA (never in mitosis, gene A-related serine/threonine kinase family that plays an important role in the initiation of mitotic cell cycle progression. This work is an attempt to emphasize the structural and functional relationship of Nek6 protein based on homology modeling and binding pocket analysis. The three-dimensional structure of Nek6 was constructed by molecular modeling studies and the best model was further assessed by PROCHECK, ProSA, and ERRAT plot in order to analyze the quality and consistency of generated model. The overall quality of computed model showed 87.4% amino acid residues under the favored region. A 3 ns molecular dynamics simulation confirmed that the structure was reliable and stable. Two lead compounds (Binding database ID: 15666, 18602 were retrieved through structure-based virtual screening and induced fit docking approaches as novel Nek6 inhibitors. Hence, we concluded that the potential compounds may act as new leads for Nek6 inhibitors designing.

  12. Novel inhibitor discovery against aromatase through virtual screening and molecular dynamic simulation: a computational approach in drug design.

    Science.gov (United States)

    Mirzaie, Sako; Chupani, Latifeh; Asadabadi, Ebrahim Barzegari; Shahverdi, Ahmad Reza; Jamalan, Mostafa

    2013-01-01

    Inhibition of aromatase (CYTP450) as a key enzyme in the estrogen biosynthesis could result in regression of estrogen-dependent tumors and even preventing the promotion of breast cancer. Although today potent steroid and non-steroid inhibitors of aromatase are available, isoflavanone derivatives as natural compounds with least side effects have been described as the candidate for a new generation of aromatase inhibitors. 2a as an isoflavanone derivative is the most potent inhibitor of aromatase, synthesized by Bonfield et al. (2012[7]). In our computational study, the mentioned compound was used as the template for virtual screening. Between 286 selected compounds with 70 % of structural similarity to 2a, 150 of them showed lower docking energy in comparison with 2a. Compound 2a_1 with 11.2 kcal/mol had the lowest docking energy. Interaction of 2a_1 with aromatase was further investigated and compared with 2a and androstenedione (ASD) as a natural substrate of aromatase, through 20 ns of molecular dynamic simulation. Analysis of trajectories showed, while ASD interacts with aromatase through hydrogen bonds and 2a just interacts via hydrophobic forces, 2a_1 not only accommodates in the hydrophobic active site of aromatase in a suitable manner but it also makes a stable coordination with iron atom of aromatase heme group via OB.

  13. Virtual Screening for the Development of Dual-Inhibitors Targeting Topoisomerase IB and Tyrosyl-DNA Phosphodiesterase 1.

    Science.gov (United States)

    Cardamone, Francesca; Pizzi, Simone; Iacovelli, Federico; Falconi, Mattia; Desideri, Alessandro

    2017-01-01

    Human topoisomerase IB is an important target in cancer therapy and drugs selectively stabilizing the topoisomerase IB-DNA covalent complex are in clinical use for several cancer types. Tyrosyl- DNA phosphodiesterase 1 is involved in the DNA repair resolving the topoisomerase IB-DNA covalent complex that is extremely dangerous for the survival of the cells since it produces an irreversible DNA damage. Given the close biological relationship between these two enzymes, the development of synergistic inhibitors, called dual-inhibitors, is an important challenge in cancer therapy and computer-aided drug design may help in the identification of the best compounds. In this review, an overview of the compounds inhibiting one of the two enzymes or acting as dual inhibitors is provided. Moreover, the general procedures of the virtual screening approach, providing a description of two widely used opensource programs, namely AutoDock4 and AutoDock Vina, are described. Finally, an application of the two programs on a selected number of dual inhibitors for tyrosyl-DNA phosphodiesterase 1 and topoisomerase IB and their performance is briefly discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Exploring the Molecular Basis for Selective Binding of Homoserine Dehydrogenase from Mycobacterium leprae TN toward Inhibitors: A Virtual Screening Study

    Science.gov (United States)

    Zhan, Dongling; Wang, Dongmei; Min, Weihong; Han, Weiwei

    2014-01-01

    Homoserine dehydrogenase (HSD) from Mycobacterium leprae TN is an antifungal target for antifungal properties including efficacy against the human pathogen. The 3D structure of HSD has been firmly established by homology modeling methods. Using the template, homoserine dehydrogenase from Thiobacillus denitrificans (PDB Id 3MTJ), a sequence identity of 40% was found and molecular dynamics simulation was used to optimize a reliable structure. The substrate and co-factor-binding regions in HSD were identified. In order to determine the important residues of the substrate (l-aspartate semialdehyde (l-ASA)) binding, the ASA was docked to the protein; Thr163, Asp198, and Glu192 may be important because they form a hydrogen bond with HSD through AutoDock 4.2 software. After use of a virtual screening technique of HSD, the four top-scoring docking hits all seemed to cation–π ion pair with the key recognition residue Lys107, and Lys207. These ligands therefore seemed to be new chemotypes for HSD. Our results may be helpful for further experimental investigations. PMID:24469317

  15. Exploring the Molecular Basis for Selective Binding of Homoserine Dehydrogenase from Mycobacterium leprae TN toward Inhibitors: A Virtual Screening Study

    Directory of Open Access Journals (Sweden)

    Dongling Zhan

    2014-01-01

    Full Text Available Homoserine dehydrogenase (HSD from Mycobacterium leprae TN is an antifungal target for antifungal properties including efficacy against the human pathogen. The 3D structure of HSD has been firmly established by homology modeling methods. Using the template, homoserine dehydrogenase from Thiobacillus denitrificans (PDB Id 3MTJ, a sequence identity of 40% was found and molecular dynamics simulation was used to optimize a reliable structure. The substrate and co-factor-binding regions in HSD were identified. In order to determine the important residues of the substrate (l-aspartate semialdehyde (l-ASA binding, the ASA was docked to the protein; Thr163, Asp198, and Glu192 may be important because they form a hydrogen bond with HSD through AutoDock 4.2 software. neuraminidaseAfter use of a virtual screening technique of HSD, the four top-scoring docking hits all seemed to cation–π ion pair with the key recognition residue Lys107, and Lys207. These ligands therefore seemed to be new chemotypes for HSD. Our results may be helpful for further experimental investigations.

  16. Recent progress in the identification and development of anti-malarial agents using virtual screening based approaches.

    Science.gov (United States)

    Shah, Priyanka; Tiwari, Sunita; Siddiqi, Mohammad Imran

    2015-01-01

    Malaria has continued to be one of the most perplexing diseases for biological science community around the world due to its prevalent devastating nature and quick developing resistance against the frontline drugs. Artimisinin-based combination therapy (ACT) has been so far found to be among the best therapies against Plasmodium pathogens but alarming emergence of resistance in parasites against every known chemotherapy has prompted the scientific community to step up all the efforts towards development of new and affordable anti-malarial drugs. Computer-aided approaches have received enormous attention in recent years in the field of identification and design of novel drugs. In this review, we summarize recently published research concerning the identification and development of anti-malarial compounds using virtual screening approaches. It would be admirable to discern the successful application of in silico studies for anti-malarial drug discovery hitherto and would certainly help in generating new avenues for pursuing integrated studies between the experimentalists and computational chemists in a systematic manner as a time and cost efficient alternative for future antimalarial drug discovery projects.

  17. Discovery of New E-Selectin Inhibitors by Virtual Screening, Fluorescence Binding Assays, and STD NMR Experiments.

    Science.gov (United States)

    Barra, Pabla A; Jiménez, Verónica A; Gavin, José A; Daranas, Antonio H; Alderete, Joel B

    2016-05-06

    E-selectin is an endothelial protein that participates in the adhesion of metastatic cancer cells, and is therefore a relevant target for antitumor therapeutic intervention. In this work, virtual screening was used to identify new E-selectin inhibitors from a subset of drug-like molecules retrieved from the ZINC database, including the physiological ligand sLe(x) as reference structure (PDB ID: 1G1T). Four hits were chosen and subjected to molecular dynamics simulations and fluorescence binding assays, which led to the determination of experimental dissociation constants between 333 and 1012 μm. The candidate with the highest affinity was studied by saturation transfer difference (STD) NMR experiments and complete relaxation and conformational exchange matrix analysis of saturation transfer (CORCEMA-ST), aimed at identifying the preferable binding mode with E-selectin. Our results revealed that this new inhibitor binds more strongly than sLe(x) in the E-selectin binding site, in good agreement with simulation predictions. These properties will prove valuable for the future design of drugs that target E-selectin. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. 5-Benzylidene-hydantoin is a new scaffold for SIRT inhibition: From virtual screening to activity assays.

    Science.gov (United States)

    Sacconnay, Lionel; Ryckewaert, Lucie; Randazzo, Giuseppe Marco; Petit, Charlotte; Passos, Carolina Dos Santos; Jachno, Jelena; Michailovienė, Vilma; Zubrienė, Asta; Matulis, Daumantas; Carrupt, Pierre-Alain; Simões-Pires, Claudia Avello; Nurisso, Alessandra

    2016-03-31

    Sirtuins (SIRTs) are a family of enzymes able to catalyze the deacetylation of the N-acetyl lysines of both histone and non-histone substrates. Inhibition of SIRTs catalytic activity was recently reported in the literature as being beneficial in human diseases, with very promising applications in cancer therapy and enzymatic neurodegeneration. By combining a structure-based virtual screening of the Specs database with cell-based assays, we identified the 5-benzylidene-hydantoin as new scaffold for the inhibition of SIRT2 catalytic activity. Compound 97 (Specs ID AH-487/41657829), active in the low μM range against SIRT2, showed the optimal physicochemical properties for passive absorption as well as relatively low cytotoxicity in vitro. Further studies revealed non-competitive and mixed-type kinetics toward acetyl-lysine substrates and NAD(+), respectively, and a non-selective profile for SIRT inhibition. A binding mode consistent with the experimental evidence was proposed by molecular modeling. Additionally, the levels of acetyl-p53 were shown to be increased in HeLa cells treated with 97. Taken together, these results encourage further investigation of 5-benzylidene-hydantoin derivatives for their SIRT-related therapeutic effects.

  19. Exploring the molecular basis for selective binding of homoserine dehydrogenase from Mycobacterium leprae TN toward inhibitors: a virtual screening study.

    Science.gov (United States)

    Zhan, Dongling; Wang, Dongmei; Min, Weihong; Han, Weiwei

    2014-01-24

    Homoserine dehydrogenase (HSD) from Mycobacterium leprae TN is an antifungal target for antifungal properties including efficacy against the human pathogen. The 3D structure of HSD has been firmly established by homology modeling methods. Using the template, homoserine dehydrogenase from Thiobacillus denitrificans (PDB Id 3MTJ), a sequence identity of 40% was found and molecular dynamics simulation was used to optimize a reliable structure. The substrate and co-factor-binding regions in HSD were identified. In order to determine the important residues of the substrate (L-aspartate semialdehyde (L-ASA)) binding, the ASA was docked to the protein; Thr163, Asp198, and Glu192 may be important because they form a hydrogen bond with HSD through AutoDock 4.2 software. neuraminidaseAfter use of a virtual screening technique of HSD, the four top-scoring docking hits all seemed to cation-π ion pair with the key recognition residue Lys107, and Lys207. These ligands therefore seemed to be new chemotypes for HSD. Our results may be helpful for further experimental investigations.

  20. Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model.

    Science.gov (United States)

    Evers, Andreas; Klebe, Gerhard

    2004-10-21

    The neurokinin-1 (NK1) receptor belongs to the family of G-protein-coupled receptors (GPCRs), which represents one of the most relevant target families in small-molecule drug design. In this paper, we describe a homology modeling of the NK1 receptor based on the high-resolution X-ray structure of rhodopsin and the successful virtual screening based on this protein model. The NK1 receptor model has been generated using our new MOBILE (modeling binding sites including ligand information explicitly) approach. Starting with preliminary homology models, it generates improved models of the protein binding pocket together with bound ligands. Ligand information is used as an integral part in the homology modeling process. For the construction of the NK1 receptor, antagonist CP-96345 was used to restrain the modeling. The quality of the obtained model was validated by probing its ability to accommodate additional known NK1 antagonists from structurally diverse classes. On the basis of the generated model and on the analysis of known NK1 antagonists, a pharmacophore model was deduced, which subsequently guided the 2D and 3D database search with UNITY. As a following step, the remaining hits were docked into the modeled binding pocket of the NK1 receptor. Finally, seven compounds were selected for biochemical testing, from which one showed affinity in the submicromolar range. Our results suggest that ligand-supported homology models of GPCRs may be used as effective platforms for structure-based drug design.

  1. High-throughput Screening of New Antimitotic Compounds Based on Potential of Virtual Organization CSLabGrid

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    Karpov, P.A.

    2015-01-01

    Full Text Available In the frameworks of virtual organization CSLabGrid using Grid calculations the repository of 3-D models of cytoskeletal proteins (tubulins and FtsZ-proteins verified by stereochemistry, is described. The repository of structures of canonical antimicrotubular compounds (inhibitors of tubulin polymerization as well as library of ligands, suitable for high-throughput screening (HTS in Grid were created. According to the results of the library HTS 1,164 compounds that demonstrated an elevated affinity to tubulin molecules: 205 — to α-tubulin and 959 — to β-tubulin were selected. It was found that among 2,886 compounds synthesized in the Institute of Organic Chemistry of NAS of Ukraine, 6 were perspective inhibitors of α- and β-tubulin polymerization in such human pathogens as Pneumocystis carinii, Giardia intestinalis Ajellomyces capsulatus, Neosartorya fumigata and Candida albicans. Respectively, these compounds were recommended for subsequent experimental evaluation of their biological activity for use as new pharmacological agents.

  2. High performance in silico virtual drug screening on many-core processors.

    Science.gov (United States)

    McIntosh-Smith, Simon; Price, James; Sessions, Richard B; Ibarra, Amaurys A

    2015-05-01

    Drug screening is an important part of the drug development pipeline for the pharmaceutical industry. Traditional, lab-based methods are increasingly being augmented with computational methods, ranging from simple molecular similarity searches through more complex pharmacophore matching to more computationally intensive approaches, such as molecular docking. The latter simulates the binding of drug molecules to their targets, typically protein molecules. In this work, we describe BUDE, the Bristol University Docking Engine, which has been ported to the OpenCL industry standard parallel programming language in order to exploit the performance of modern many-core processors. Our highly optimized OpenCL implementation of BUDE sustains 1.43 TFLOP/s on a single Nvidia GTX 680 GPU, or 46% of peak performance. BUDE also exploits OpenCL to deliver effective performance portability across a broad spectrum of different computer architectures from different vendors, including GPUs from Nvidia and AMD, Intel's Xeon Phi and multi-core CPUs with SIMD instruction sets.

  3. Virtual screening of the inhibitors targeting at the viral protein 40 of Ebola virus

    Institute of Scientific and Technical Information of China (English)

    V.Karthick; N.Nagasundaram; C.George Priya Doss; Chiranjib Chakraborty; R.Siva; Aiping Lu; Ge Zhang

    2016-01-01

    Background:The Ebola virus is highly pathogenic and destructive to humans and other primates.The Ebola virus encodes viral protein 40 (VP40),which is highly expressed and regulates the assembly and release of viral particles in the host cell.Because VP40 plays a prominent role in the life cycle of the Ebola virus,it is considered as a key target for antiviral treatment.However,there is currently no FDA-approved drug for treating Ebola virus infection,resulting in an urgent need to develop effective antiviral inhibitors that display good safety profiles in a short duration.Methods:This study aimed to screen the effective lead candidate against Ebola infection.First,the lead molecules were filtered based on the docking score.Second,Lipinski rule of five and the other drug likeliness properties are predicted to assess the safety profile of the lead candidates.Finally,molecular dynamics simulations was performed to validate the lead compound.Results:Our results revealed that emodin-8-beta-D-glucoside from the Traditional Chinese Medicine Database (TCMD) represents an active lead candidate that targets the Ebola virus by inhibiting the activity of VP40,and displays good pharmacokinetic properties.Conclusion:This report will considerably assist in the development of the competitive and robust antiviral agents against Ebola infection.

  4. Effective virtual screening strategy focusing on the identification of novel Bruton's tyrosine kinase inhibitors.

    Science.gov (United States)

    Xiao, Jianhu; Zhang, Shengping; Luo, Minghao; Zou, Yi; Zhang, Yihua; Lai, Yisheng

    2015-07-01

    Dysregulation of the B-cell receptor (BCR) signaling pathway plays a vital role in the pathogenesis and development of B-cell malignancies. Bruton's tyrosine kinase (BTK), a key component in the BCR signaling, has been validated as a valuable target for the treatment of B-cell malignancies. In an attempt to find novel and potent BTK inhibitors, both ligand- and structure-based pharmacophore models were generated using Discovery Studio 2.5 and Ligandscout 3.11 with the aim of screening the ChemBridge database. The resulting hits were then subjected to sequential docking experiments using two independent docking programs, CDOCKER and Glide. Molecules displaying high glide scores and H-bond interactions with the key residue Met477 in both of the docking programs were retained. Drug-like criteria including Lipinski's rule of five and ADMET properties filters were employed for further refinement of the retrieved hits. By clustering, eight promising compounds with novel chemical scaffolds were finally selected and the top two ranking compounds were evaluated by molecular dynamics simulation. We believe that these compounds are of great potential in BTK inhibition and will be used for further investigation. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Yeast two-hybrid screening for proteins that interact with α1-adrenergic receptors

    Institute of Scientific and Technical Information of China (English)

    TanZHANG; QiXU; Feng-rongCHEN; Qi-deHAN; You-yiZHANG

    2004-01-01

    AIM: To find novel proteins that may bind to α1A-adrenergic receptor (α1A-AR) and investigate their interactions with the other two α1-AR subtypes (α1B-AR and α1D-AR) with an expectation to provide new leads for the function study of the receptors. METHODS: Yeast two-hybrid assay was performed to screen a human brain cDNA library using the C terminus of α1A-AR (α1A-AR-CT) as bait. X-Gal assay and o-nitrophenyl-beta-D-galactopyranoside (ONPG) assay were subsequently conducted to further qualitatively or quantitatively confirm the interactions between receptors and the three identified proteins. RESULTS: (1) Selection medium screening identified segments of bone morphogenetic protein-1 (BMP-1), active Bcr-related protein (Abr), and filamin-C as binding partners of α1A-AR-CT in yeast cells respectively. Besides, protein segments of BMP-1 and Abr could only specifically interact with α1A-AR-CT while filamin-C segment interacted with all three α1-AR subtypes. (2) In X-Gal assay, the cotransformants of α1A-AR-CT and BMP-1 segments turned strong blue at about 30 min while other positive transformants only developed weak blue at about 5-6 h. (3) In ONPG assay, interaction (shown in β-galactosidase activity) between α1A-AR-CT and BMP-1 segments was about 30 times stronger than that of control (P<0.01), while other positive interactions were only about 2-5 times as strong as those of controls (P<0.05). CONCLUSION: In yeast cells BMP-1, Abr and/or filamin-C could interact with three α1-AR subtypes, among which, interaction between BMP-1 and α1A-AR was the strongest while other interactions between proteins and receptors were relatively weak.

  6. Yeast two-hybrid screening for proteins that interact with α1-adrenergic receptors

    Institute of Scientific and Technical Information of China (English)

    Tan ZHANG; Qi XU; Feng-rong CHEN; Qi-de HAN; You-yi ZHANG

    2004-01-01

    AIM: To find novel proteins that may bind to α1A-adrenergic receptor (α1A-AR) and investigate their interactions with the other two α1-AR subtypes (α1B-AR and α1D-AR) with an expectation to provide new leads for the function study of the receptors. METHODS: Yeast two-hybrid assay was performed to screen a human brain cDNA library using the C terminus of α1A-AR (α1A-AR-CT) as bait. X-Gal assay and o-nitrophenyl-beta-D-galactopyranoside(ONPG) assay were subsequently conducted to further qualitatively or quantitatively confirm the interactions between receptors and the three identified proteins. RESULTS: (1) Selection medium screening identified segments of bone morphogenetic protein-1 (BMP-1), active Bcr-related protein (Abr), and filamin-C as binding partners ofα1A-AR-CT in yeast cells respectively. Besides, protein segments of BMP-1 and Abr could only specifically interact with α1A-AR-CT while filamin-C segment interacted with all three α1-AR subtypes. (2) In X-Gal assay, the cotransformants of α1A-AR-CT and BMP-1 segments turned strong blue at about 30 min while other positive transformants only developed weak blue at about 5-6 h. (3) In ONPG assay, interaction (shown in β-galactosidase activity) between α1A-AR-CT and BMP-1 segments was about 30 times stronger than that of control (P<0.01),while other positive interactions were only about 2-5 times as strong as those of controls (P<0.05). CONCLUSION:In yeast cells BMP-1, Abr and/or filamin-C could interact with three α1-AR subtypes, among which, interaction between BMP-1 and α1A-AR was the strongest while other interactions between proteins and receptors were relatively weak.

  7. Search for β2 adrenergic receptor ligands by virtual screening via grid computing and investigation of binding modes by docking and molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Qifeng Bai

    Full Text Available We designed a program called MolGridCal that can be used to screen small molecule database in grid computing on basis of JPPF grid environment. Based on MolGridCal program, we proposed an integrated strategy for virtual screening and binding mode investigation by combining molecular docking, molecular dynamics (MD simulations and free energy calculations. To test the effectiveness of MolGridCal, we screened potential ligands for β2 adrenergic receptor (β2AR from a database containing 50,000 small molecules. MolGridCal can not only send tasks to the grid server automatically, but also can distribute tasks using the screensaver function. As for the results of virtual screening, the known agonist BI-167107 of β2AR is ranked among the top 2% of the screened candidates, indicating MolGridCal program can give reasonable results. To further study the binding mode and refine the results of MolGridCal, more accurate docking and scoring methods are used to estimate the binding affinity for the top three molecules (agonist BI-167107, neutral antagonist alprenolol and inverse agonist ICI 118,551. The results indicate agonist BI-167107 has the best binding affinity. MD simulation and free energy calculation are employed to investigate the dynamic interaction mechanism between the ligands and β2AR. The results show that the agonist BI-167107 also has the lowest binding free energy. This study can provide a new way to perform virtual screening effectively through integrating molecular docking based on grid computing, MD simulations and free energy calculations. The source codes of MolGridCal are freely available at http://molgridcal.codeplex.com.

  8. Pharmacoinformatics exploration of polyphenol oxidases leading to novel inhibitors by virtual screening and molecular dynamic simulation study.

    Science.gov (United States)

    Hassan, Mubashir; Abbas, Qamar; Ashraf, Zaman; Moustafa, Ahmed A; Seo, Sung-Yum

    2017-06-01

    Polyphenol oxidases (PPOs)/tyrosinases are metal-dependent enzymes and known as important targets for melanogenesis. Although considerable attempts have been conducted to control the melanin-associated diseases by using various inhibitors. However, the exploration of the best anti-melanin inhibitor without side effect still remains a challenge in drug discovery. In present study, protein structure prediction, ligand-based pharmacophore modeling, virtual screening, molecular docking and dynamic simulation study were used to screen the strong novel inhibitor to cure melanogenesis. The 3D structures of PPO1 and PPO2 were built through homology modeling, while the 3D crystal structures of PPO3 and PPO4 were retrieved from PDB. Pharmacophore modeling was performed using LigandScout 3.1 software and top five models were selected to screen the libraries (2601 of Aurora and 727, 842 of ZINC). Top 10 hit compounds (C1-10) were short-listed having strong binding affinities for PPO1-4. Drug and synthetic accessibility (SA) scores along with absorption, distribution, metabolism, excretion and toxicity (ADMET) assessment were employed to scrutinize the best lead hit. C4 (name) hit showed the best predicted SA score (5.75), ADMET properties and drug-likeness behavior among the short-listed compounds. Furthermore, docking simulations were performed to check the binding affinity of C1-C10 compounds against target proteins (PPOs). The binding affinity values of complex between C4 and PPOs were higher than those of other complexes (-11.70, -12.1, -9.90 and -11.20kcal/mol with PPO1, PPO2, PPO3, or PPO4, respectively). From comparative docking energy and binding analyses, PPO2 may be considered as better target for melanogenesis than others. The potential binding modes of C4, C8 and C10 against PPO2 were explored using molecular dynamics simulations. The root mean square deviation and fluctuation (RMSD/RMSF) graphs results depict the significance of C4 over the other compounds

  9. Structure-based drug design of a novel family of chalcones as PPARα agonists: virtual screening, synthesis, and biological activities in vitro

    Institute of Scientific and Technical Information of China (English)

    Xiang-hua LI; Han-jun ZOU; An-hui WU; Yang-liang YE; Jian-hua SHEN

    2007-01-01

    Aim: To design and synthesize a novel class of peroxisome proliferator-activated receptors (PPAR)α agonists, which is obtained by the combination of the classi- cal fibrate "head group", a linker with appropriate length and a chalcone. Methods: Thirty seven compounds were designed and identified employing the virtual screening approach. Six compounds were then selected for synthesis and bioas- say according to the virtual screening results, structural similarity, and synthetic complexity. Results: Six new compounds (4b and 4d-h) were synthesized and bioassayed. All were found to be potent PPARα agonists, compound 4 h being the most prominent with a 50% effective concentration value of 0.06 μmol/L. Conclusion: This study provides a promising novel family of chalcones with a potential hypolipidemic effect.

  10. E-pharmacophore-based virtual screening to identify GSK-3β inhibitors.

    Science.gov (United States)

    Natarajan, Pradeep; Priyadarshini, Vani; Pradhan, Dibyabhaba; Manne, Munikumar; Swargam, Sandeep; Kanipakam, Hema; Bhuma, Vengamma; Amineni, Umamaheswari

    2016-10-01

    Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase which has attracted significant attention during recent years in drug design studies. The deregulation of GSK-3β increased the loss of hippocampal neurons by triggering apoptosis-mediating production of neurofibrillary tangles and alleviates memory deficits in Alzheimer's disease (AD). Given its role in the formation of neurofibrillary tangles leading to AD, it has been a major therapeutic target for intervention in AD, hence was targeted in the present study. Twenty crystal structures were refined to generate pharmacophore models based on energy involvement in binding co-crystal ligands. Four common e-pharmacophore models were optimized from the 20 pharmacophore models. Shape-based screening of four e-pharmacophore models against nine established small molecule databases using Phase v3.9 had resulted in 1800 compounds having similar pharmacophore features. Rigid receptor docking (RRD) was performed for 1800 compounds and 20 co-crystal ligands with GSK-3β to generate dock complexes. Interactions of the best scoring lead obtained through RRD were further studied with quantum polarized ligand docking (QPLD), induced fit docking (IFD) and molecular mechanics/generalized Born surface area. Comparing the obtained leads to 20 co-crystal ligands resulted in 18 leads among them, lead1 had the lowest docking score, lower binding free energy and better binding orientation toward GSK-3β. The 50 ns MD simulations run confirmed the stable nature of GSK-3β-lead1 docking complex. The results from RRD, QPLD, IFD and MD simulations confirmed that lead1 might be used as a potent antagonist for GSK-3β.

  11. Heterogeneous classifier fusion for ligand-based virtual screening: or, how decision making by committee can be a good thing.

    Science.gov (United States)

    Riniker, Sereina; Fechner, Nikolas; Landrum, Gregory A

    2013-11-25

    The concept of data fusion - the combination of information from different sources describing the same object with the expectation to generate a more accurate representation - has found application in a very broad range of disciplines. In the context of ligand-based virtual screening (VS), data fusion has been applied to combine knowledge from either different active molecules or different fingerprints to improve similarity search performance. Machine-learning (ML) methods based on fusion of multiple homogeneous classifiers, in particular random forests, have also been widely applied in the ML literature. The heterogeneous version of classifier fusion - fusing the predictions from different model types - has been less explored. Here, we investigate heterogeneous classifier fusion for ligand-based VS using three different ML methods, RF, naïve Bayes (NB), and logistic regression (LR), with four 2D fingerprints, atom pairs, topological torsions, RDKit fingerprint, and circular fingerprint. The methods are compared using a previously developed benchmarking platform for 2D fingerprints which is extended to ML methods in this article. The original data sets are filtered for difficulty, and a new set of challenging data sets from ChEMBL is added. Data sets were also generated for a second use case: starting from a small set of related actives instead of diverse actives. The final fused model consistently outperforms the other approaches across the broad variety of targets studied, indicating that heterogeneous classifier fusion is a very promising approach for ligand-based VS. The new data sets together with the adapted source code for ML methods are provided in the Supporting Information .

  12. Discovery of Specific Inhibitors for Intestinal E. coli  β-Glucuronidase through In Silico Virtual Screening

    Directory of Open Access Journals (Sweden)

    Ta-Chun Cheng

    2015-01-01

    Full Text Available Glucuronidation is a major metabolism process of detoxification for carcinogens, 4-(methylnitrosamino-1-(3-pyridy-1-butanone (NNK and 1,2-dimethylhydrazine (DMH, of reactive oxygen species (ROS. However, intestinal E. coli   β-glucuronidase (eβG has been considered pivotal to colorectal carcinogenesis. Specific inhibition of eβG may prevent reactivating the glucuronide-carcinogen and protect the intestine from ROS-mediated carcinogenesis. In order to develop specific eβG inhibitors, we found that 59 candidate compounds obtained from the initial virtual screening had high inhibition specificity against eβG but not human βG. In particular, we found that compounds 7145 and 4041 with naphthalenylidene-benzenesulfonamide (NYBS are highly effective and selective to inhibit eβG activity. Compound 4041  (IC50=2.8 μM shows a higher inhibiting ability than compound 7145  (IC50=31.6 μM against eβG. Furthermore, the molecular docking analysis indicates that compound 4041 has two hydrophobic contacts to residues L361 and I363 in the bacterial loop, but 7145 has one contact to L361. Only compound 4041 can bind to key residue (E413 at active site of eβG via hydrogen-bonding interactions. These novel NYBS-based eβG specific inhibitors may provide as novel candidate compounds, which specifically inhibit eβG to reduce eβG-based carcinogenesis and intestinal injury.

  13. Homology modeling, molecular dynamics, and virtual screening of NorA efflux pump inhibitors of Staphylococcus aureus

    Science.gov (United States)

    Bhaskar, Baki Vijaya; Babu, Tirumalasetty Muni Chandra; Reddy, Netala Vasudeva; Rajendra, Wudayagiri

    2016-01-01

    Emerging drug resistance in clinical isolates of Staphylococcus aureus might be implicated to the overexpression of NorA efflux pump which is capable of extruding numerous structurally diverse compounds. However, NorA efflux pump is considered as a potential drug target for the development of efflux pump inhibitors. In the present study, NorA model was constructed based on the crystal structure of glycerol-3-phosphate transporter (PDBID: 1PW4). Molecular dynamics (MD) simulation was performed using NAMD2.7 for NorA which is embedded in the hydrated lipid bilayer. Structural design of NorA unveils amino (N)- and carboxyl (C)-terminal domains which are connected by long cytoplasmic loop. N and C domains are composed of six transmembrane α-helices (TM) which exhibits pseudo-twofold symmetry and possess voluminous substrate binding cavity between TM helices. Molecular docking of reserpine, totarol, ferruginol, salvin, thioxanthene, phenothiazine, omeprazole, verapamil, nalidixic acid, ciprofloxacin, levofloxacin, and acridine to NorA found that all the molecules were bound at the large hydrophobic cleft and indicated significant interactions with the key residues. In addition, structure-based virtual screening was employed which indicates that 14 potent novel lead molecules such as CID58685302, CID58685367, CID5799283, CID5578487, CID60028372, ZINC12196383, ZINC72140751, ZINC72137843, ZINC39227983, ZINC43742707, ZINC12196375, ZINC66166948, ZINC39228014, and ZINC14616160 have highest binding affinity for NorA. These lead molecules displayed considerable pharmacological properties as evidenced by Lipinski rule of five and prophecy of toxicity risk assessment. Thus, the present study will be helpful in designing and synthesis of a novel class of NorA efflux pump inhibitors that restore the susceptibilities of drug compounds. PMID:27757014

  14. Rational Design of Small-Molecule Stabilizers of Spermine Synthase Dimer by Virtual Screening and Free Energy-Based Approach

    Science.gov (United States)

    Zhang, Zhe; Martiny, Virginie; Lagorce, David; Ikeguchi, Yoshihiko; Alexov, Emil; Miteva, Maria A.

    2014-01-01

    Snyder-Robinson Syndrome (SRS) is a rare mental retardation disorder which is caused by the malfunctioning of an enzyme, the spermine synthase (SMS), which functions as a homo-dimer. The malfunctioning of SMS in SRS patients is associated with several identified missense mutations that occur away from the active site. This investigation deals with a particular SRS-causing mutation, the G56S mutation, which was shown computationally and experimentally to destabilize the SMS homo-dimer and thus to abolish SMS enzymatic activity. As a proof-of-concept, we explore the possibility to restore the enzymatic activity of the malfunctioning SMS mutant G56S by stabilizing the dimer through small molecule binding at the mutant homo-dimer interface. For this purpose, we designed an in silico protocol that couples virtual screening and a free binding energy-based approach to identify potential small-molecule binders on the destabilized G56S dimer, with the goal to stabilize it and thus to increase SMS G56S mutant activity. The protocol resulted in extensive list of plausible stabilizers, among which we selected and tested 51 compounds experimentally for their capability to increase SMS G56S mutant enzymatic activity. In silico analysis of the experimentally identified stabilizers suggested five distinctive chemical scaffolds. This investigation suggests that druggable pockets exist in the vicinity of the mutation sites at protein-protein interfaces which can be used to alter the disease-causing effects by small molecule binding. The identified chemical scaffolds are drug-like and can serve as original starting points for development of lead molecules to further rescue the disease-causing effects of the Snyder-Robinson syndrome for which no efficient treatment exists up to now. PMID:25340632

  15. Rational design of small-molecule stabilizers of spermine synthase dimer by virtual screening and free energy-based approach.

    Directory of Open Access Journals (Sweden)

    Zhe Zhang

    Full Text Available Snyder-Robinson Syndrome (SRS is a rare mental retardation disorder which is caused by the malfunctioning of an enzyme, the spermine synthase (SMS, which functions as a homo-dimer. The malfunctioning of SMS in SRS patients is associated with several identified missense mutations that occur away from the active site. This investigation deals with a particular SRS-causing mutation, the G56S mutation, which was shown computationally and experimentally to destabilize the SMS homo-dimer and thus to abolish SMS enzymatic activity. As a proof-of-concept, we explore the possibility to restore the enzymatic activity of the malfunctioning SMS mutant G56S by stabilizing the dimer through small molecule binding at the mutant homo-dimer interface. For this purpose, we designed an in silico protocol that couples virtual screening and a free binding energy-based approach to identify potential small-molecule binders on the destabilized G56S dimer, with the goal to stabilize it and thus to increase SMS G56S mutant activity. The protocol resulted in extensive list of plausible stabilizers, among which we selected and tested 51 compounds experimentally for their capability to increase SMS G56S mutant enzymatic activity. In silico analysis of the experimentally identified stabilizers suggested five distinctive chemical scaffolds. This investigation suggests that druggable pockets exist in the vicinity of the mutation sites at protein-protein interfaces which can be used to alter the disease-causing effects by small molecule binding. The identified chemical scaffolds are drug-like and can serve as original starting points for development of lead molecules to further rescue the disease-causing effects of the Snyder-Robinson syndrome for which no efficient treatment exists up to now.

  16. The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies

    Directory of Open Access Journals (Sweden)

    Chuang Chih-Kuang

    2011-01-01

    Full Text Available Abstract Background Alzheimer's disease (AD is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. The most dramatic abnormalities are those of the cholinergic system. Acetylcholinesterase (AChE plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD. Methods In this study, we suggest a workflow for the identification and prioritization of potential compounds targeted against AChE. In order to elucidate the essential structural features for AChE, three-dimensional pharmacophore models were constructed using Discovery Studio 2.5.5 (DS 2.5.5 program based on a set of known AChE inhibitors. Results The best five-features pharmacophore model, which includes one hydrogen bond donor and four hydrophobic features, was generated from a training set of 62 compounds that yielded a correlation coefficient of R = 0.851 and a high prediction of fit values for a set of 26 test molecules with a correlation of R2 = 0.830. Our pharmacophore model also has a high Güner-Henry score and enrichment factor. Virtual screening performed on the NCI database obtained new inhibitors which have the potential to inhibit AChE and to protect neurons from Aβ toxicity. The hit compounds were subsequently subjected to molecular docking and evaluated by consensus scoring function, which resulted in 9 compounds with high pharmacophore fit values and predicted biological activity scores. These compounds showed interactions with important residues at the active site. Conclusions The information gained from this study may assist in the discovery of potential AChE inhibitors that are highly selective for its dual binding sites.

  17. Exploring dual inhibitory role of febrifugine analogues against Plasmodium utilizing structure-based virtual screening and molecular dynamic simulation.

    Science.gov (United States)

    Pandey, Rajan Kumar; Narula, Aruna; Naskar, Manisha; Srivastava, Shubham; Verma, Parmila; Malik, Ruchi; Shah, Priyanka; Prajapati, Vijay Kumar

    2017-03-01

    Malaria is an endemic disease caused by the protozoan parasite Plasomodium falciparum. Febrifugine analogues are natural compound obtained from the traditional Chinese herbs have shown significant antimalarial and anticancerous efficacy in experimental model. Development of resistance against the existing antimalarial drug has alarmed the scientific innovators to find a potential antimalarial molecule which can be further used by endemic countries for the elimination of this disease. In this study, structure-based virtual screening and molecular dynamics (MD) base approaches were used to generate potential antimalarial compound against plasmepsin II and prolyl-tRNA synthetase of Plasmodium. Here, we have docked series of febrifugine analogues (n = 11,395) against plasmepsin II in three different docking modes and then it was compared with previously reported target prolyl-tRNA synthetase. Extra precision docking resulted into 235 ligands having better docking score were subject for QikProp analysis. Better ligands (n = 39) obtained from QikProp analysis were subject for ADMET prediction and docking protocol validation through the estimation of receiver operator characteristics. In the later stage, 24 ligands obtained from ADMET study were subject for the estimation of binding energy through MM-GBSA and same were also docked against prolyl-tRNA synthetase to get compounds with dual inhibitor role. Finally, MD simulation and 2D fingerprint MACCS study of two best ligands have shown significant interaction with plasmepsin II and homology against known active ligand with noteworthy MACCS index, respectively. This study concludes that FA12 could be potential drug candidate to fight against Plasmodium falciparum parasites.

  18. Hybrid PolyLingual Object Model: An Efficient and Seamless Integration of Java and Native Components on the Dalvik Virtual Machine

    Directory of Open Access Journals (Sweden)

    Yukun Huang

    2014-01-01

    Full Text Available JNI in the Android platform is often observed with low efficiency and high coding complexity. Although many researchers have investigated the JNI mechanism, few of them solve the efficiency and the complexity problems of JNI in the Android platform simultaneously. In this paper, a hybrid polylingual object (HPO model is proposed to allow a CAR object being accessed as a Java object and as vice in the Dalvik virtual machine. It is an acceptable substitute for JNI to reuse the CAR-compliant components in Android applications in a seamless and efficient way. The metadata injection mechanism is designed to support the automatic mapping and reflection between CAR objects and Java objects. A prototype virtual machine, called HPO-Dalvik, is implemented by extending the Dalvik virtual machine to support the HPO model. Lifespan management, garbage collection, and data type transformation of HPO objects are also handled in the HPO-Dalvik virtual machine automatically. The experimental result shows that the HPO model outweighs the standard JNI in lower overhead on native side, better executing performance with no JNI bridging code being demanded.

  19. Virtual-screening workflow tutorials and prospective results from the Teach-Discover-Treat competition 2014 against malaria [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Sereina Riniker

    2017-07-01

    Full Text Available The first challenge in the 2014 competition launched by the Teach-Discover-Treat (TDT initiative asked for the development of a tutorial for ligand-based virtual screening, based on data from a primary phenotypic high-throughput screen (HTS against malaria. The resulting Workflows were applied to select compounds from a commercial database, and a subset of those were purchased and tested experimentally for anti-malaria activity. Here, we present the two most successful Workflows, both using machine-learning approaches, and report the results for the 114 compounds tested in the follow-up screen. Excluding the two known anti-malarials quinidine and amodiaquine and 31 compounds already present in the primary HTS, a high hit rate of 57% was found.

  20. Toward fully automated high performance computing drug discovery: a massively parallel virtual screening pipeline for docking and molecular mechanics/generalized Born surface area rescoring to improve enrichment.

    Science.gov (United States)

    Zhang, Xiaohua; Wong, Sergio E; Lightstone, Felice C

    2014-01-27

    In this work we announce and evaluate a high throughput virtual screening pipeline for in-silico screening of virtual compound databases using high performance computing (HPC). Notable features of this pipeline are an automated receptor preparation scheme with unsupervised binding site identification. The pipeline includes receptor/target preparation, ligand preparation, VinaLC docking calculation, and molecular mechanics/generalized Born surface area (MM/GBSA) rescoring using the GB model by Onufriev and co-workers [J. Chem. Theory Comput. 2007, 3, 156-169]. Furthermore, we leverage HPC resources to perform an unprecedented, comprehensive evaluation of MM/GBSA rescoring when applied to the DUD-E data set (Directory of Useful Decoys: Enhanced), in which we selected 38 protein targets and a total of ∼0.7 million actives and decoys. The computer wall time for virtual screening has been reduced drastically on HPC machines, which increases the feasibility of extremely large ligand database screening with more accurate methods. HPC resources allowed us to rescore 20 poses per compound and evaluate the optimal number of poses to rescore. We find that keeping 5-10 poses is a good compromise between accuracy and computational expense. Overall the results demonstrate that MM/GBSA rescoring has higher average receiver operating characteristic (ROC) area under curve (AUC) values and consistently better early recovery of actives than Vina docking alone. Specifically, the enrichment performance is target-dependent. MM/GBSA rescoring significantly out performs Vina docking for the folate enzymes, kinases, and several other enzymes. The more accurate energy function and solvation terms of the MM/GBSA method allow MM/GBSA to achieve better enrichment, but the rescoring is still limited by the docking method to generate the poses with the correct binding modes.

  1. Identification of Important Chemical Features of 11β-Hydroxysteroid Dehydrogenase Type1 Inhibitors: Application of Ligand Based Virtual Screening and Density Functional Theory

    Directory of Open Access Journals (Sweden)

    Keun Woo Lee

    2012-04-01

    Full Text Available 11ß-Hydroxysteroid dehydrogenase type1 (11ßHSD1 regulates the conversion from inactive cortisone to active cortisol. Increased cortisol results in diabetes, hence quelling the activity of 11ßHSD1 has been thought of as an effective approach for the treatment of diabetes. Quantitative hypotheses were developed and validated to identify the critical chemical features with reliable geometric constraints that contribute to the inhibition of 11ßHSD1 function. The best hypothesis, Hypo1, which contains one-HBA; one-Hy-Ali, and two-RA features, was validated using Fischer’s randomization method, a test and a decoy set. The well validated, Hypo1, was used as 3D query to perform a virtual screening of three different chemical databases. Compounds selected by Hypo1 in the virtual screening were filtered by applying Lipinski’s rule of five, ADMET, and molecular docking. Finally, five hit compounds were selected as virtual novel hit molecules for 11ßHSD1 based on their electronic properties calculated by Density functional theory.

  2. Lung segmentation refinement based on optimal surface finding utilizing a hybrid desktop/virtual reality user interface.

    Science.gov (United States)

    Sun, Shanhui; Sonka, Milan; Beichel, Reinhard R

    2013-01-01

    Recently, the optimal surface finding (OSF) and layered optimal graph image segmentation of multiple objects and surfaces (LOGISMOS) approaches have been reported with applications to medical image segmentation tasks. While providing high levels of performance, these approaches may locally fail in the presence of pathology or other local challenges. Due to the image data variability, finding a suitable cost function that would be applicable to all image locations may not be feasible. This paper presents a new interactive refinement approach for correcting local segmentation errors in the automated OSF-based segmentation. A hybrid desktop/virtual reality user interface was developed for efficient interaction with the segmentations utilizing state-of-the-art stereoscopic visualization technology and advanced interaction techniques. The user interface allows a natural and interactive manipulation of 3-D surfaces. The approach was evaluated on 30 test cases from 18 CT lung datasets, which showed local segmentation errors after employing an automated OSF-based lung segmentation. The performed experiments exhibited significant increase in performance in terms of mean absolute surface distance errors (2.54±0.75 mm prior to refinement vs. 1.11±0.43 mm post-refinement, p≪0.001). Speed of the interactions is one of the most important aspects leading to the acceptance or rejection of the approach by users expecting real-time interaction experience. The average algorithm computing time per refinement iteration was 150 ms, and the average total user interaction time required for reaching complete operator satisfaction was about 2 min per case. This time was mostly spent on human-controlled manipulation of the object to identify whether additional refinement was necessary and to approve the final segmentation result. The reported principle is generally applicable to segmentation problems beyond lung segmentation in CT scans as long as the underlying segmentation utilizes the

  3. Decision support tool for Virtual Power Players: Hybrid Particle Swarm Optimization applied to Day-ahead Vehicle-To-Grid Scheduling

    DEFF Research Database (Denmark)

    Soares, João; Valle, Zita; Morais, Hugo

    2013-01-01

    This paper presents a decision support Tool methodology to help virtual power players (VPPs) in the Smart Grid (SGs) context to solve the day-ahead energy ressource scheduling considering the intensive use of Distributed Generation (DG) and Vehicle-To-Grid (V2G). The main focus is the application...... of a new hybrid method combing a particle swarm approach and a deterministic technique based on mixedinteger linear programming (MILP) to solve the day-ahead scheduling minimizing total operation costs from the aggregator point of view. A realistic mathematical formulation, considering the electric network...... constraints and V2G charging and discharging efficiencies is presented. Full AC power flow calculation is included in the hybrid method to allow taking into account the network constraints. A case study with a 33-bus distribution network and 1800 V2G resources is used to illustrate the performance...

  4. PCR-Reverse Blot Hybridization Assay for Screening and Identification of Pathogens in Sepsis

    OpenAIRE

    Choi, Yeonim; Wang, Hye-young; Lee, Gyusang; Park, Soon-Deok; Jeon, Bo-Young; Uh, Young; Kim, Jong Bae; Lee, Hyeyoung

    2013-01-01

    Rapid and accurate identification of the pathogens involved in bloodstream infections is crucial for the prompt initiation of appropriate therapy, as this can decrease morbidity and mortality rates. A PCR-reverse blot hybridization assay for sepsis, the reverse blot hybridization assay (REBA) Sepsis-ID test, was developed; it uses pan-probes to distinguish Gram-positive and -negative bacteria and fungi. In addition, the assay was designed to identify bacteria and fungi using six genus-specifi...

  5. Pre-implantation genetic screening using fluorescence in situ hybridization in couples of Indian ethnicity: Is there a scope?

    Directory of Open Access Journals (Sweden)

    Shailaja Gada Saxena

    2014-01-01

    Full Text Available Context: There is a high incidence of numerical chromosomal aberration in couples with repeated in vitro fertilization (IVF failure, advanced maternal age, repeated unexplained abortions, severe male factor infertility and unexplained infertility. Pre-implantation genetic screening (PGS, a variant of pre-implantation genetic diagnosis, screens numerical chromosomal aberrations in couples with normal karyotype, experiencing poor reproductive outcome. The present study includes the results of the initial pilot study on 9 couples who underwent 10 PGS cycles. Aim: The aim of the present study was to evaluate the beneficial effects of PGS in couples with poor reproductive outcome. Settings and Design: Data of initial 9 couples who underwent 10 PGS for various indications was evaluated. Subjects and Methods: Blastomere biopsy was performed on cleavage stage embryos and subjected to two round fluorescence in situ hybridization (FISH testing for chromosomes 13, 18, 21, X and Y as a two-step procedure. Results: Six of the 9 couples (10 PGS cycles conceived, including a twin pregnancy in a couple with male factor infertility, singleton pregnancies in a couple with secondary infertility, in three couples with adverse obstetric outcome in earlier pregnancies and in one couple with repeated IVF failure. Conclusion: In the absence of availability of array-comparative genomic hybridization in diagnostic clinical scenario for PGS and promising results with FISH based PGS as evident from the current pilot study, it is imperative to offer the best available services in the present scenario for better pregnancy outcome for patients.

  6. 苹果矮生型杂交后代筛选%Screening of Apple Dwarf Hybrids

    Institute of Scientific and Technical Information of China (English)

    鄢新民; 王献革; 李学营; 郝婕; 冯建忠

    2012-01-01

    Dwarf and close planting is the development trend of world apple production. The use of dwarfing rootstocks or dwarf varieties is the main way to realize the dwarf and close planting. The prediction technique for dwarf performance is critical, which directly impacts on the breeding efficiency. More than 4 000 apple hybrids from 16 combinations were selected, the internode length, the branch resistance value and the ratio of wood to bark are determined. The results show that 200 hybrids are screened primarily with the internode length less than 1.55 cm, frrom which 105 hybrids are screened with the resistance value less than 211.3 kΩ, then 43 hybrids are further screened with the ratio of wood to bark more than 17%. The dwarf strains or rootstocks are hopeful to be selected for apple production.%矮化密植栽培是世界苹果生产的发展趋势,利用矮化砧木或矮生型品种是实现苹果矮化密植栽培的主要途径。在矮化苹果育种中,矮生性能的预测技术非常关键,直接影响着育种效率。本研究以16个苹果杂交组合共计4000余株苹果杂交后代为材料,选择节间长度、枝条电阻值和枝皮率等作为树体矮生评价指标,对杂交后代进行了测定。结果表明:初步筛选出节间较短(节间长度〈1.55 cm)的实生后代个体200株;在此基础上,又筛选出电阻值较小(电阻值〈211.3 kΩ)的个体105株;进一步又筛选出枝皮率较高的矮生型个体(枝皮率〉17%)43株。有望通过复选实现突破,为苹果生产提供可用于矮化栽培的苹果(或砧木)优系。

  7. Screening virtual basado en topología molecular: una nueva metodología en el descubrimiento de agentes anticonvulsivos

    OpenAIRE

    Talevi, Alan

    2007-01-01

    La presente tesis se dividirá en dos partes. La primera de ellas, de carácter introductoria, versará sobre las motivaciones y los fundamentos del trabajo de tesis, describiendo la epilepsia y el estado actual de su terapéutica y proporcionando el marco teórico para comprender las bases y los alcances de los estudios QSAR, la Topología Molecular y las técnicas de Screening Virtual (SV). En la segunda se expondrán los resultados obtenidos mediante aplicación de estas metodologías en la búsqueda...

  8. Comparison of Hybrid capture 2 testing at different thresholds with cytology as primary cervical screening test

    NARCIS (Netherlands)

    Rijkaart, D. C.; Coupe, V. M. H.; van Kemenade, F. J.; Heideman, D. A. M.; Hesselink, A. T.; Verweij, W.; Rozendaal, L.; Verheijen, R. H.; Snijders, P. J.; Berkhof, J.; Meijer, C. J. L. M.

    2010-01-01

    BACKGROUND: We evaluated the performance of primary high-risk human papillomavirus (hrHPV) testing by hybrid capture 2 (HC2) with different thresholds for positivity, in comparison with conventional cytology. METHODS: We used data of 25 871 women (aged 30-60 years) from the intervention group of the

  9. Comparison of Hybrid capture 2 testing at different thresholds with cytology as primary cervical screening test

    NARCIS (Netherlands)

    Rijkaart, D. C.; Coupe, V. M. H.; van Kemenade, F. J.; Heideman, D. A. M.; Hesselink, A. T.; Verweij, W.; Rozendaal, L.; Verheijen, R. H.; Snijders, P. J.; Berkhof, J.; Meijer, C. J. L. M.

    2010-01-01

    BACKGROUND: We evaluated the performance of primary high-risk human papillomavirus (hrHPV) testing by hybrid capture 2 (HC2) with different thresholds for positivity, in comparison with conventional cytology. METHODS: We used data of 25 871 women (aged 30-60 years) from the intervention group of the

  10. Screening for insect and disease resistance and aflatoxin accumulation in experimental maize hybrids

    Science.gov (United States)

    In order to develop new maize germplasm lines with resistance to multiple insect pests, disease, and aflatoxin accumulation in temperate region, a set of new experimental hybrids was made using exotic tropical and subtropical maize inbred lines. The evaluation of these breeding crosses for insect a...

  11. DOVIS 2.0: an efficient and easy to use parallel virtual screening tool based on AutoDock 4.0.

    Science.gov (United States)

    Jiang, Xiaohui; Kumar, Kamal; Hu, Xin; Wallqvist, Anders; Reifman, Jaques

    2008-09-08

    Small-molecule docking is an important tool in studying receptor-ligand interactions and in identifying potential drug candidates. Previously, we developed a software tool (DOVIS) to perform large-scale virtual screening of small molecules in parallel on Linux clusters, using AutoDock 3.05 as the docking engine. DOVIS enables the seamless screening of millions of compounds on high-performance computing platforms. In this paper, we report significant advances in the software implementation of DOVIS 2.0, including enhanced screening capability, improved file system efficiency, and extended usability. To keep DOVIS up-to-date, we upgraded the software's docking engine to the more accurate AutoDock 4.0 code. We developed a new parallelization scheme to improve runtime efficiency and modified the AutoDock code to reduce excessive file operations during large-scale virtual screening jobs. We also implemented an algorithm to output docked ligands in an industry standard format, sd-file format, which can be easily interfaced with other modeling programs. Finally, we constructed a wrapper-script interface to enable automatic rescoring of docked ligands by arbitrarily selected third-party scoring programs. The significance of the new DOVIS 2.0 software compared with the previous version lies in its improved performance and usability. The new version makes the computation highly efficient by automating load balancing, significantly reducing excessive file operations by more than 95%, providing outputs that conform to industry standard sd-file format, and providing a general wrapper-script interface for rescoring of docked ligands. The new DOVIS 2.0 package is freely available to the public under the GNU General Public License.

  12. DOVIS 2.0: an efficient and easy to use parallel virtual screening tool based on AutoDock 4.0

    Directory of Open Access Journals (Sweden)

    Wallqvist Anders

    2008-09-01

    Full Text Available Abstract Background Small-molecule docking is an important tool in studying receptor-ligand interactions and in identifying potential drug candidates. Previously, we developed a software tool (DOVIS to perform large-scale virtual screening of small molecules in parallel on Linux clusters, using AutoDock 3.05 as the docking engine. DOVIS enables the seamless screening of millions of compounds on high-performance computing platforms. In this paper, we report significant advances in the software implementation of DOVIS 2.0, including enhanced screening capability, improved file system efficiency, and extended usability. Implementation To keep DOVIS up-to-date, we upgraded the software's docking engine to the more accurate AutoDock 4.0 code. We developed a new parallelization scheme to improve runtime efficiency and modified the AutoDock code to reduce excessive file operations during large-scale virtual screening jobs. We also implemented an algorithm to output docked ligands in an industry standard format, sd-file format, which can be easily interfaced with other modeling programs. Finally, we constructed a wrapper-script interface to enable automatic rescoring of docked ligands by arbitrarily selected third-party scoring programs. Conclusion The significance of the new DOVIS 2.0 software compared with the previous version lies in its improved performance and usability. The new version makes the computation highly efficient by automating load balancing, significantly reducing excessive file operations by more than 95%, providing outputs that conform to industry standard sd-file format, and providing a general wrapper-script interface for rescoring of docked ligands. The new DOVIS 2.0 package is freely available to the public under the GNU General Public License.

  13. Virtual Trackballs Revisited

    DEFF Research Database (Denmark)

    Henriksen, Knud; Sporring, Jon; Hornbæk, Kasper

    2004-01-01

    Rotation of three-dimensional objects by a two-dimensional mouse is a typical task in computer-aided design, operation simulations, and desktop virtual reality. The most commonly used rotation technique is a virtual trackball surrounding the object and operated by the mouse pointer. This article...... reviews and provides a mathematical foundation for virtual trackballs. The first, but still popular, virtual trackball was described by Chen et al. [CHECK END OF SENTENCE]. We show that the virtual trackball by Chen et al. does not rotate the object along the intended great circular arc on the virtual...... trackball and we give a correction. Another popular virtual trackball is Shoemake's quaternion implementation [CHECK END OF SENTENCE], which we show to be a special case of the virtual trackball by Chen et al.. Shoemake extends the scope of the virtual trackball to the full screen. Unfortunately, Shoemake...

  14. Toward a comprehensive hybrid physical-virtual reality simulator of peripheral anesthesia with ultrasound and neurostimulator guidance.

    Science.gov (United States)

    Samosky, Joseph T; Allen, Pete; Boronyak, Steve; Branstetter, Barton; Hein, Steven; Juhas, Mark; Nelson, Douglas A; Orebaugh, Steven; Pinto, Rohan; Smelko, Adam; Thompson, Mitch; Weaver, Robert A

    2011-01-01

    We are developing a simulator of peripheral nerve block utilizing a mixed-reality approach: the combination of a physical model, an MRI-derived virtual model, mechatronics and spatial tracking. Our design uses tangible (physical) interfaces to simulate surface anatomy, haptic feedback during needle insertion, mechatronic display of muscle twitch corresponding to the specific nerve stimulated, and visual and haptic feedback for the injection syringe. The twitch response is calculated incorporating the sensed output of a real neurostimulator. The virtual model is isomorphic with the physical model and is derived from segmented MRI data. This model provides the subsurface anatomy and, combined with electromagnetic tracking of a sham ultrasound probe and a standard nerve block needle, supports simulated ultrasound display and measurement of needle location and proximity to nerves and vessels. The needle tracking and virtual model also support objective performance metrics of needle targeting technique.

  15. Integration of genetic virtual screening patterns and latent multivariate modeling techniques for QSAR optimization based on combinations and/or interactions between peptides and proteins

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Both the concept and the model of snug quantitative structure-activity relationship (QSAR) were pro-posed and developed for molecular design through constructing QSAR based on some known mode of receptor/ligand interactions. Many disadvantages of traditional models can be avoided by using the proposed method because the traditional models only determined upon molecular structural features in sample sets themselves. A genetic virtual screening of peptide/protein combinations (GVSPPC) is proposed for the first time by utilizing this idea to examine peptide/protein affinity activities. A genetic algorithm (GA) was developed for screening combinative targets with an interaction mode for virtual receptors. GVSPPC succeeds in disposing difficulties in rational QSAR,in order to search for the ligand/receptor interactions on conditions of unknown structures. Some bioactive oligo-/poly-peptide systems covering 58 angiotensin converting enzyme (ACE) inhibitors and 18 double site mutation residues in camel antibody protein cAb-Lys3 were investigated by GVSPPC with satisfactory results (R 2 cu>0.91,Q 2 cv > 0.86,ERMS=0.19-0.95),respectively,which demonstrates that GVSPPC is more inter-pretable in the ligand-receptor interaction than the traditional QSAR method.

  16. Identification of novel inhibitors against Mycobacterium tuberculosis L-alanine dehydrogenase (MTB-AlaDH) through structure-based virtual screening.

    Science.gov (United States)

    Saxena, Shalini; Devi, Parthiban Brindha; Soni, Vijay; Yogeeswari, Perumal; Sriram, Dharmarajan

    2014-02-01

    Mycobacterium tuberculosis (MTB) the etiological agent of tuberculosis (TB) survives in the human host for decades evading the immune system in a latent or persistent state. The Rv2780 (ald) gene that codes for L-alanine dehydrogenase (L-AlaDH) enzyme catalyzes reversible oxidative deamination of L-alanine to pyruvate and is overexpressed under hypoxic and nutrient starvation conditions in MTB. At present, as there is no suitable drug available to treat dormant tuberculosis; it is essential to identify drug candidates that could potentially treat dormant TB. Availability of crystal structure of MTB L-AlaDH bound with co-factor NAD+ facilitated us to employ structure-based virtual screening approach to obtain new hits from a commercial library of Asinex database using energy-optimized pharmacophore modeling. The resulting pharmacophore consisted of three hydrogen bond donor sites (D) and two hydrogen bond acceptor sites (A). The database compounds with a fitness score more than 1.0 were further subjected to Glide high-throughput virtual screening and docking. Thus, we report the identification of best five hits based on structure-based design and their in vitro enzymatic inhibition studies revealed IC₅₀ values in the range of 35-80 μM.

  17. Integration of genetic virtual screening patterns and latent multivariate modeling techniques for QSAR optimization based on combinations and/or interactions between peptides and proteins

    Institute of Scientific and Technical Information of China (English)

    LI ZhiLiang; CHEN Gang; LI GenRong; TIAN FeiFei; WU ShiRong; YANG ShanBin; YANG ShengXi; ZHOU Yuan; ZHANG QiaoXia; QIN RenHui; MEI Hu

    2008-01-01

    Both the concept and the model of snug quantitative structure-activity relationship (QSAR) were pro-posed and developed for molecular design through constructing QSAR based on some known mode of receptor/ligand interactions. Many disadvantages of traditional models can be avoided by using the proposed method because the traditional models only determined upon molecular structural features in sample sets themselves. A genetic virtual screening of peptide/protein combinations (GVSPPC) is proposed for the first time by utilizing this idea to examine peptide/protein affinity activities. A genetic algorithm (GA) was developed for screening combinative targets with an interaction mode for virtual receptors. GVSPPC succeeds in disposing difficulties in rational QSAR, in order to search for the ligand/receptor interactions on conditions of unknown structures. Some bioactive oligo-/poly-peptide systems covering 58 angiotensin converting enzyme (ACE) inhibitors and 18 double site mutation residues in camel antibody protein cAb-Lys3 were investigated by GVSPPC with satisfactory results (Rcu2 > 0.91, Qcv2 0.86, ERMS = 0.19-0.95), respectively, which demonstrates that GVSPPC is more inter-pretable in the ligand-receptor interaction than the traditional QSAR method.

  18. The discovery of a novel and selective inhibitor of PTP1B over TCPTP: 3D QSAR pharmacophore modeling, virtual screening, synthesis, and biological evaluation.

    Science.gov (United States)

    Ma, Ying; Jin, Yuan-Yuan; Wang, Ye-Liu; Wang, Run-Ling; Lu, Xin-Hua; Kong, De-Xin; Xu, Wei-Ren

    2014-06-01

    Given the special role of insulin and leptin signaling in various biological responses, protein-tyrosine phosphatase-1B (PTP1B) was regarded as a novel therapeutic target for treating type 2 diabetes and obesity. However, owing to the highly conserved (sequence identity of about 74%) in active pocket, targeting PTP1B for drug discovery is a great challenge. In this study, we employed the software package Discovery Studio to develop 3D QSAR pharmacophore models for PTP1B and TCPTP inhibitors. It was further validated by three methods (cost analysis, test set prediction, and Fisher's test) to show that the models can be used to predict the biological activities of compounds without costly and time-consuming synthesis. The criteria for virtual screening were also validated by testing the selective PTP1B inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed a novel and selective inhibitor of PTP1B over TCPTP. After that, a most likely binding mode was proposed. Thus, the findings reported here may provide a new strategy in discovering selective PTP1B inhibitors.

  19. Atom pair 2D-fingerprints perceive 3D-molecular shape and pharmacophores for very fast virtual screening of ZINC and GDB-17.

    Science.gov (United States)

    Awale, Mahendra; Reymond, Jean-Louis

    2014-07-28

    Three-dimensional (3D) molecular shape and pharmacophores are important determinants of the biological activity of organic molecules; however, a precise computation of 3D-shape is generally too slow for virtual screening of very large databases. A reinvestigation of the concept of atom pairs initially reported by Carhart et al. and extended by Schneider et al. showed that a simple atom pair fingerprint (APfp) counting atom pairs at increasing topological distances in 2D-structures without atom property assignment correlates with various representations of molecular shape extracted from the 3D-structures. A related 55-dimensional atom pair fingerprint extended with atom properties (Xfp) provided an efficient pharmacophore fingerprint with good performance for ligand-based virtual screening such as the recovery of active compounds from decoys in DUD, and overlap with the ROCS 3D-pharmacophore scoring function. The APfp and Xfp data were organized for web-based extremely fast nearest-neighbor searching in ZINC (13.5 M compounds) and GDB-17 (50 M random subset) freely accessible at www.gdb.unibe.ch .

  20. Novel butyrylcholinesterase inhibitors through pharmacophore modeling, virtual screening and DFT-based approaches along-with design of bioisosterism-based analogues.

    Science.gov (United States)

    Gogoi, Dhrubajyoti; Chaliha, Amrita Kashyap; Sarma, Diganta; Kakoti, Bibhuti Bhusan; Buragohain, Alak Kumar

    2017-01-01

    Ligand and structure-based pharmacophore models were used to identify the important chemical features of butyrylcholinesterase (BChE) inhibitors. A training set of 16 known structurally diverse compounds with a wide range of inhibitory activity against BChE was used to develop a quantitative ligand-based pharmacophore (Hypo1) model to identify novel BChE inhibitors in virtual screening databases. A structure-based pharmacophore hypothesis (Phar1) was also developed with the ligand-binding site of BChE in consideration. Further, the models were validated using test set, Fisher's Randomization and Leave-one-out validation methods. Well-validated pharmacophore hypotheses were further used as 3D queries in virtual screening and 430 compounds were finally selected for molecular docking analysis. Subsequently, ADMET, DFT and chemical similarity search were employed to narrow down on seven compounds as potential drug candidates. Analogues of the best hit were further developed through a bioisosterism-guided approach to further generate a library of potential BChE inhibitors.

  1. A modified reverse one-hybrid screen identifies transcriptional activation in Phyochrome-Interacting Factor 3

    Science.gov (United States)

    Transcriptional activation domains (TAD) are difficult to predict and identify, since they are not conserved and have little consensus. Here, we describe a yeast-based screening method that is able to identify individual amino acid residues involved in transcriptional activation in a high throughput...

  2. Screened Hybrid and DFT + U Studies of the Structural, Electronic, and Optical Properties of U3O8

    Energy Technology Data Exchange (ETDEWEB)

    Wen, Xiaodong; Martin, Richard L.; Scuseria, Gustavo E.; Rudin, Sven P.; Batista, Enrique R.; Burrell, Anthony K.

    2012-11-26

    A systematic comparison of the structures and electronic and optical properties of U3O8 in the c2mm, P¯62m, and P21/m structures (the α, β, and γ phases, respectively) is performed using density functional theory + U (PBE + U) and the Heyd–Scuseria–Ernzerhof screened hybrid functional (HSE). The relationship between the semiconducting C2mm phase of U3O8 and the high temperature, metallic P¯62m phase is explored in more detail. Our calculated results show that the HSE functional gives a better description of the electronic and optical properties when compared with available experimental data for the α and β phases, but neither approach does particularly well for the high pressure γ phase.

  3. Screened hybrid and DFT + U studies of the structural, electronic, and optical properties of U3O8

    Science.gov (United States)

    Wen, Xiao-Dong; Martin, Richard L.; Scuseria, Gustavo E.; Rudin, Sven P.; Batista, Enrique R.; Burrell, Anthony K.

    2013-01-01

    A systematic comparison of the structures and electronic and optical properties of U3O8 in the c2mm, P\\bar {6}2 m, and P21/m structures (the α, β, and γ phases, respectively) is performed using density functional theory + U (PBE + U) and the Heyd-Scuseria-Ernzerhof screened hybrid functional (HSE). The relationship between the semiconducting C2mm phase of U3O8 and the high temperature, metallic P\\bar {6}2 m phase is explored in more detail. Our calculated results show that the HSE functional gives a better description of the electronic and optical properties when compared with available experimental data for the α and β phases, but neither approach does particularly well for the high pressure γ phase.

  4. Electronic and optical properties of (U,Th)O2 compound from screened hybrid density functional studies

    Science.gov (United States)

    Mo, Chongjie; Yang, Yu; Kang, Wei; Zhang, Ping

    2016-04-01

    The electronic structure and optical properties for the (U,Th)O2 compound are systematically studied by employing the Heyd-Scuseria-Ernzerh method (HSE) of screened hybrid density functional. The electronic band gap of (U,Th)O2 is predicted to be 3.06 eV, in the middle of the values of UO2 and ThO2. Based on wavefunction analysis, we conclude (U,Th)O2 to be a Mott insulator in its ground state. The frequency dependent dielectric functions and optical properties are then calculated and compared with those of ThO2 and UO2. At the visible light frequency range, the adsorption coefficients for ThO2, UO2 and (U,Th)O2 are totally different, which gives an accessible method to predict the proportion of U atoms in an arbitrary unknown (U,Th)O2 compounds from the adsorption spectrum of visible lights.

  5. Screening of aplastic anaemia-related genes in bone marrow CD4+ T cells by suppressive subtractive hybridization

    Institute of Scientific and Technical Information of China (English)

    ZHENG Miao; LIU Wen-li; FU Jin-rong; SUN Han-ying; ZHOU Jian-feng; XU Hui-zhen

    2007-01-01

    Background CD4+ T cells play a crucial role in the pathogenesis of aplastic anaemia. However, the mechanisms of over-proliferation, activation, infiltration of bone marrow and damage to haematopoietic cells of CD4+ T cells in aplastic anaemia are unclear. Therefore, we screened differentially expressed genes of bone marrow CD4+ T cells of aplastic anaemia patients and normal donors by suppressive subtractive hybridization to investigate the pathogenesis of aplastic anaemia.Methods The bone marrow mononuclear cells of a first visit aplastic anaemia patient and a healthy donor of the same age and sex were isolated using lymphocyte separating medium by density gradient centrifugation. With the patients as "tester" and donor as "driver", their CD4+T cells were separated with magnetic bead sorting and a cDNA library established by suppressive subtractive hybridization. Then 15 of the resulting subtracted cDNA clones were randomly selected for DNA sequencing and homological analysis. With semiquantitative RT-PCR, bone marrow samples from 20 patients with aplastic anaemia and 20 healthy donors assessed the expression levels of differentially expressed genes from SSH library.Results PCR detected 89 clones in the library containing an inserted fragment of 100 bp to 700 bp. Among 15 sequenced clones, 12 were known genes including 3 repeated genes. Compared with normal donors, there were 9/12 genes over-expressed in bone marrow CD4+T cells of patients with aplastic anaemia. The effects of these genes included protein synthesis, biology oxidation, signal transduction, proliferative regulation and cell migration. Not all these genes had been reported in the mechanisms of haematopoietic damage mediated by CD4+ T cells in aplastic anaemia.Conclusions Screening and cloning genes, which regulate functions of CD4+ T cells, are helpful in elucidating the mechanisms of over proliferation, activation, infiltrating bone marrow and damaging haematopoietic cells of CD4+ T cells in

  6. Accurate Modeling of the Cubic and Antiferrodistortive Phases of SrTiO3 with Screened Hybrid Density Functional Theory

    CERN Document Server

    El-Mellouhi, Fadwa; Lucero, Melissa J; Scuseria, Gustavo E

    2011-01-01

    We have calculated the properties of SrTiO3 (STO) using a wide array of density functionals ranging from standard semi-local functionals to modern range-separated hybrids, combined with several basis sets of varying size/quality. We show how these combination's predictive ability varies signi?cantly, both for STO's cubic and antiferrodistortive (AFD) phases, with the greatest variation in functional/basis set e?cacy seen in modeling the AFD phase. The screened hybrid functionals we utilized predict the structural properties of both phases in very good agreement with experiment, especially if used with large (but still computationally tractable) basis sets. The most accurate results presented in this study, namely those from HSE06/modi?ed-def2-TZVP, stand as the most accurate modeling of STO to date when compared to the literature; these results agree well with experimental structural and electronic properties as well as providing insight into the band structure alteration during the phase transition.

  7. Realization of Reconfigurable Virtual Environments for Virtual Testing

    Institute of Scientific and Technical Information of China (English)

    Wen-Yan Wu; Zheng-Xu Zhao

    2005-01-01

    This paper presents the design and implementation of reconfigurable virtual environments (VEs) for virtual testing. It proposes a hybrid design approach that is derived from a so-called integration and composition of the reconfiguration strategy. The designing process has thus evolved from binding virtual objects using reconfiguration rules within the context of virtual testing scenarios. Therefore reconfigurable virtual environments are established with improved flexibility and scalability, tailored to a wide range of virtual testing applications. Those virtual environments integrate virtual testing scenarios, data acquisition, databases, rule mapping and application interfaces, which yield modular testing functions and an open-ended system architecture with a set of extensible interface tools to realize data exchange within reconfigurable VEs.This enables virtual testing scenarios to be reconfigured interactively based on real time data and communication between virtual environments and real environments. A virtual testing application has been implemented using reconfigurable VEs.

  8. Phylogeny-function analysis of (meta)genomic libraries: screening for expression of ribosomal RNA genes by large-insert library fluorescent in situ hybridization (LIL-FISH)

    NARCIS (Netherlands)

    Leveau, J.H.J.; Gerards, S.; De Boer, W.; Van Veen, J.A.

    2004-01-01

    We assessed the utility of fluorescent in situ hybridization (FISH) in the screening of clone libraries of (meta)genomic or environmental DNA for the presence and expression of bacterial ribosomal RNA (rRNA) genes. To establish proof-of-principle, we constructed a fosmid-based library in Escherichia

  9. Screening for drought tolerance: comparison of maize hybrids under water deficit condition

    Directory of Open Access Journals (Sweden)

    Qurban Ali

    2016-02-01

    Full Text Available Background: Maize is an important cereal crop, grown throughout the globe for human food and livestock feed, but biotic and abiotic factors had shown adverse effects on biomass and grain yield. Changing climatic conditions have imposed drought (water scarcity as a major problem to combat with yield losses and biomass in maize and other cereals. Methods: The prescribed study was conducted to evaluate F1 hybrids at seedling subject to 45% moisture level. The data was recorded and subjected to multivariate analysis to find the significant variation attributed by various traits under stress conditions for efficient root/shoot development. Results: Significant differences were found in F1 hybrids for all studied traits. Higher heritability was found for root length, shoot length and fresh shoot weight, while fresh shoot weight, dry shoot weight and dry root weight showed higher genetic advance. Significant correlation was found for dry root weight to fresh shoot length and fresh root length, fresh root weight to fresh root/shoot weight ratio and fresh shoot weight. The hybrids Sh-139×B-316, Raka-poshi×B-316, B-327×B-316, Sh-139×EV-340, EV-1097Q×EV-347, EV-1097Q×EV-340, EV-1097Q×Pop/209 and B-327×EV-340 showed higher and positive heterosis and heterobeltiosis for most of the studied traits. To assess the overall variation on dependent structure, we used multivariate analysis, an important tool in breeding program, for efficient selection. Conclusions: EV-1097Q×Pop/209 and Sh-139×EV-340 showed significant results for root and shoot development under various water stress regimes at seedling stage, thus further studies should be carried out to find out the known and un-known loci regarding root and shoot development traits in high yielding maize cultivars under arid/semi-arid regions.

  10. Aneuploidy screening by array comparative genomic hybridization improves success rates of in vitro fertilization: A multicenter Indian study

    Directory of Open Access Journals (Sweden)

    Aditi Kotdawala

    2016-01-01

    Full Text Available Objective: To evaluate the usefulness of preimplantation genetic screening (PGS using array comparative genomic hybridization (aCGH in the Indian population. Materials and Methods: This is a retrospective, multicenter study including 235 PGS cycles following intracytoplasmic sperm injection performed at six different infertility centers from September 2013 to June 2015. Patients were divided as per maternal age in several groups (40 years and as per indication for undergoing PGS. Indications for performing PGS were recurrent miscarriage, repetitive implantation failure, severe male factor, previous trisomic pregnancy, and advanced maternal age (≥35. Day 3 embryo biopsy was performed and analyzed by aCGH followed by day 5 embryo transfer in the same cycle or the following cycle. Outcomes such as pregnancy rates (PRs/transfer, implantation rates, miscarriage rates, percentage of abnormal embryos, and number of embryos with more than one aneuploidy and chaotic patterns were recorded for all the treated subjects based on different age and indication groups. Results: aCGH helped in identifying aneuploid embryos, thus leading to consistent implantation (range: 33.3%-42.9% and PRs per transfer (range: 31.8%-54.9% that were obtained for all the indications in all the age groups, after performing PGS. Conclusion: Aneuploidy is one of the major factors which affect embryo implantation. aCGH can be successfully employed for screening of aneuploid embryos. When euploid embryos are transferred, an increase in PRs can be achieved irrespective of the age or the indication.

  11. A Modified Reverse One-Hybrid Screen Identifies Transcriptional Activation Domains in PHYTOCHROME-INTERACTING FACTOR 3.

    Science.gov (United States)

    Dalton, Jutta C; Bätz, Ulrike; Liu, Jason; Curie, Gemma L; Quail, Peter H

    2016-01-01

    Transcriptional activation domains (TADs) are difficult to predict and identify, since they are not conserved and have little consensus. Here, we describe a yeast-based screening method that is able to identify individual amino acid residues involved in transcriptional activation in a high throughput manner. A plant transcriptional activator, PIF3 (phytochrome interacting factor 3), was fused to the yeast GAL4-DNA-binding Domain (BD), driving expression of the URA3 (Orotidine 5'-phosphate decarboxylase) reporter, and used for negative selection on 5-fluroorotic acid (5FOA). Randomly mutagenized variants of PIF3 were then selected for a loss or reduction in transcriptional activation activity by survival on FOA. In the process, we developed a strategy to eliminate false positives from negative selection that can be used for both reverse-1- and 2-hybrid screens. With this method we were able to identify two distinct regions in PIF3 with transcriptional activation activity, both of which are functionally conserved in PIF1, PIF4, and PIF5. Both are collectively necessary for full PIF3 transcriptional activity, but neither is sufficient to induce transcription autonomously. We also found that the TAD appear to overlap physically with other PIF3 functions, such as phyB binding activity and consequent phosphorylation. Our protocol should provide a valuable tool for identifying, analyzing and characterizing novel TADs in eukaryotic transcription factors, and thus potentially contribute to the unraveling of the mechanism underlying transcriptional activation.

  12. A Modified Reverse One-Hybrid Screen Identifies Transcriptional Activation Domains in PHYTOCHROME-INTERACTING FACTOR 3

    Science.gov (United States)

    Dalton, Jutta C.; Bätz, Ulrike; Liu, Jason; Curie, Gemma L.; Quail, Peter H.

    2016-01-01

    Transcriptional activation domains (TADs) are difficult to predict and identify, since they are not conserved and have little consensus. Here, we describe a yeast-based screening method that is able to identify individual amino acid residues involved in transcriptional activation in a high throughput manner. A plant transcriptional activator, PIF3 (phytochrome interacting factor 3), was fused to the yeast GAL4-DNA-binding Domain (BD), driving expression of the URA3 (Orotidine 5′-phosphate decarboxylase) reporter, and used for negative selection on 5-fluroorotic acid (5FOA). Randomly mutagenized variants of PIF3 were then selected for a loss or reduction in transcriptional activation activity by survival on FOA. In the process, we developed a strategy to eliminate false positives from negative selection that can be used for both reverse-1- and 2-hybrid screens. With this method we were able to identify two distinct regions in PIF3 with transcriptional activation activity, both of which are functionally conserved in PIF1, PIF4, and PIF5. Both are collectively necessary for full PIF3 transcriptional activity, but neither is sufficient to induce transcription autonomously. We also found that the TAD appear to overlap physically with other PIF3 functions, such as phyB binding activity and consequent phosphorylation. Our protocol should provide a valuable tool for identifying, analyzing and characterizing novel TADs in eukaryotic transcription factors, and thus potentially contribute to the unraveling of the mechanism underlying transcriptional activation. PMID:27379152

  13. Screening of hepatocyte proteins binding to NS5ABP37 protein by yeast-two hybrid system

    Institute of Scientific and Technical Information of China (English)

    Lei Zhang; Qing-yong Ma; Xian-kui Meng; Kang Li; Jun Cheng

    2009-01-01

    Objective To investigate the biological function of NS5ABP37 and to look for proteins interacting with NS5ABP37 protein in hepatocytes. Methods We constructed bait plasmid expressing NS5ABP37 protein of hepatitis C virus (HCV) by cloning the gene of NS5ABP37 protein into pGBKT7, then the recombinant plasmid DNA was transformed into yeast AH109 (α type). The transformed yeast AH109 was mated with yeast Y187 (α type) containing liver cDNA library plasmid in 2×YPDA medium. Diploid yeast was plated on synthetic dropout nutrient medium (SD/-Trp-Leu-His-Ade) containing X-α-gal for selection and screening. After extracting and sequencing of plasmids from positive (blue) colonies, we made a sequence analysis by bioinformatics. Results We screened twenty-five proteins binding to NS5ABP37, including Homo sapiens cyclin Ⅰ (CCNI) gene, Homo sapiens matrix metallopeptidase 25 (MMP25) and Homo sapiens talin 1. Conclusion The yeast-two hybrid system is an effective method for identifying hepatocyte proteins interacting with NS5ABP37 of HCV. And the biological function of NS5ABP37 may be associated with glycometabolism, lipid metabolism and apoptosis.

  14. A Hybrid Intelligent Diagnosis Approach for Quick Screening of Alzheimer’s Disease Based on Multiple Neuropsychological Rating Scales

    Directory of Open Access Journals (Sweden)

    Ziming Yin

    2015-01-01

    Full Text Available Neuropsychological testing is an effective means for the screening of Alzheimer’s disease. Multiple neuropsychological rating scales should be used together to get subjects’ comprehensive cognitive state due to the limitation of a single scale, but it is difficult to operate in primary clinical settings because of the inadequacy of time and qualified clinicians. Aiming at identifying AD’s stages more accurately and conveniently in screening, we proposed a computer-aided diagnosis approach based on critical items extracted from multiple neuropsychological scales. The proposed hybrid intelligent approach combines the strengths of rough sets, genetic algorithm, and Bayesian network. There are two stages: one is attributes reduction technique based on rough sets and genetic algorithm, which can find out the most discriminative items for AD diagnosis in scales; the other is uncertain reasoning technique based on Bayesian network, which can forecast the probability of suffering from AD. The experimental data set consists of 500 cases collected by a top hospital in China and each case is determined by the expert panel. The results showed that the proposed approach could not only reduce items drastically with the same classification precision, but also perform better on identifying different stages of AD comparing with other existing scales.

  15. Erythrovirus B19 infection in acquired immunodeficiency syndrome: screening by histopathology, immunohistochemistry, and in situ hybridization

    Directory of Open Access Journals (Sweden)

    Sérgio Setúbal

    2006-06-01

    Full Text Available Erythrovirus B19 infects erythrocytic progenitors, transiently interrupting erythropoiesis. In AIDS patients it causes chronic anemia amenable to treatment. We looked for evidences of B19 infection in stored bone marrow material from patients with acquired immunodeficiency syndrome. Histological sections were made from stored paraffin blocks from 33 autopsies (39 blocks and 35 biopsies (45 blocks, 30 patients performed from 1988 to 2002. They were examined after hematoxylin-eosin (HE staining, immunohistochemical (IHC, and in situ hybridization. HE revealed intra-nuclear inclusion bodies ("lantern cells" suggesting B19 infection in 19 sections corresponding to 19 of 63 patients examined with this test. Seven of 78 sections subjected to immunohistochemistry were positive, corresponding to 7 of 58 patients examined with this test. Fourteen sections corresponding to 13 of the 20 HE and/or IHC positive patients were subjected to in situ hybridization, with six positives results. Among the 13 patients subjected to the three techniques, only one gave unequivocal positive results in all and was considered a true positive. The frequency of B19 infection (1/63 patients in the material examined can be deemed low.

  16. An in situ hybridization-based screen for heterogeneously expressed genes in mouse ES cells.

    Science.gov (United States)

    Carter, Mark G; Stagg, Carole A; Falco, Geppino; Yoshikawa, Toshiyuki; Bassey, Uwem C; Aiba, Kazuhiro; Sharova, Lioudmila V; Shaik, Nabeebi; Ko, Minoru S H

    2008-02-01

    We previously reported that Zscan4 showed heterogeneous expression patterns in mouse embryonic stem (ES) cells. To identify genes that show similar expression patterns, we carried out high-throughput in situ hybridization assays on ES cell cultures for 244 genes. Most of the genes are involved in transcriptional regulation, and were selected using microarray-based comparisons of gene expression profiles in ES and embryonal carcinoma (EC) cells versus differentiated cell types. Pou5f1 (Oct4, Oct3/4) and Krt8 (EndoA) were used as controls. Hybridization signals were detected on ES cell colonies for 147 genes (60%). The majority (136 genes) of them showed relatively homogeneous expression in ES cell colonies. However, we found that two genes unequivocally showed Zscan4-like spotted expression pattern (spot-in-colony pattern; Whsc2 and Rhox9). We also found that nine genes showed relatively heterogeneous expression pattern (mosaic-in-colony pattern: Zfp42/Rex1, Rest, Atf4, Pa2g4, E2f2, Nanog, Dppa3/Pgc7/Stella, Esrrb, and Fscn1). Among these genes, Zfp42/Rex1 showed unequivocally heterogeneous expression in individual ES cells prepared by the CytoSpin. These results show the presence of different types or states of cells within ES cell cultures otherwise thought to be undifferentiated and homogeneous, suggesting a previously unappreciated complexity in ES cell cultures.

  17. Dalvik virtual machine performance improvement based on hybrid concurrent model%基于混合并发模式的Dalvik虚拟机性能优化

    Institute of Scientific and Technical Information of China (English)

    李茜; 肖萍

    2012-01-01

    To improve Dalvik virtual machine performance, a hybrid concurrent model based on multi-thread mechanism for Java virtual machine was proposed. This model implemented performance optimization by overlapping the production of native code with program execution through multi-thread control and hot-function table, and some critical issues in the design and implementation were also discussed. The experimental results show that this model can improve the Java execution speed efficiently in Dalvik.%为了改进Dalvik虚拟机的性能,提出了一种基于多线程调度机制的Java虚拟机混合并发模式.该模式利用多线程并发调度和热方法表,通过将Java字节码的编译与执行过程相重叠来提高程序的执行效率,进而提升Dalvik虚拟机的处理速度;并对该模式设计与实现的关键技术进行了分析.实验结果表明,混合并发模式能够有效地提高Dalvik虚拟机中Java程序的执行速度.

  18. Using a hybrid brain computer interface and virtual reality system to monitor and promote cortical reorganization through motor activity and motor imagery training.

    Science.gov (United States)

    Bermúdez i Badia, S; García Morgade, A; Samaha, H; Verschure, P F M J

    2013-03-01

    Stroke is one of the leading causes of adult disability with high economical and societal costs. In recent years, novel rehabilitation paradigms have been proposed to address the life-long plasticity of the brain to regain motor function. We propose a hybrid brain-computer interface (BCI)-virtual reality (VR) system that combines a personalized motor training in a VR environment, exploiting brain mechanisms for action execution and observation, and a neuro-feedback paradigm using mental imagery as a way to engage secondary or indirect pathways to access undamaged cortico-spinal tracts. Furthermore, we present the development and validation experiments of the proposed system. More specifically, EEG data on nine naïve healthy subjects show that a simultaneous motor activity and motor imagery paradigm is more effective at engaging cortical motor areas and related networks to a larger extent. Additionally, we propose a motor imagery driven BCI-VR version of our system that was evaluated with nine different healthy subjects. Data show that users are capable of controlling a virtual avatar in a motor imagery training task that dynamically adjusts its difficulty to the capabilities of the user. User self-report questionnaires indicate enjoyment and acceptance of the proposed system.

  19. Flavivirus NS3 and NS5 proteins interaction network: a high-throughput yeast two-hybrid screen

    Directory of Open Access Journals (Sweden)

    Canard Bruno

    2011-10-01

    Full Text Available Abstract Background The genus Flavivirus encompasses more than 50 distinct species of arthropod-borne viruses, including several major human pathogens, such as West Nile virus, yellow fever virus, Japanese encephalitis virus and the four serotypes of dengue viruses (DENV type 1-4. Each year, flaviviruses cause more than 100 million infections worldwide, some of which lead to life-threatening conditions such as encephalitis or haemorrhagic fever. Among the viral proteins, NS3 and NS5 proteins constitute the major enzymatic components of the viral replication complex and are essential to the flavivirus life cycle. Results We report here the results of a high-throughput yeast two-hybrid screen to identify the interactions between human host proteins and the flavivirus NS3 and NS5 proteins. Using our screen results and literature curation, we performed a global analysis of the NS3 and NS5 cellular targets based on functional annotation with the Gene Ontology features. We finally created the first flavivirus NS3 and NS5 proteins interaction network and analysed the topological features of this network. Our proteome mapping screen identified 108 human proteins interacting with NS3 or NS5 proteins or both. The global analysis of the cellular targets revealed the enrichment of host proteins involved in RNA binding, transcription regulation, vesicular transport or innate immune response regulation. Conclusions We proposed that the selective disruption of these newly identified host/virus interactions could represent a novel and attractive therapeutic strategy in treating flavivirus infections. Our virus-host interaction map provides a basis to unravel fundamental processes about flavivirus subversion of the host replication machinery and/or immune defence strategy.

  20. Comparative molecular surface analysis (CoMSA) for virtual combinatorial library screening of styrylquinoline HIV-1 blocking agents.

    Science.gov (United States)

    Niedbala, Halina; Polanski, Jaroslaw; Gieleciak, Rafal; Musiol, Robert; Tabak, Dominik; Podeszwa, Barbara; Bak, Andrzej; Palka, Anna; Mouscadet, Jean-Francois; Gasteiger, Johann; Le Bret, Marc

    2006-12-01

    We used comparative molecular surface analysis to design molecules for the synthesis as part of the search for new HIV-1 integrase inhibitors. We analyzed the virtual combinatorial library (VCL) constituted from various moieties of styrylquinoline and styrylquinazoline inhibitors. Since imines can be applied in a strategy of dynamic combinatorial chemistry (DCC), we also tested similar compounds in which the -C=N- or -N=C- linker connected the heteroaromatic and aromatic moieties. We then used principal component analysis (PCA) or self-organizing maps (SOM), namely, the Kohonen neural networks to obtain a clustering plot analyzing the diversity of the VCL formed. Previously synthesized compounds of known activity, used as molecular probes, were projected onto this plot, which provided a set of promising virtual drugs. Moreover, we further modified the above mentioned VCL to include the single bond linker -C-N- or -N-C-. This allowed increasing compound stability but expanded also the diversity between the available molecular probes and virtual targets. The application of the CoMSA with SOM indicated important differences between such compounds and active molecular probes. We synthesized such compounds to verify the computational predictions.

  1. Hybrid Motion Planning Method for Autonomous Robots Using Kinect Based Sensor Fusion and Virtual Plane Approach in Dynamic Environments

    Directory of Open Access Journals (Sweden)

    Doopalam Tuvshinjargal

    2015-01-01

    Full Text Available A new reactive motion planning method for an autonomous vehicle in dynamic environments is proposed. The new dynamic motion planning method combines a virtual plane based reactive motion planning technique with a sensor fusion based obstacle detection approach, which results in improving robustness and autonomy of vehicle navigation within unpredictable dynamic environments. The key feature of the new reactive motion planning method is based on a local observer in the virtual plane which allows the effective transformation of complex dynamic planning problems into simple stationary in the virtual plane. In addition, a sensor fusion based obstacle detection technique provides the pose estimation of moving obstacles by using a Kinect sensor and a sonar sensor, which helps to improve the accuracy and robustness of the reactive motion planning approach in uncertain dynamic environments. The performance of the proposed method was demonstrated through not only simulation studies but also field experiments using multiple moving obstacles even in hostile environments where conventional method failed.

  2. Synthesis and biological screening by novel hybrid fluorocarbon hydrocarbon compounds for use as artificial blood substitutes

    Science.gov (United States)

    Moacanin, J.; Scherer, K.; Toronto, A.; Lawson, D.; Terranova, T.; Yavrouian, A.; Astle, L.; Harvey, S.; Kaaelble, D. H.

    1979-01-01

    A series of hybrid fluorochemicals of general structure R(1)R(2)R(3)CR(4) was prepared where the R(i)'s (i=1,2,3) is a saturated fluoroalkyl group of formula C sub N F sub 2n+1, and R(4) is an alkyl group C sub n H sub 2n+1 or a related moiety containing amino, ether, or ester functions but no CF bonds. Compounds of this class containing approximately eight to twenty carbons total have physical properties suitable for use as the oxygen carrying phase of fluorochemical emulsion artificial blood. The chemical synthesis, and physical and biological testing of pure single isomers of the proposed artificial blood candidate compounds are included. Significant results are given.

  3. [Identification of C(2)M interacting proteins by yeast two-hybrid screening].

    Science.gov (United States)

    Shanshan, Yue; Laixin, Xia

    2015-11-01

    The synaptonemal complex (SC) is a huge structure which assembles between the homologous chromosomes during meiotic prophase I. Drosophila germ cell-specific nucleoprotein C(2)M clustering at chromosomes can induce SC formation. To further study the molecular function and mechanism of C(2)M in meiosis, we constructed a bait vector for C(2)M and used the yeast two-hybrid system to identify C(2)M interacting proteins. Forty interacting proteins were obtained, including many DNA and histone binding proteins, ATP synthases and transcription factors. Gene silencing assays in Drosophila showed that two genes, wech and Psf1, may delay the disappearance of SC. These results indicate that Wech and Psf1 may form a complex with C(2)M to participate in the formation or stabilization of the SC complex.

  4. A virtual high-throughput screening approach to the discovery of novel inhibitors of the bacterial leucine transporter, LeuT.

    Science.gov (United States)

    Simmons, Katie J; Gotfryd, Kamil; Billesbølle, Christian B; Loland, Claus J; Gether, Ulrik; Fishwick, Colin W G; Johnson, A Peter

    2013-03-01

    Membrane proteins are intrinsically involved in both human and pathogen physiology, and are the target of 60% of all marketed drugs. During the past decade, advances in the studies of membrane proteins using X-ray crystallography, electron microscopy and NMR-based techniques led to the elucidation of over 250 unique membrane protein crystal structures. The aim of the European Drug Initiative for Channels and Transporter (EDICT) project is to use the structures of clinically significant membrane proteins for the development of lead molecules. One of the approaches used to achieve this is a virtual high-throughput screening (vHTS) technique initially developed for soluble proteins. This paper describes application of this technique to the discovery of inhibitors of the leucine transporter (LeuT), a member of the neurotransmitter:sodium symporter (NSS) family.

  5. A virtual high-throughput screening approach to the discovery of novel inhibitors of the bacterial leucine transporter, LeuT

    DEFF Research Database (Denmark)

    Simmons, Katie J; Gotfryd, Kamil; Billesbølle, Christian B

    2013-01-01

    this is a virtual high-throughput screening (vHTS) technique initially developed for soluble proteins. This paper describes application of this technique to the discovery of inhibitors of the leucine transporter (LeuT), a member of the neurotransmitter:sodium symporter (NSS) family.......Abstract Membrane proteins are intrinsically involved in both human and pathogen physiology, and are the target of 60% of all marketed drugs. During the past decade, advances in the studies of membrane proteins using X-ray crystallography, electron microscopy and NMR-based techniques led...... to the elucidation of over 250 unique membrane protein crystal structures. The aim of the European Drug Initiative for Channels and Transporter (EDICT) project is to use the structures of clinically significant membrane proteins for the development of lead molecules. One of the approaches used to achieve...

  6. Overview on the current status on virtual high-throughput screening and combinatorial chemistry approaches in multi-target anticancer drug discovery; Part II.

    Science.gov (United States)

    Geromichalos, George D; Alifieris, Constantinos E; Geromichalou, Elena G; Trafalis, Dimitrios T

    2016-01-01

    Conventional drug design embraces the "one gene, one drug, one disease" philosophy. Nowadays, new generation of anticancer drugs, able to inhibit more than one pathway, is believed to play a major role in contemporary anticancer drug research. In this way, polypharmacology, focusing on multi-target drugs, has emerged as a new paradigm in drug discovery. A number of recent successful drugs have in part or in whole emerged from a structure-based research approach. Many advances including crystallography and informatics are behind these successes. In this part II we will review the role and methodology of ligand-, structure- and fragment-based computer-aided drug design computer aided drug desing (CADD), virtual high throughput screening (vHTS), de novo drug design, fragment-based design and structure-based molecular docking, homology modeling, combinatorial chemistry and library design, pharmacophore model chemistry and informatics in modern drug discovery.

  7. Systematic Comparison of the Performance of Different 2D and 3D Ligand-Based Virtual Screening Methodologies to Discover Anticonvulsant Drugs.

    Science.gov (United States)

    Di Ianni, Mauricio E; Gantner, Melisa E; Ruiz, María E; Castro, Eduardo A; Bruno-Blanch, Luis E; Talevi, Alan

    2015-01-01

    Virtual screening encompasses a wide range of computational approaches aimed at the high-throughput, cost-efficient exploration of chemical libraries or databases to discover new bioactive compounds or novel medical indications of known drugs. Here, we have performed a systematic comparison of the performance of a large number of 2D and 3D ligand-based approaches (2D and 3D similarity, QSAR models, pharmacophoric hypothesis) in a simulated virtual campaign on a chemical library containing 50 known anticonvulsant drugs and 950 decoys with no previous reports of anticonvulsant effect. To perform such comparison, we resorted to Receiver Operating Characteristic curves. We also tested the relative performance of consensus methodologies. Our results indicate that the selective combination of the individual approaches (through voting and ranking combination schemes) significantly outperforms the individual algorithms and/or models. Among the best-performing individual approaches, 2D similarity search based on circular fingerprints and 3D similarity approaches should be highlighted. Combining the results from different query molecules also led to enhanced enrichment.

  8. Octopus: a platform for the virtual high-throughput screening of a pool of compounds against a set of molecular targets.

    Science.gov (United States)

    Maia, Eduardo Habib Bechelane; Campos, Vinícius Alves; Dos Reis Santos, Bianca; Costa, Marina Santos; Lima, Iann Gabriel; Greco, Sandro J; Ribeiro, Rosy I M A; Munayer, Felipe M; da Silva, Alisson Marques; Taranto, Alex Gutterres

    2017-01-01

    Octopus is an automated workflow management tool that is scalable for virtual high-throughput screening (vHTS). It integrates MOPAC2016, MGLTools, PyMOL, and AutoDock Vina. In contrast to other platforms, Octopus can perform docking simulations of an unlimited number of compounds into a set of molecular targets. After generating the ligands in a drawing package in the Protein Data Bank (PDB) format, Octopus can carry out geometry refinement using the semi-empirical method PM7 implemented in MOPAC2016. Docking simulations can be performed using AutoDock Vina and can utilize the Our Own Molecular Targets (OOMT) databank. Finally, the proposed software compiles the best binding energies into a standard table. Here, we describe two successful case studies that were verified by biological assay. In the first case study, the vHTS process was carried out for 22 (phenylamino)urea derivatives. The vHTS process identified a metalloprotease with the PDB code 1GKC as a molecular target for derivative LE&007. In a biological assay, compound LE&007 was found to inhibit 80% of the activity of this enzyme. In the second case study, compound Tx001 was submitted to the Octopus routine, and the results suggested that Plasmodium falciparum ATP6 (PfATP6) as a molecular target for this compound. Following an antimalarial assay, Tx001 was found to have an inhibitory concentration (IC50) of 8.2 μM against PfATP6. These successful examples illustrate the utility of this software for finding appropriate molecular targets for compounds. Hits can then be identified and optimized as new antineoplastic and antimalarial drugs. Finally, Octopus has a friendly Linux-based user interface, and is available at www.drugdiscovery.com.br . Graphical Abstract Octopus: A platform for inverse virtual screening (IVS) to search new molecular targets for drugs.

  9. In silico exploration of c-KIT inhibitors by pharmaco-informatics methodology: pharmacophore modeling, 3D QSAR, docking studies, and virtual screening.

    Science.gov (United States)

    Chaudhari, Prashant; Bari, Sanjay

    2016-02-01

    c-KIT is a component of the platelet-derived growth factor receptor family, classified as type-III receptor tyrosine kinase. c-KIT has been reported to be involved in, small cell lung cancer, other malignant human cancers, and inflammatory and autoimmune diseases associated with mast cells. Available c-KIT inhibitors suffer from tribulations of growing resistance or cardiac toxicity. A combined in silico pharmacophore and structure-based virtual screening was performed to identify novel potential c-KIT inhibitors. In the present study, five molecules from the ZINC database were retrieved as new potential c-KIT inhibitors, using Schrödinger's Maestro 9.0 molecular modeling suite. An atom-featured 3D QSAR model was built using previously reported c-KIT inhibitors containing the indolin-2-one scaffold. The developed 3D QSAR model ADHRR.24 was found to be significant (R2 = 0.9378, Q2 = 0.7832) and instituted to be sufficiently robust with good predictive accuracy, as confirmed through external validation approaches, Y-randomization and GH approach [GH score 0.84 and Enrichment factor (E) 4.964]. The present QSAR model was further validated for the OECD principle 3, in that the applicability domain was calculated using a "standardization approach." Molecular docking of the QSAR dataset molecules and final ZINC hits were performed on the c-KIT receptor (PDB ID: 3G0E). Docking interactions were in agreement with the developed 3D QSAR model. Model ADHRR.24 was explored for ligand-based virtual screening followed by in silico ADME prediction studies. Five molecules from the ZINC database were obtained as potential c-KIT inhibitors with high in -silico predicted activity and strong key binding interactions with the c-KIT receptor.

  10. Using consensus-shape clustering to identify promiscuous ligands and protein targets and to choose the right query for shape-based virtual screening.

    Science.gov (United States)

    Pérez-Nueno, Violeta I; Ritchie, David W

    2011-06-27

    Ligand-based shape matching approaches have become established as important and popular virtual screening (VS) techniques. However, despite their relative success, many authors have discussed how best to choose the initial query compounds and which of their conformations should be used. Furthermore, it is increasingly the case that pharmaceutical companies have multiple ligands for a given target and these may bind in different ways to the same pocket. Conversely, a given ligand can sometimes bind to multiple targets, and this is clearly of great importance when considering drug side-effects. We recently introduced the notion of spherical harmonic-based "consensus shapes" to help deal with these questions. Here, we apply a consensus shape clustering approach to the 40 protein-ligand targets in the DUD data set using PARASURF/PARAFIT. Results from clustering show that in some cases the ligands for a given target are split into two subgroups which could suggest they bind to different subsites of the same target. In other cases, our clustering approach sometimes groups together ligands from different targets, and this suggests that those ligands could bind to the same targets. Hence spherical harmonic-based clustering can rapidly give cross-docking information while avoiding the expense of performing all-against-all docking calculations. We also report on the effect of the query conformation on the performance of shape-based screening of the DUD data set and the potential gain in screening performance by using consensus shapes calculated in different ways. We provide details of our analysis of shape-based screening using both PARASURF/PARAFIT and ROCS, and we compare the results obtained with shape-based and conventional docking approaches using MSSH/SHEF and GOLD. The utility of each type of query is analyzed using commonly reported statistics such as enrichment factors (EF) and receiver-operator-characteristic (ROC) plots as well as other early performance metrics.

  11. Synthesis, characterization and antimicrobial screening of hybrid molecules containing quinoline, pyrimidine and morpholine analogues

    Indian Academy of Sciences (India)

    N C Desai; K M Rajpara; V V Joshi; H V Vaghani; H M Satodiya

    2013-03-01

    In an attempt to find new bio-active molecules, a series of compounds -(4-(2-chloroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)-2-morpholinoacetamides (5a-l) were synthesized by multistep reactions. Compounds were characterized by IR, NMR and mass spectra. Antimicrobial screening of title compounds (5a-l) was carried out against Gram-positive bacteria (Staphylococcus aureus, Streptococcus pyogenes), Gramnegative bacteria (Escherichia coli, Pseudomonas aeruginosa) and fungi (Candida albicans, Aspergillus niger, Aspergillus clavatus) using serial broth dilution method. On the basis of statistical analysis, it is observed that these compounds gave significant co-relation. Newly synthesized compounds 5e, 5f, 5g, 5i and 5l showed significant potency against different microbial strains.

  12. Identification of interacting proteins with aryl hydrocarbon receptor in scallop Chlamys farreri by yeast two hybrid screening.

    Science.gov (United States)

    Cai, Yuefeng; Pan, Luqing; Miao, Jingjing; Liu, Tong

    2016-11-01

    The aryl hydrocarbon receptor (AhR) belongs to the basic-helix-loop helix (bHLH) Per-Arnt-Sim (PAS) family of transcription factors. AhR has been known primarily for its role in the regulation of several drug and xenobiotic metabolizing enzymes, as well as the mediation of the toxicity of certain xenobiotics, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Although the AhR is well-studied as a mediator of the toxicity of certain xenobiotics in marine bivalves, the normal physiological function remains unknown. In order to explore the function of the AhR, the bait protein expression plasmid pGBKT7-CfAhR and the cDNA library of gill from Chlamys farreri were constructed. By yeast two hybrid system, after multiple screening with the high screening rate medium, rotary verification, sequencing and bioinformatics analysis, the interactions of the CfAhR with receptor for activated protein kinase C 1 (RACK1), thyroid peroxidase-like protein (TPO), Toll-like receptor 4(TLR 4), androglobin-like, store-operated Ca(2+) entry (SocE), ADP/ATP carrier protein, cytochrome b, thioesterase, actin, ferritin subunit 1, poly-ubiquitin, short-chain collagen C4-like and one hypothetical protein in gill cells were identified. This study suggests that the CfAhR played fundamental roles in immune system homeostasis, oxidative stress response, and in grow and development of C. farreri. The elucidation of these protein interactions is of much importance both in understanding the normal physiological function of AhR, and as potential targets for further research on protein function in AhR interactions.

  13. 3D-QSAR and virtual screening studies of thiazolidine-2,4-dione analogs: Validation of experimental inhibitory potencies towards PIM-1 kinase

    Science.gov (United States)

    Asati, Vivek; Bharti, Sanjay Kumar; Budhwani, Ashok Kumar

    2017-04-01

    The proviral insertion site in moloney murine leukemia virus (PIM) is a family of serine/threonine kinase of Ca2+-calmodulin-dependent protein kinase (CAMK) group which is responsible for the activation and regulation of cellular transcription and translation. The three isoforms of PIM kinase (PIM-1, PIM-2 and PIM-3) share high homology and functional idleness are widely expressed and involved in a variety of biological processes including cell survival, proliferation, differentiation and apoptosis. Altered expression of PIM-1 kinase correlated with hematologic malignancies and solid tumors. In the present study, atom-based 3D-QSAR, docking and virtual screening studies have been performed on a series of thiazolidine-2,4-dione derivatives as PIM-1 kinase inhibitors. 3D-QSAR and docking approach has shortlisted the most active thiazolidine-2,4-dione derivatives such as 28, 31, 33 and 35 with the incorporation of more than one structural feature in a single molecule. External validations by various parameters and molecular docking studies at the active site of PIM-1 kinase have proved the reliability of the developed 3D-QSAR model. The generated pharmacophore (AADHR.33) from 3D-QSAR study was used for screening of drug like compounds from ZINC database, where ZINC15056464 and ZINC83292944 showed potential binding affinities at the active site amino acid residues (LYS67, GLU171, ASP128 and ASP186) of PIM-1 kinase (PDB ID: "pdb:4DTK").

  14. High throughput virtual screening and in silico ADMET analysis for rapid and efficient identification of potential PAP248-286 aggregation inhibitors as anti-HIV agents

    Science.gov (United States)

    Malik, Ruchi; Bunkar, Devendra; Choudhary, Bhanwar Singh; Srivastava, Shubham; Mehta, Pakhuri; Sharma, Manish

    2016-10-01

    Human semen is principal vehicle for transmission of HIV-1 and other enveloped viruses. Several endogenous peptides present in semen, including a 39-amino acid fragments of prostatic acid phosphatase (PAP248-286) assemble into amyloid fibrils named as semen-derived enhancer of viral infection (SEVI) that promote virion attachment to target cells which dramatically enhance HIV virus infection by up to 105-fold. Epigallocatechin-3-gallate (EGCG), a polyphenolic compound, is the major catechin found in green tea which disaggregates existing SEVI fibers, and inhibits the formation of SEVI fibers. The aim of this study was to screen a number of relevant polyphenols to develop a rational approach for designing PAP248-286 aggregation inhibitors as potential anti-HIV agents. The molecular docking based virtual screening results showed that polyphenolic compounds 2-6 possessed good docking score and interacted well with the active site residues of PAP248-286. Amino acid residues of binding site namely; Lys255, Ser256, Leu258 and Asn265 are involved in binding of these compounds. In silico ADMET prediction studies on these hits were also found to be promising. Polyphenolic compounds 2-6 identified as hits may act as novel leads for inhibiting aggregation of PAP248-286 into SEVI.

  15. Constructing and Validating High-Performance MIEC-SVM Models in Virtual Screening for Kinases: A Better Way for Actives Discovery.

    Science.gov (United States)

    Sun, Huiyong; Pan, Peichen; Tian, Sheng; Xu, Lei; Kong, Xiaotian; Li, Youyong; Dan Li; Hou, Tingjun

    2016-04-22

    The MIEC-SVM approach, which combines molecular interaction energy components (MIEC) derived from free energy decomposition and support vector machine (SVM), has been found effective in capturing the energetic patterns of protein-peptide recognition. However, the performance of this approach in identifying small molecule inhibitors of drug targets has not been well assessed and validated by experiments. Thereafter, by combining different model construction protocols, the issues related to developing best MIEC-SVM models were firstly discussed upon three kinase targets (ABL, ALK, and BRAF). As for the investigated targets, the optimized MIEC-SVM models performed much better than the models based on the default SVM parameters and Autodock for the tested datasets. Then, the proposed strategy was utilized to screen the Specs database for discovering potential inhibitors of the ALK kinase. The experimental results showed that the optimized MIEC-SVM model, which identified 7 actives with IC50 < 10 μM from 50 purchased compounds (namely hit rate of 14%, and 4 in nM level) and performed much better than Autodock (3 actives with IC50 < 10 μM from 50 purchased compounds, namely hit rate of 6%, and 2 in nM level), suggesting that the proposed strategy is a powerful tool in structure-based virtual screening.

  16. Overview on the current status of virtual high-throughput screening and combinatorial chemistry approaches in multi-target anticancer drug discovery; Part I.

    Science.gov (United States)

    Geromichalos, George D; Alifieris, Constantinos E; Geromichalou, Elena G; Trafalis, Dimitrios T

    2016-01-01

    Conventional drug design embraces the "one gene, one drug, one disease" philosophy. Nowadays, new generation of anti- cancer drugs, able to inhibit more than one pathway, is believed to play a major role in contemporary anticancer drug research. In this way, polypharmacology, focusing on multi-target drugs, has emerged as a new paradigm in drug discovery. A number of recent successful drugs have in part or in whole emerged from a structure-based research approach. Many advances including crystallography and informatics are behind these successes. Increasing insight into the genetics and molecular biology of cancer has resulted in the identification of an increasing number of potential molecular targets, for anticancer drug discovery and development. These targets can be approached through exploitation of emerging structural biology, "rational" drug design, screening of chemical libraries, or a combination of these methods. The result is the rapid discovery of new anticancer drugs. In this article we discuss the application of molecular modeling, molecular docking and virtual high-throughput screening to multi-targeted anticancer drug discovery. Efforts have been made to employ in silico methods for facilitating the search and design of selective multi-target agents. These computer aided molecular design methods have shown promising potential in facilitating drug discovery directed at selective multiple targets and is expected to contribute to intelligent lead anticancer drugs.

  17. A QSAR approach for virtual screening of lead-like molecules en route to antitumor and antibiotic drugs from marine and microbial natural products

    Directory of Open Access Journals (Sweden)

    Florbela Pereira

    2014-05-01

    Figure 1. The unreported 15 lead antibiotic MNPs and MbNPs from AntiMarin database, using the best Rfs antibiotic model with a probability of being antibiotic greater than or equal to 0.8. Figure 2. The selected 4 lead antitumor MNPs and MbNPs from the AntiMarin database, using the best Rfs antitumor model with a probability of being antitumor greater than or equal to 0.8. The present work corroborates by one side the results of our previous work6 and enables the presentation of a new set of possible lead like bioactive compounds. Additionally, it is shown the usefulness of quantum-chemical descriptors in the discrimination of biological active and inactive compounds. The use of the εHOMO quantum-chemical descriptor in the discrimination of large scale data sets of lead-like or drug-like compounds has never been reported. This approach results in the reduction, in great extent, of the number of compounds used in real screens, and it reinforces the results of our previous work. Furthermore, besides the virtual screening, the computational methods can be very useful to build appropriate databases, allowing for effective shortcuts of NP extracts dereplication procedures, which will certainly result in increasing the efficiency of drug discovery.

  18. Virtual screen for repurposing approved and experimental drugs for candidate inhibitors of EBOLA virus infection [v2; ref status: indexed, http://f1000r.es/53d

    Directory of Open Access Journals (Sweden)

    Veljko Veljkovic

    2015-02-01

    Full Text Available The ongoing Ebola virus epidemic has presented numerous challenges with respect to control and treatment because there are no approved drugs or vaccines for the Ebola virus disease (EVD. Herein is proposed simple theoretical criterion for fast virtual screening of molecular libraries for candidate inhibitors of Ebola virus infection. We performed a repurposing screen of 6438 drugs from DrugBank using this criterion and selected 267 approved and 382 experimental drugs as candidates for treatment of EVD including 15 anti-malarial drugs and 32 antibiotics. An open source Web server allowing screening of molecular libraries for candidate drugs for treatment of EVD was also established.

  19. Virtual screen for repurposing approved and experimental drugs for candidate inhibitors of EBOLA virus infection [v1; ref status: indexed, http://f1000r.es/51s

    Directory of Open Access Journals (Sweden)

    Veljko Veljkovic

    2015-02-01

    Full Text Available The ongoing Ebola virus epidemic has presented numerous challenges with respect to control and treatment because there are no approved drugs or vaccines for the Ebola virus disease (EVD. Herein is proposed simple theoretical criterion for fast virtual screening of molecular libraries for candidate inhibitors of Ebola virus infection. We performed a repurposing screen of 6438 drugs from DrugBank using this criterion and selected 267 approved and 382 experimental drugs as candidates for treatment of EVD including 15 anti-malarial drugs and 32 antibiotics. An open source Web server allowing screening of molecular libraries for candidate drugs for treatment of EVD was also established.

  20. Identification of potential influenza virus endonuclease inhibitors through virtual screening based on the 3D-QSAR model.

    Science.gov (United States)

    Kim, J; Lee, C; Chong, Y

    2009-01-01

    Influenza endonucleases have appeared as an attractive target of antiviral therapy for influenza infection. With the purpose of designing a novel antiviral agent with enhanced biological activities against influenza endonuclease, a three-dimensional quantitative structure-activity relationships (3D-QSAR) model was generated based on 34 influenza endonuclease inhibitors. The comparative molecular similarity index analysis (CoMSIA) with a steric, electrostatic and hydrophobic (SEH) model showed the best correlative and predictive capability (q(2) = 0.763, r(2) = 0.969 and F = 174.785), which provided a pharmacophore composed of the electronegative moiety as well as the bulky hydrophobic group. The CoMSIA model was used as a pharmacophore query in the UNITY search of the ChemDiv compound library to give virtual active compounds. The 3D-QSAR model was then used to predict the activity of the selected compounds, which identified three compounds as the most likely inhibitor candidates.

  1. Screening for proteins interacting with MCM7 in human lung cancer library using yeast two hybrid system

    Directory of Open Access Journals (Sweden)

    Yuchen HAN

    2008-08-01

    Full Text Available Background and objective MCM7 is a subunit of the MCM complex that plays a key role in DNA replication initiation. But little is known about its interaction proteins. In this study yeast two hybrid screening was used to identify the MCM7 interacting proteins. Methods Yeast expression vector containing human full length MCM7-pGBKT7 plasmid was constructed, and with a library of cDNAs from human lung cancer-pACT2 plasmid was transformed into yeast strain AH109, and was electively grew in X-a-gal auxotrophy medium SD/-Trp-Leu-His-Ade, and the blue colonies were picked up, the plasmid of the yeast colonies was extracted , and transformed into E. Coli to extract DNA and performed sequence analysis. Results Eleven proteins were identified which could specifically interact with MCM7 proteins, among these five were cytoskeleton proteins, six were enzymes, kinases and related receptors. Conclusion The investigation provides functional clues for further exploration of MCM7 gene.

  2. Discovery of potent, novel Nrf2 inducers via quantum modeling, virtual screening, and in vitro experimental validation.

    Science.gov (United States)

    Williamson, Tracy P; Amirahmadi, Sara; Joshi, Gururaj; Kaludov, Nikola K; Martinov, Martin N; Johnson, Delinda A; Johnson, Jeffrey A

    2012-12-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is the master transcription factor of the antioxidant response element pathway, coordinating the induction of detoxifying and antioxidant enzymes. Nrf2 is normally sequestered in the cytoplasm by Kelch-like ECH-associating protein 1 (Keap1). To identify novel small molecules that will disturb Nrf2-Keap1 binding and promote activation of the Nrf2- antioxidant response element pathway, we generated a quantum model based on the structures of known Nrf2- antioxidant response element activators. We used the quantum model to perform in silico screening on over 18 million commercially available chemicals to identify the structures predicted to activate the Nrf2- antioxidant response element pathway based on the quantum model. The top hits were tested in vitro, and half of the predicted hits activated the Nrf2-antioxidant response element pathway significantly in primary cell culture. In addition, we identified a new family of Nrf2-antioxidant response element-activating structures that all have comparable activity to tBHQ and protect against oxidative stress and dopaminergic toxins in vitro. The improved ability to identify potent activators of Nrf2 through the combination of in silico and in vitro screening described here improves the speed and cost associated with screening Nrf2-antioxidant response element -activating compounds for drug development.

  3. Identification of natural compound inhibitors for multidrug efflux pumps of Escherichia coli and Pseudomonas aeruginosa using in silico high-throughput virtual screening and in vitro validation.

    Science.gov (United States)

    Aparna, Vasudevan; Dineshkumar, Kesavan; Mohanalakshmi, Narasumani; Velmurugan, Devadasan; Hopper, Waheeta

    2014-01-01

    Pseudomonas aeruginosa and Escherichia coli are resistant to wide range of antibiotics rendering the treatment of infections very difficult. A main mechanism attributed to the resistance is the function of efflux pumps. MexAB-OprM and AcrAB-TolC are the tripartite efflux pump assemblies, responsible for multidrug resistance in P. aeruginosa and E. coli respectively. Substrates that are more susceptible for efflux are predicted to have a common pharmacophore feature map. In this study, a new criterion of excluding compounds with efflux substrate-like features was used, thereby refining the selection process and enriching the inhibitor identification process. An in-house database of phytochemicals was created and screened using high-throughput virtual screening against AcrB and MexB proteins and filtered by matching with the common pharmacophore models (AADHR, ADHNR, AAHNR, AADHN, AADNR, AAADN, AAADR, AAANR, AAAHN, AAADD and AAADH) generated using known efflux substrates. Phytochemical hits that matched with any one or more of the efflux substrate models were excluded from the study. Hits that do not have features similar to the efflux substrate models were docked using XP docking against the AcrB and MexB proteins. The best hits of the XP docking were validated by checkerboard synergy assay and ethidium bromide accumulation assay for their efflux inhibition potency. Lanatoside C and diadzein were filtered based on the synergistic potential and validated for their efflux inhibition potency using ethidium bromide accumulation study. These compounds exhibited the ability to increase the accumulation of ethidium bromide inside the bacterial cell as evidenced by these increase in fluorescence in the presence of the compounds. With this good correlation between in silico screening and positive efflux inhibitory activity in vitro, the two compounds, lanatoside C and diadzein could be promising efflux pump inhibitors and effective to use in combination therapy against drug

  4. The yeast two hybrid system in a screen for proteins interacting with axolotl (Ambystoma mexicanum) Msx1 during early limb regeneration.

    Science.gov (United States)

    Abuqarn, Mehtap; Allmeling, Christina; Amshoff, Inga; Menger, Bjoern; Nasser, Inas; Vogt, Peter M; Reimers, Kerstin

    2011-07-01

    Urodele amphibians are exceptional in their ability to regenerate complex body structures such as limbs. Limb regeneration depends on a process called dedifferentiation. Under an inductive wound epidermis terminally differentiated cells transform to pluripotent progenitor cells that coordinately proliferate and eventually redifferentiate to form the new appendage. Recent studies have developed molecular models integrating a set of genes that might have important functions in the control of regenerative cellular plasticity. Among them is Msx1, which induced dedifferentiation in mammalian myotubes in vitro. Herein, we screened for interaction partners of axolotl Msx1 using a yeast two hybrid system. A two hybrid cDNA library of 5-day-old wound epidermis and underlying tissue containing more than 2×10⁶ cDNAs was constructed and used in the screen. 34 resulting cDNA clones were isolated and sequenced. We then compared sequences of the isolated clones to annotated EST contigs of the Salamander EST database (BLASTn) to identify presumptive orthologs. We subsequently searched all no-hit clone sequences against non redundant NCBI sequence databases using BLASTx. It is the first time, that the yeast two hybrid system was adapted to the axolotl animal model and successfully used in a screen for proteins interacting with Msx1 in the context of amphibian limb regeneration.

  5. Does Feedback Design Matter? A Neurofeedback Study Comparing Immersive Virtual Reality and Traditional Training Screens in Elderly

    Directory of Open Access Journals (Sweden)

    Silvia Erika Kober

    2017-09-01

    Full Text Available Neurofeedback (NF is a Brain-Computer Interface (BCI application, in which the brain activity is fed back to the user in real-time enabling voluntary brain control. In this context, the significance of the feedback design is mainly unexplored. Highly immersive feedback scenarios using virtual reality (VR technique are available. However, their effects on subjective user experience as well as on objective outcome measures remain open. In the present article, we discuss the general pros and cons of using VR as feedback modality in BCI applications. Furthermore, we report on the results of an empirical study, in which the effects of traditional two-dimensional and three-dimensional VR based feedback scenarios on NF training performance and user experience in healthy older individuals and neurologic patients were compared. In conclusion, we suggest indications and contraindications of immersive VR feedback designs in BCI applications. Our results show that findings in healthy individuals are not always transferable to patient populations having an impact on serious game and feedback design.

  6. Comprehensive predictions of target proteins based on protein-chemical interaction using virtual screening and experimental verifications

    Directory of Open Access Journals (Sweden)

    Kobayashi Hiroki

    2012-04-01

    Full Text Available Abstract Background Identification of the target proteins of bioactive compounds is critical for elucidating the mode of action; however, target identification has been difficult in general, mostly due to the low sensitivity of detection using affinity chromatography followed by CBB staining and MS/MS analysis. Results We applied our protocol of predicting target proteins combining in silico screening and experimental verification for incednine, which inhibits the anti-apoptotic function of Bcl-xL by an unknown mechanism. One hundred eighty-two target protein candidates were computationally predicted to bind to incednine by the statistical prediction method, and the predictions were verified by in vitro binding of incednine to seven proteins, whose expression can be confirmed in our cell system. As a result, 40% accuracy of the computational predictions was achieved successfully, and we newly found 3 incednine-binding proteins. Conclusions This study revealed that our proposed protocol of predicting target protein combining in silico screening and experimental verification is useful, and provides new insight into a strategy for identifying target proteins of small molecules.

  7. Design, synthesis and biological evaluation of small molecule inhibitors of CD4-gp120 binding based on virtual screening.

    Science.gov (United States)

    Lalonde, Judith M; Elban, Mark A; Courter, Joel R; Sugawara, Akihiro; Soeta, Takahiro; Madani, Navid; Princiotto, Amy M; Kwon, Young Do; Kwong, Peter D; Schön, Arne; Freire, Ernesto; Sodroski, Joseph; Smith, Amos B

    2011-01-01

    The low-molecular-weight compound JRC-II-191 inhibits infection of HIV-1 by blocking the binding of the HIV-1 envelope glycoprotein gp120 to the CD4 receptor and is therefore an important lead in the development of a potent viral entry inhibitor. Reported here is the use of two orthogonal screening methods, gold docking and ROCS shape-based similarity searching, to identify amine-building blocks that, when conjugated to the core scaffold, yield novel analogs that maintain similar affinity for gp120. Use of this computational approach to expand SAR produced analogs of equal inhibitory activity but with diverse capacity to enhance viral infection. The novel analogs provide additional lead scaffolds for the development of HIV-1 entry inhibitors that employ protein-ligand interactions in the vestibule of gp120 Phe 43 cavity.

  8. 3D QSAR modeling of 4-nerolidylcatechol derivatives and virtual screening for identification of potent plasmodium inhibitor

    Directory of Open Access Journals (Sweden)

    Dhrubajyoti Gogoi

    2014-08-01

    Full Text Available The present study was aim to develop a three dimensional quantitative structure–activity relationships (3D QSAR model based on the structure of 4-nerolidylcatechol (IC50=0.67 µM, a novel plant derived Plasmodium inhibitor and its derivatives for identification of efficient antimalarial lead. A statisti-cally validated Partial Least-Squares (PLS based Molecular Field Analysis (MFA model was built up using the training set of eight 4-nerolidylcatechol derivatives and their diverse conformers. A statistically reliable model with good predictive power (cross-validated correlation coefficient q2=0.769 was obtained. Hence, the generated model was used to screen a library of 30,000 compounds of chembridge database (http://www.chembridge.com. Results of drug likeness prediction and ADMET study has suggested six compounds as potential antimalarial/plasmodial lead.

  9. Screening of genes related to ovarian development in the swimming crab, Portunus trituberculatus, by suppression subtractive hybridization.

    Science.gov (United States)

    Yu, Z B; Mu, C K; Song, W W; Li, R H; Chen, Y E; Wang, C L

    2015-12-29

    The swimming crab, Portunus trituberculatus, is an important marine animal and is widely cultured in China. In the present study, suppression subtractive hybridization was applied to identify the differentially expressed genes in the ovaries of mature and immature P. trituberculatus. One hundred and seventy six expressed sequence tag (ESTs) were identified, of which 100 were down-regulated, and 76 up-regulated. BLAST analysis identified 51 unigenes, of which 27 were down-regulated, and 24 up-regulated. Quantitative real-time reverse transcriptase polymerase chain reaction results indicated that the SSH technique is valuable in screening genes related to ovarian development. Genes identified in this study encoded proteins corresponding to a wide range of functions and included immune response protein, transcription initiation factor, metabolic proteins, chromosome, histone h3, ovarian development-related protein, and vitellogenin. In addition, 64 metabolic pathways were annotated in differentially expressed ESTs by using the Kyoto Encyclopedia of Genes and Genomes pathway. Four annotated pathways (oxidative phosphorylation, carbon metabolism, fatty acid degradation, and protein digestion and absorption) appeared to be involved in ovarian development. In ontology analysis, 5.83% of the cellular process genes in reverse subtraction cDNA library are involved in reproduction, and 5.88% involved in developmental process. In up-regulated genes, myosin II-expressed polehole-like protein; histone h3; ovigerous-hair stripping substance; peritrophin 48; and ovarian development-related protein appeared to be involved in ovarian development. Identification of differentially expressed genes in the mature and immature ovary of the swimming crab provides new insights for further studies on the mechanism underlying ovarian development in this species.

  10. Screening of hepatocyte proteins binding to complete S protein of hepatitis B virus by yeast-two hybrid system

    Institute of Scientific and Technical Information of China (English)

    Gui-Qin Bai; Jun Cheng; Shu-Lin Zhang; Yan-Ping Huang; Lin Wang; Yan Liu; Shu-Mei Lin

    2005-01-01

    AIM: To investigate the biological function of complete S protein and to look for proteins interacting with complete S protein in hepatocytes.METHODS: We constructed bait plasmid expressing complete S protein of HBV by cloning the gene of complete S protein into pGBKT7, then the recombinant plasmid DNA was transformed into yeast AH109 (a type). The transformed yeast AH109 was mated with yeast Y187 (α type) containing liver cDNA library plasmid in 2xYPDA medium. Diploid yeast was plated on synthetic dropout nutrient medium (SD/Trp-Leu-His-Ade) containing X-α-gal for selection and screening. After extracting and sequencing of plasmids from positive (blue) colonies, we underwent sequence analysis by bioinformatics.RESULTS: Nineteen colonies were selected and sequenced.Among them, five colonies were Homo sapiens solute carrier family 25, member 23 (SLC25A23), one was Homo sapiens calreticulin, one was human serum albumin (ALB)gene, one was Homo sapiens metallothionein 2A, two were Homo sapiens betaine-homocysteine methyltransferase,three were Homo sapiensNa+ and H+ coupled amino acid transport system N, one was Homo sapiens CD81 antigen (target of anti-proliferative antibody 1) (CD81), three were Homo sapiens diazepam binding inhibitor, two colonies were new genes with unknown function.CONCLUSION: The yeast-two hybrid system is an effective method for identifying hepatocyte proteins interacting with complete S protein of HBV. The complete S protein may bind to different proteins i.e., its multiple functions in vivo.

  11. Context-dependent individualization of nucleotides and virtual genomic hybridization allow the precise location of human SNPs.

    Science.gov (United States)

    Reyes, José; Gómez-Romero, Laura; Ibarra-Soria, Ximena; Palacios-Flores, Kim; Arriola, Luis R; Wences, Alejandro; García, Delfino; Boege, Margareta; Dávila, Guillermo; Flores, Margarita; Palacios, Rafael

    2011-09-13

    We have entered the era of individual genomic sequencing, and can already see exponential progress in the field. It is of utmost importance to exclude false-positive variants from reported datasets. However, because of the nature of the used algorithms, this task has not been optimized to the required level of precision. This study presents a unique strategy for identifying SNPs, called COIN-VGH, that largely minimizes the presence of false-positives in the generated data. The algorithm was developed using the X-chromosome-specific regions from the previously sequenced genomes of Craig Venter and James Watson. The algorithm is based on the concept that a nucleotide can be individualized if it is analyzed in the context of its surrounding genomic sequence. COIN-VGH consists of defining the most comprehensive set of nucleotide strings of a defined length that map with 100% identity to a unique position within the human reference genome (HRG). Such set is used to retrieve sequence reads from a query genome (QG), allowing the production of a genomic landscape that represents a draft HRG-guided assembly of the QG. This landscape is analyzed for specific signatures that indicate the presence of SNPs. The fidelity of the variation signature was assessed using simulation experiments by virtually altering the HRG at defined positions. Finally, the signature regions identified in the HRG and in the QG reads are aligned and the precise nature and position of the corresponding SNPs are detected. The advantages of COIN-VGH over previous algorithms are discussed.

  12. Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: a structure-based drug designing approach.

    Science.gov (United States)

    Kesharwani, Rajesh Kumar; Singh, Durg Vijay; Misra, Krishna

    2013-01-01

    Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64) and leupeptin respectively were retrieved from protein data bank (PDB) and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in case of falcipain-III, 15 designed leupeptin analogues having

  13. Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: A structure-based drug designing approach

    Directory of Open Access Journals (Sweden)

    Rajesh Kumar Kesharwani

    2013-04-01

    Full Text Available Background & objectives: Cysteine proteases (falcipains, a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Methods: Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64 and leupeptin respectively were retrieved from protein data bank (PDB and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. Results: The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in

  14. Per-residue energy decomposition pharmacophore model to enhance virtual screening in drug discovery: a study for identification of reverse transcriptase inhibitors as potential anti-HIV agents.

    Science.gov (United States)

    Cele, Favourite N; Ramesh, Muthusamy; Soliman, Mahmoud Es

    2016-01-01

    A novel virtual screening approach is implemented herein, which is a further improvement of our previously published "target-bound pharmacophore modeling approach". The generated pharmacophore library is based only on highly contributing amino acid residues, instead of arbitrary pharmacophores, which are most commonly used in the conventional approaches in literature. Highly contributing amino acid residues were distinguished based on free binding energy contributions obtained from calculation from molecular dynamic (MD) simulations. To the best of our knowledge; this is the first attempt in the literature using such an approach; previous approaches have relied on the docking score to generate energy-based pharmacophore models. However, docking scores are reportedly unreliable. Thus, we present a model for a per-residue energy decomposition, constructed from MD simulation ensembles generating a more trustworthy pharmacophore model, which can be applied in drug discovery workflow. This work is aimed at introducing a more rational approach to the field of drug design, rather than comparing the validity of this approach against those previously reported. We recommend additional computational and experimental work to further validate this approach. This approach was used to screen for potential reverse transcriptase inhibitors using the pharmacophoric features of compound GSK952. The complex was subjected to docking, thereafter, MD simulation confirmed the stability of the system. Experimentally determined inhibitors with known HIV-reverse transcriptase inhibitory activity were used to validate the protocol. Two potential hits (ZINC46849657 and ZINC54359621) showed a significant potential with regard to free binding energy. Reported results obtained from this work confirm that this new approach is favorable in the future of the drug design industry.

  15. Tyrosine kinase syk non-enzymatic inhibitors and potential anti-allergic drug-like compounds discovered by virtual and in vitro screening.

    Directory of Open Access Journals (Sweden)

    Bruno O Villoutreix

    Full Text Available In the past decade, the spleen tyrosine kinase (Syk has shown a high potential for the discovery of new treatments for inflammatory and autoimmune disorders. Pharmacological inhibitors of Syk catalytic site bearing therapeutic potential have been developed, with however limited specificity towards Syk. To address this topic, we opted for the design of drug-like compounds that could impede the interaction of Syk with its cellular partners while maintaining an active kinase protein. To achieve this challenging task, we used the powerful potential of intracellular antibodies for the modulation of cellular functions in vivo, combined to structure-based in silico screening. In our previous studies, we reported the anti-allergic properties of the intracellular antibody G4G11. With the aim of finding functional mimics of G4G11, we developed an Antibody Displacement Assay and we isolated the drug-like compound C-13, with promising in vivo anti-allergic activity. The likely binding cavity of this compound is located at the close vicinity of G4G11 epitope, far away from the catalytic site of Syk. Here we report the virtual screen of a collection of 500,000 molecules against this new cavity, which led to the isolation of 1000 compounds subsequently evaluated for their in vitro inhibitory effects using the Antibody Displacement Assay. Eighty five compounds were selected and evaluated for their ability to inhibit the liberation of allergic mediators from mast cells. Among them, 10 compounds inhibited degranulation with IC₅₀ values ≤ 10 µM. The most bioactive compounds combine biological activity, significant inhibition of antibody binding and strong affinity for Syk. Moreover, these molecules show a good potential for oral bioavailability and are not kinase catalytic site inhibitors. These bioactive compounds could be used as starting points for the development of new classes of non-enzymatic inhibitors of Syk and for drug discovery endeavour in the

  16. A successful virtual screening application: prediction of anticonvulsant activity in MES test of widely used pharmaceutical and food preservatives methylparaben and propylparaben.

    Science.gov (United States)

    Talevi, Alan; Bellera, Carolina L; Castro, Eduardo A; Bruno-Blanch, Luis E

    2007-09-01

    A discriminant function based on topological descriptors was derived from a training set composed by anticonvulsants of clinical use or in clinical phase of development and compounds with other therapeutic uses. This model was internally and externally validated and applied in the virtual screening of chemical compounds from the Merck Index 13th. Methylparaben (Nipagin), a preservative widely used in food, cosmetics and pharmaceutics, was signaled as active by the discriminant function and tested in mice in the Maximal Electroshock (MES) test (i.p. administration), according to the NIH Program for Anticonvulsant Drug Development. Based on the results of Methylparaben, Propylparaben (Nipasol), another preservative usually used in association with the former, was also tested. Both methyl and propylparaben were found active in mice at doses of 30, 100, and 300 mg/kg. The discovery of the anticonvulsant activities in the MES test of methylparaben and propylparaben might be useful for the development of new anticonvulsant medications, specially considering the well-known toxicological profile of these drugs.

  17. Materials space of solid-state electrolytes: unraveling chemical composition-structure-ionic conductivity relationships in garnet-type metal oxides using cheminformatics virtual screening approaches.

    Science.gov (United States)

    Kireeva, Natalia; Pervov, Vladislav S

    2017-08-09

    The organic electrolytes of most current commercial rechargeable Li-ion batteries (LiBs) are flammable, toxic, and have limited electrochemical energy windows. All-solid-state battery technology promises improved safety, cycling performance, electrochemical stability, and possibility of device miniaturization and enables a number of breakthrough technologies towards the development of new high power and energy density microbatteries for electronics with low processing cost, solid oxide fuel cells, electrochromic devices, etc. Currently, rational materials design is attracting significant attention, which has resulted in a strong demand for methodologies that can accelerate the design of materials with tailored properties; cheminformatics can be considered as an efficient tool in this respect. This study was focused on several aspects: (i) identification of the parameters responsible for high Li-ion conductivity in garnet structured oxides; (ii) development of quantitative models to elucidate composition-structure-Li ionic conductivity relationships, taking into account the experimental details of sample preparation; (iii) circumscription of the materials space of solid garnet-type electrolytes, which is attractive for virtual screening. Several candidate compounds have been recommended for synthesis as potential solid state electrolyte materials.

  18. New scoring functions for virtual screening from molecular dynamics simulations with a quantum-refined force-field (QRFF-MD). Application to cyclin-dependent kinase 2.

    Science.gov (United States)

    Ferrara, Ph; Curioni, A; Vangrevelinghe, E; Meyer, T; Mordasini, T; Andreoni, W; Acklin, P; Jacoby, E

    2006-01-01

    A recently introduced new methodology based on ultrashort (50-100 ps) molecular dynamics simulations with a quantum-refined force-field (QRFF-MD) is here evaluated in its ability both to predict protein-ligand binding affinities and to discriminate active compounds from inactive ones. Physically based scoring functions are derived from this approach, and their performance is compared to that of several standard knowledge-based scoring functions. About 40 inhibitors of cyclin-dependent kinase 2 (CDK2) representing a broad chemical diversity were considered. The QRFF-MD method achieves a correlation coefficient, R(2), of 0.55, which is significantly better than that obtained by a number of traditional approaches in virtual screening but only slightly better than that obtained by consensus scoring (R(2) = 0.50). Compounds from the Available Chemical Directory, along with the known active compounds, were docked into the ATP binding site of CDK2 using the program Glide, and the 650 ligands from the top scored poses were considered for a QRFF-MD analysis. Combined with structural information extracted from the simulations, the QRFF-MD methodology results in similar enrichment of known actives compared to consensus scoring. Moreover, a new scoring function is introduced that combines a QRFF-MD based scoring function with consensus scoring, which results in substantial improvement on the enrichment profile.

  19. DockBench: An Integrated Informatic Platform Bridging the Gap between the Robust Validation of Docking Protocols and Virtual Screening Simulations

    Directory of Open Access Journals (Sweden)

    Alberto Cuzzolin

    2015-05-01

    Full Text Available Virtual screening (VS is a computational methodology that streamlines the drug discovery process by reducing costs and required resources through the in silico identification of potential drug candidates. Structure-based VS (SBVS exploits knowledge about the three-dimensional (3D structure of protein targets and uses the docking methodology as search engine for novel hits. The success of a SBVS campaign strongly depends upon the accuracy of the docking protocol used to select the candidates from large chemical libraries. The identification of suitable protocols is therefore a crucial step in the setup of SBVS experiments. Carrying out extensive benchmark studies, however, is usually a tangled task that requires users’ proficiency in handling different file formats and philosophies at the basis of the plethora of existing software packages. We present here DockBench 1.0, a platform available free of charge that eases the pipeline by automating the entire procedure, from docking benchmark to VS setups. In its current implementation, DockBench 1.0 handles seven docking software packages and offers the possibility to test up to seventeen different protocols. The main features of our platform are presented here and the results of the benchmark study of human Checkpoint kinase 1 (hChk1 are discussed as validation test.

  20. Computer-aided discovery in antimicrobial research: In silico model for virtual screening of potent and safe anti-pseudomonas agents.

    Science.gov (United States)

    Speck-Planche, Alejandro; Cordeiro, Maria N D S

    2015-01-01

    Resistance of bacteria to current antibiotics is an alarming health problem. In this sense, Pseudomonas represents a genus of Gram-negative pathogens, which has emerged as one of the most dangerous species causing nosocomial infections. Despite the effort of the scientific community, drug resistant strains of bacteria belonging to Pseudomonas spp. prevail. The high costs associated to drug discovery and the urgent need for more efficient antimicrobial chemotherapies envisage the fact that computeraided methods can rationalize several stages involved in the development of a new drug. In this work, we introduce a chemoinformatic methodology devoted to the construction of a multitasking model for quantitative-structure biological effect relationships (mtk-QSBER). The purpose of this model was to perform simultaneous predictions of anti-Pseudomonas activities and ADMET (absorption, distribution, metabolism, elimination, and toxicity) properties of organic compounds. The mtk-QSBER model was created from a large and heterogeneous dataset (more than 54000 cases) and displayed accuracies higher than 90% in both training and prediction sets. In order to demonstrate the applicability of our mtk-QSBER model, we used the investigational antibacterial drug delafloxacin as a case of study, for which experimental results were recently reported. The predictions performed for many biological effects of this drug exhibited a remarkable convergence with the experimental assays, confirming that our model can serve as useful tool for virtual screening of potent and safer anti-Pseudomonas agents.

  1. Virtual screening of human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase against the NCI diversity set by use of AutoDock to identify novel nonfolate inhibitors.

    Science.gov (United States)

    Li, Chenglong; Xu, Lan; Wolan, Dennis W; Wilson, Ian A; Olson, Arthur J

    2004-12-30

    AICAR transformylase (5-aminoimidazole-4-carboxamide ribonucleotide transformylase) is a folate-dependent activity of the bifunctional protein ATIC (AICAR transformylase and IMP cyclohydrolase) and is responsible for catalyzing the penultimate step of the de novo purine biosynthetic pathway. As such, AICAR transformylase has been proposed as a potential target for antineoplastic drug design. Virtual screening of the human AICAR transformylase active site by use of AutoDock against the NCI diversity set, a library of compounds with nonredundant pharmacophore profiles, has revealed 44 potential inhibitor candidates. In vitro inhibition assay of 16 soluble compounds from this list revealed that eight compounds with novel scaffolds, relative to the general folate template, had micromolar inhibition. Subsequent extension of docking trials on compounds with similar scaffolds from the entire NCI-3D database has unveiled 11 additional inhibitors that were confirmed by the in vitro inhibition assay. In particular, one compound, NSC30171, had nanomolar inhibition (K(i) = 154 nM, IC(50) = 600 nM) against AICAR transformylase. These 19 inhibitors serve as novel templates/scaffolds for development of more potent and specific non-folate-based AICAR transformylase inhibitors.

  2. Identification of the Beer Component Hordenine as Food-Derived Dopamine D2 Receptor Agonist by Virtual Screening a 3D Compound Database

    Science.gov (United States)

    Sommer, Thomas; Hübner, Harald; El Kerdawy, Ahmed; Gmeiner, Peter; Pischetsrieder, Monika; Clark, Timothy

    2017-03-01

    The dopamine D2 receptor (D2R) is involved in food reward and compulsive food intake. The present study developed a virtual screening (VS) method to identify food components, which may modulate D2R signalling. In contrast to their common applications in drug discovery, VS methods are rarely applied for the discovery of bioactive food compounds. Here, databases were created that exclusively contain substances occurring in food and natural sources (about 13,000 different compounds in total) as the basis for combined pharmacophore searching, hit-list clustering and molecular docking into D2R homology models. From 17 compounds finally tested in radioligand assays to determine their binding affinities, seven were classified as hits (hit rate = 41%). Functional properties of the five most active compounds were further examined in β-arrestin recruitment and cAMP inhibition experiments. D2R-promoted G-protein activation was observed for hordenine, a constituent of barley and beer, with approximately identical ligand efficacy as dopamine (76%) and a Ki value of 13 μM. Moreover, hordenine antagonised D2-mediated β-arrestin recruitment indicating functional selectivity. Application of our databases provides new perspectives for the discovery of bioactive food constituents using VS methods. Based on its presence in beer, we suggest that hordenine significantly contributes to mood-elevating effects of beer.

  3. A successful virtual screening application: prediction of anticonvulsant activity in MES test of widely used pharmaceutical and food preservatives methylparaben and propylparaben

    Science.gov (United States)

    Talevi, Alan; Bellera, Carolina L.; Castro, Eduardo A.; Bruno-Blanch, Luis E.

    2007-09-01

    A discriminant function based on topological descriptors was derived from a training set composed by anticonvulsants of clinical use or in clinical phase of development and compounds with other therapeutic uses. This model was internally and externally validated and applied in the virtual screening of chemical compounds from the Merck Index 13th. Methylparaben (Nipagin), a preservative widely used in food, cosmetics and pharmaceutics, was signaled as active by the discriminant function and tested in mice in the Maximal Electroshock (MES) test (i.p. administration), according to the NIH Program for Anticonvulsant Drug Development. Based on the results of Methylparaben, Propylparaben (Nipasol), another preservative usually used in association with the former, was also tested. Both methyl and propylparaben were found active in mice at doses of 30, 100, and 300 mg/kg. The discovery of the anticonvulsant activities in the MES test of methylparaben and propylparaben might be useful for the development of new anticonvulsant medications, specially considering the well-known toxicological profile of these drugs.

  4. VSDMIP 1.5: an automated structure- and ligand-based virtual screening platform with a PyMOL graphical user interface.

    Science.gov (United States)

    Cabrera, Álvaro Cortés; Gil-Redondo, Rubén; Perona, Almudena; Gago, Federico; Morreale, Antonio

    2011-09-01

    A graphical user interface (GUI) for our previously published virtual screening (VS) and data management platform VSDMIP (Gil-Redondo et al. J Comput Aided Mol Design, 23:171-184, 2009) that has been developed as a plugin for the popular molecular visualization program PyMOL is presented. In addition, a ligand-based VS module (LBVS) has been implemented that complements the already existing structure-based VS (SBVS) module and can be used in those cases where the receptor's 3D structure is not known or for pre-filtering purposes. This updated version of VSDMIP is placed in the context of similar available software and its LBVS and SBVS capabilities are tested here on a reduced set of the Directory of Useful Decoys database. Comparison of results from both approaches confirms the trend found in previous studies that LBVS outperforms SBVS. We also show that by combining LBVS and SBVS, and using a cluster of ~100 modern processors, it is possible to perform complete VS studies of several million molecules in less than a month. As the main processes in VSDMIP are 100% scalable, more powerful processors and larger clusters would notably decrease this time span. The plugin is distributed under an academic license upon request from the authors. © Springer Science+Business Media B.V. 2011

  5. DockBench: An Integrated Informatic Platform Bridging the Gap between the Robust Validation of Docking Protocols and Virtual Screening Simulations.

    Science.gov (United States)

    Cuzzolin, Alberto; Sturlese, Mattia; Malvacio, Ivana; Ciancetta, Antonella; Moro, Stefano

    2015-05-29

    Virtual screening (VS) is a computational methodology that streamlines the drug discovery process by reducing costs and required resources through the in silico identification of potential drug candidates. Structure-based VS (SBVS) exploits knowledge about the three-dimensional (3D) structure of protein targets and uses the docking methodology as search engine for novel hits. The success of a SBVS campaign strongly depends upon the accuracy of the docking protocol used to select the candidates from large chemical libraries. The identification of suitable protocols is therefore a crucial step in the setup of SBVS experiments. Carrying out extensive benchmark studies, however, is usually a tangled task that requires users' proficiency in handling different file formats and philosophies at the basis of the plethora of existing software packages. We present here DockBench 1.0, a platform available free of charge that eases the pipeline by automating the entire procedure, from docking benchmark to VS setups. In its current implementation, DockBench 1.0 handles seven docking software packages and offers the possibility to test up to seventeen different protocols. The main features of our platform are presented here and the results of the benchmark study of human Checkpoint kinase 1 (hChk1) are discussed as validation test.

  6. Dual histamine H3R/serotonin 5-HT4R ligands with antiamnesic properties: pharmacophore-based virtual screening and polypharmacology.

    Science.gov (United States)

    Lepailleur, Alban; Freret, Thomas; Lemaître, Stéphane; Boulouard, Michel; Dauphin, François; Hinschberger, Antoine; Dulin, Fabienne; Lesnard, Aurélien; Bureau, Ronan; Rault, Sylvain

    2014-06-23

    In recent years, preclinical and clinical studies have generated considerable interest in the development of histamine H3 receptor (H3R) antagonists as novel treatment for degenerative disorders associated with impaired cholinergic function. To identify novel scaffolds for H3R antagonism, a common feature-based pharmacophore model was developed and used to screen the 17,194 compounds of the CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie) chemical library. Out of 268 virtual hits which have been gathered in 34 clusters, we were particularly interested in tricyclic derivatives also exhibiting a potent 5HT4R affinity. Benzo[h][1,6]naphthyridine derivatives showed the highest H3R affinity, and compound 17 (H3R Ki = 41.6 nM; 5-HT4R Ki = 208 nM) completely reversed the amnesiant effect of scopolamine at 3 mg/kg in a spatial working memory experiment. For the first time we demonstrated the feasibility to combine H3R and 5-HT4R activities in a single molecule, raising the exciting possibility that dual H3R antagonist/5HT4R agonist have potential for the treatment of neurodegenerative diseases such as Alzheimer's disease.

  7. Homology modeling and virtual screening studies of FGF-7 protein-a structure-based approach to design new molecules against tumor angiogenesis.

    Science.gov (United States)

    Vadija, Rajender; Mustyala, Kiran Kumar; Nambigari, Navaneetha; Dulapalli, Ramasree; Dumpati, Rama Krishna; Ramatenki, Vishwanath; Vellanki, Santhi Prada; Vuruputuri, Uma

    2016-07-01

    Keratinocyte growth factor (KGF) protein is a member of the fibroblast growth factor (FGF) family, which is also known as FGF-7. The FGF-7 plays an important role in tumor angiogenesis. In the present work, FGF-7 is treated as a potential therapeutic target to prevent angiogenesis in cancerous tissue. Computational techniques are applied to evaluate and validate the 3D structure of FGF-7 protein. The active site region of the FGF-7 protein is identified based on hydrophobicity calculations using CASTp and Q-site Finder active site prediction tools. The protein-protein docking study of FGF-7 with its natural receptor FGFR2b is carried out to confirm the active site region in FGF-7. The amino acid residues Asp34, Arg67, Glu116, and Thr194 in FGF-7 interact with the receptor protein (FGFR2b). A grid is generated at the active site region of FGF-7 using Glide module of Schrödinger suite. Subsequently, a virtual screening study is carried out at the active site using small molecular structural databases to identify the ligand molecules. The binding interactions of the ligand molecules, with piperazine moiety as a pharmacophore, are observed at Arg67 and Glu149 residues of the FGF-7 protein. The identified ligand molecules against the FGF-7 protein show permissible pharmacokinetic properties (ADME). The ligand molecules with good docking scores and satisfactory pharmacokinetic properties are prioritized and identified as novel ligands for the FGF-7 protein in cancer therapy.

  8. Virtual Screening of M3 Protein Antagonists for Finding a Model to Study the Gammaherpesvirus Damaged Immune System and Chemokine Related Diseases

    Directory of Open Access Journals (Sweden)

    Ibrahim Torktaz

    2013-12-01

    Full Text Available Introduction: M3 protein is a chemokine decoy receptor involved in pathogenesis of persistent infection with gammaherpesvirus and complications related to the latency of this pathogen. We proposed that antagonists of the M3 would provide a unique opportunity for studying new therapeutic strategies in disordered immune system, immune-deficient states and role of chemokines in pathogenesis development. Methods: Comparative modeling and fold recognition algorithms have been used for prediction of M3 protein 3-D model. Evaluation of the models using Q-mean and ProSA-web score, has led to choosing predicted model by fold recognition algorithm as the best model which was minimized regarding energy level using Molegro Virtual Docker 2011.4.3.0 (MVD software. Pockets and active sites of model were recognized using MVD cavity detection, and MetaPocket algorithms. Ten thousand compounds accessible on KEGG database were screened; MVD was used for computer simulated docking study; MolDock SE was selected as docking scoring function and final results were evaluated based on MolDock and Re-rank score. Results: Docking data suggested that prilocaine, which is generally applied as a topical anesthetic, binds strongly to 3-D model of M3 protein. Conclusion: This study proposes that prilocaine is a potential inhibitor of M3 protein and possibly has immune enhancing properties.

  9. Identification of potential Gly/NMDA receptor antagonists by cheminformatics approach: a combination of pharmacophore modelling, virtual screening and molecular docking studies.

    Science.gov (United States)

    Ugale, V G; Bari, S B

    2016-01-01

    The Gly/NMDA receptor has become known as potential target for the management of neurodegenerative diseases. Discovery of Gly/NMDA antagonists has thus attracted much attention in recent years. In the present research, a cheminformatics approach has been used to determine structural requirements for Gly/NMDA antagonism and to identify potential antagonists. Here, 37 quinoxaline derivatives were selected to develop a significant pharmacophore model with good certainty. The selected model was validated by leave-one-out cross-validation, an external test set, decoy set and Y-randomization test. Applicability domain was verified by the standardization approach. The validated 3D-QSAR model was used to screen virtual hits from the ZINC database by pharmacophore mapping. Molecular docking was used for assessment of receptor-ligand binding modes and binding affinities. The GlideScore and molecular interactions with critical amino acids were considered as crucial features to identify final hits. Furthermore, hits were analysed for in silico pharmacokinetic parameters and Lipinski's rule of five, demonstrating their potential as drug-like candidates. The PubChem and SciFinder search tools were used to authenticate the novelty of leads retrieved. Finally, five different leads have been suggested as putative novel candidates for the exploration of potent Gly/NMDA receptor antagonists.

  10. Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening

    Science.gov (United States)

    Temml, Veronika; Garscha, Ulrike; Romp, Erik; Schubert, Gregor; Gerstmeier, Jana; Kutil, Zsofia; Matuszczak, Barbara; Waltenberger, Birgit; Stuppner, Hermann; Werz, Oliver; Schuster, Daniela

    2017-01-01

    Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation. Targeting both LT biosynthesis and the conversion of EETs with a dual inhibitor of FLAP and sEH may represent a novel, powerful anti-inflammatory strategy. We present a pharmacophore-based virtual screening campaign that led to 20 hit compounds of which 4 targeted FLAP and 4 were sEH inhibitors. Among them, the first dual inhibitor for sEH and FLAP was identified, N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N’-(3,4-dichlorophenyl)urea with IC50 values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay. PMID:28218273

  11. Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening

    Science.gov (United States)

    Temml, Veronika; Garscha, Ulrike; Romp, Erik; Schubert, Gregor; Gerstmeier, Jana; Kutil, Zsofia; Matuszczak, Barbara; Waltenberger, Birgit; Stuppner, Hermann; Werz, Oliver; Schuster, Daniela

    2017-02-01

    Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation. Targeting both LT biosynthesis and the conversion of EETs with a dual inhibitor of FLAP and sEH may represent a novel, powerful anti-inflammatory strategy. We present a pharmacophore-based virtual screening campaign that led to 20 hit compounds of which 4 targeted FLAP and 4 were sEH inhibitors. Among them, the first dual inhibitor for sEH and FLAP was identified, N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N’-(3,4-dichlorophenyl)urea with IC50 values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay.

  12. Pistacia lentiscus Oleoresin: Virtual Screening and Identification of Masticadienonic and Isomasticadienonic Acids as Inhibitors of 11β-Hydroxysteroid Dehydrogenase 1.

    Science.gov (United States)

    Vuorinen, Anna; Seibert, Julia; Papageorgiou, Vassilios P; Rollinger, Judith M; Odermatt, Alex; Schuster, Daniela; Assimopoulou, Andreana N

    2015-04-01

    In traditional medicine, the oleoresinous gum of Pistacia lentiscus var. chia, so-called mastic gum, has been used to treat multiple conditions such as coughs, sore throats, eczema, dyslipidemia, and diabetes. Mastic gum is rich in triterpenes, which have been postulated to exert antidiabetic effects and improve lipid metabolism. In fact, there is evidence of oleanonic acid, a constituent of mastic gum, acting as a peroxisome proliferator-activated receptor γ agonist, and mastic gum being antidiabetic in mice in vivo. Despite these findings, the exact antidiabetic mechanism of mastic gum remains unknown. Glucocorticoids play a key role in regulating glucose and fatty acid metabolism, and inhibition of 11β-hydroxysteroid dehydrogenase 1 that converts inactive cortisone to active cortisol has been proposed as a promising approach to combat metabolic disturbances including diabetes. In this study, a pharmacophore-based virtual screening was applied to filter a natural product database for possible 11β-hydroxysteroid dehydrogenase 1 inhibitors. The hit list analysis was especially focused on the triterpenoids present in Pistacia species. Multiple triterpenoids, such as masticadienonic acid and isomasticadienonic acid, main constituents of mastic gum, were identified. Indeed, masticadienonic acid and isomasticadienonic acid selectively inhibited 11β-hydroxysteroid dehydrogenase 1 over 11β-hydroxysteroid dehydrogenase 2 at low micromolar concentrations. These findings suggest that inhibition of 11β-hydroxysteroid dehydrogenase 1 contributes to the antidiabetic activity of mastic gum.

  13. Prediction of dual agents as an activator of mutant p53 and inhibitor of Hsp90 by docking, molecular dynamic simulation and virtual screening.

    Science.gov (United States)

    Abbasi, Maryam; Sadeghi-Aliabadi, Hojjat; Hassanzadeh, Farshid; Amanlou, Massoud

    2015-09-01

    Heat shock protein90s (Hsp90s) play a crucial role in the development of cancer, and their inhibitors are a main target for tumor suppression. P53 also is a tumor suppressor, but in cancer cells, mutations in the p53 gene lead to the inactivation and accumulation of protein. For instance, the ninth p53 cancer mutation, Y220C, destabilizes the p53 core domain. Small molecules have been assumed to bind to Y220C DNA-binding domain and reactivate cellular mutant p53 functions. In this study, one of the mutant p53 activators is suggested as an Hsp90 inhibitor according to a pyrazole scaffold. To confirm a new ligand as a dual agent, molecular docking and molecular dynamic simulations were performed on both proteins (p53 and Hsp90). Molecular dynamic simulations were also conducted to evaluate the obtained results on the other two pyrazole structures, one known as Hsp90 inhibitor and the other as the reported mutant p53 activator. The findings indicate that the new ligand was stable in the active site of both proteins. Finally, a virtual screening was performed on ZINC database, and a set of new dual agents was proposed according to the new ligand scaffold. Copyright © 2015. Published by Elsevier Inc.

  14. Discovering new mTOR inhibitors for cancer treatment through virtual screening methods and in vitro assays

    Science.gov (United States)

    Wang, Ling; Chen, Lei; Yu, Miao; Xu, Li-Hui; Cheng, Bao; Lin, Yong-Sheng; Gu, Qiong; He, Xian-Hui; Xu, Jun

    2016-01-01

    Mammalian target of rapamycin (mTOR) is an attractive target for new anticancer drug development. We recently developed in silico models to distinguish mTOR inhibitors and non-inhibitors. In this study, we developed an integrated strategy for identifying new mTOR inhibitors using cascaded in silico screening models. With this strategy, fifteen new mTOR kinase inhibitors including four compounds with IC50 values below 10 μM were discovered. In particular, compound 17 exhibited potent anticancer activities against four tumor cell lines, including MCF-7, HeLa, MGC-803, and C6, with IC50 values of 1.90, 2.74, 3.50 and 11.05 μM. Furthermore, cellular studies and western blot analyses revealed that 17 induces cell death via apoptosis by targeting both mTORC1 and mTORC2 within cells and arrests the cell cycle of HeLa at the G1/G0-phase. Finally, multi-nanosecond explicit solvent simulations and MM/GBSA analyses were carried out to study the inhibitory mechanisms of 13, 17, and 40 for mTOR. The potent compounds presented here are worthy of further investigation.

  15. Potential Broad Spectrum Inhibitors of the Coronavirus 3CLpro: A Virtual Screening and Structure-Based Drug Design Study.

    Science.gov (United States)

    Berry, Michael; Fielding, Burtram C; Gamieldien, Junaid

    2015-12-15

    Human coronaviruses represent a significant disease burden; however, there is currently no antiviral strategy to combat infection. The outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) less than 10 years later demonstrates the potential of coronaviruses to cross species boundaries and further highlights the importance of identifying novel lead compounds with broad spectrum activity. The coronavirus 3CL(pro) provides a highly validated drug target and as there is a high degree of sequence homology and conservation in main chain architecture the design of broad spectrum inhibitors is viable. The ZINC drugs-now library was screened in a consensus high-throughput pharmacophore modeling and molecular docking approach by Vina, Glide, GOLD and MM-GBSA. Molecular dynamics further confirmed results obtained from structure-based techniques. A highly defined hit-list of 19 compounds was identified by the structure-based drug design methodologies. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds is bioactive is excellent. Additionally, the compounds segregate into 15 significantly dissimilar (p < 0.05) clusters based on shape and features, which represent valuable scaffolds that can be used as a basis for future anti-coronaviral inhibitor discovery experiments. Importantly though, the enriched subset of 19 compounds identified from the larger library has to be validated experimentally.

  16. Virtual Screening and Molecular Docking Study of Bloom’s Syndrome Protein (BLM for Finding Potential Lead Drug Candidate

    Directory of Open Access Journals (Sweden)

    Manoj Kumar Verma

    2014-06-01

    Full Text Available Increased levels of locus-specific mutations within the BLM result in development of Bloom Syndrome and patients are found to be immune deficient. HRDC domain amino acid Lys1270 is presumably to play role in mediating interactions with DNA. Single point mutation of Lys1270 (K1270V reduces the potency of Double Holliday junction (DHJ DNA unwinding so BLM lead to its functional loss. Quadruplex formation have role in immunoglobulin heavy chain switching and inhibiting RecQ helicases activity in-vitro in BLM. Variety of G-Quadruplex ligands are employed by molecular docking for arriving at lead compound identification. The scoring function of docking results describes protein-ligand interaction and it conjointly instructed that docking of ligand at mutational binding site shows some repressing function to make potential lead drug molecule. So as to know the elaborated purposeful functional mechanism of protein and to relate impact of mutation with function and activity; dock screening, hit identification and lead optimization facilitate in design of lead drug compound.

  17. Organizaciones Virtuales Organizaciones Virtuales

    Directory of Open Access Journals (Sweden)

    Gladis Cecilia Villegas Arias

    2003-06-01

    Full Text Available Virtual Organizations are new organizational forms originated from both the replacementof face to face communications by remote communications supported by electronic means,and from the accesibility of real time information about the operation of the company, forall employees.This article pursues the following goals: 1 To define virtual organization, review its sociotechnical antecedents and propose a preliminary classification into inter-organizationaland intra-organizational forms.  2 To discuss the characteristics of virtual organizationsand their impact on organizational design, and 3 To compare virtual organizations toother organizational forms.Las organizaciones virtuales son formas organizativas nuevas, que resultan de: primero, reemplazar las interacciones cara a cara con interacciones remotas, soportadas por comunicaciones electrónicas y segundo,  proveer acceso en tiempo real a toda la información de la empresa para todos los trabajadores.En este artículo se busca: 1 Definir organización virtual, revisar sus antecedentes y proponeruna clasificación básica preliminar de las mismas  2 Discutir las características de las organizaciones virtuales y sus implicaciones para el diseño organizativo 3 Comparar estaforma organizativa a las formas organizativas no virtuales.

  18. Virtually teaching virtual leadership

    DEFF Research Database (Denmark)

    Henriksen, Thomas Duus; Nielsen, Rikke Kristine; Børgesen, Kenneth

    2017-01-01

    This paper seeks to investigate the challenges to virtual collaboration and leadership on basis of findings from a virtual course on collaboration and leadership. The course used for this experiment was designed as a practical approach, which allowed participants to experience curriculum phenomen...

  19. Differentiation of AmpC beta-lactamase binders vs. decoys using classification kNN QSAR modeling and application of the QSAR classifier to virtual screening

    Science.gov (United States)

    Hsieh, Jui-Hua; Wang, Xiang S.; Teotico, Denise; Golbraikh, Alexander; Tropsha, Alexander

    2008-09-01

    structure based docking and scoring approaches in identifying promising hits by virtual screening of molecular libraries.

  20. Virtual Screening and Molecular Dynamics Study of Potential Negative Allosteric Modulators of mGluR1 from Chinese Herbs

    Directory of Open Access Journals (Sweden)

    Ludi Jiang

    2015-07-01

    Full Text Available The metabotropic glutamate subtype 1 (mGluR1, a member of the metabotropic glutamate receptors, is a therapeutic target for neurological disorders. However, due to the lower subtype selectivity of mGluR1 orthosteric compounds, a new targeted strategy, known as allosteric modulators research, is needed for the treatment of mGluR1-related diseases. Recently, the structure of the seven-transmembrane domain (7TMD of mGluR1 has been solved, which reveals the binding site of allosteric modulators and provides an opportunity for future subtype-selectivity drug design. In this study, a series of computer-aided drug design methods were utilized to discover potential mGluR1 negative allosteric modulators (NAMs. Pharmacophore models were constructed based on three different structure types of mGluR1 NAMs. After validation using the built-in parameters and test set, the optimal pharmacophore model of each structure type was selected and utilized as a query to screen the Traditional Chinese Medicine Database (TCMD. Then, three different hit lists of compounds were obtained. Molecular docking was used based on the latest crystal structure of mGluR1-7TMD to further filter these hits. As a compound with high QFIT and LibDock Score was preferred, a total of 30 compounds were retained. MD simulation was utilized to confirm the stability of potential compounds binding. From the computational results, thesinine-4ʹ-O-β-d-glucoside, nigrolineaxanthone-P and nodakenin might exhibit negative allosteric moderating effects on mGluR1. This paper indicates the applicability of molecular simulation technologies for discovering potential natural mGluR1 NAMs from Chinese herbs.

  1. Generation of high-affinity fully human anti-interleukin-8 antibodies from its cDNA by two-hybrid screening and affinity maturation in yeast.

    Science.gov (United States)

    Ding, Ling; Azam, Mark; Lin, Yu-Huei; Sheridan, James; Wei, Shuanghong; Gupta, Gigi; Singh, Rakesh K; Pauling, Michelle H; Chu, Waihei; Tran, Antares; Yu, Nai-Xuan; Hu, Jiefeng; Wang, Wei; Long, Hao; Xiang, Dong; Zhu, Li; Hua, Shao-Bing

    2010-10-01

    We have developed a technology for rapidly generating novel and fully human antibodies by simply using the antigen DNA. A human single-chain variable fragment (scFv) antibody library was constructed in a yeast two-hybrid vector with high complexity. After cloning cDNA encoding the mature sequence of human interleukin-8 (hIL8) into the yeast two-hybrid system vector, we have screened the human scFv antibody library and obtained three distinct scFv clones that could specifically bind to hIL8. One clone was chosen for further improvement by a novel affinity maturation process using the error-prone PCR of the scFv sequence followed by additional rounds of yeast two-hybrid screening. The scFv antibodies of both primary and affinity-matured scFv clones were expressed in E. coli. All purified scFvs showed specific binding to hIL8 in reciprocal coimmunoprecipitation and ELISA assays. All scFvs, as well as a fully human IgG antibody converted from one of the scFv clones and expressed in the mammalian cells, were able to effectively inhibit hIL8 in neutrophil chemotaxis assays. The technology described can generate fully human antibodies with high efficiency and low cost.

  2. Screening of the interacting proteins with NifA in Azospirillum brasilense Sp7 by the yeast two-hybrid system

    Institute of Scientific and Technical Information of China (English)

    CHEN Sanfeng; GUAN Yu; TU Ran; SUN Wengai; LI Jilun

    2005-01-01

    NifA in Azospirillum brasilense plays a key role in regulating the synthesis and activity of nitrogenase in response to ammonia and oxygen available. In this work we used the yeast two-hybrid system to identify the proteins that interact with NifA. The nifA gene was fused to the yeast two-hybrid vector pGBD-C2, and three A. brasilense Sp7 genomic libraries for use in yeast two-hybrid studies were constructed. Screening of the libraries identified four clones encoding proteins that interact with NifA. The confirmation of the interactions of each gene product of the four clones and NifA were carried out by exchanging the vectors for nifA and the four clones and by mutageneses of the four clones with shift reading frame experiments in yeast two-hybrid studies. DNA sequence analyses showed that two clones encode proteins containing PAS domains that play an important role in signal transduction. One clone has high similarity with the fhuE gene of Escherichia coli, whose gene product is involved in iron uptake and transportation, and the other clone encodes an unknown protein.

  3. Phylogeny-function analysis of (meta)genomic libraries: screening for expression of ribosomal RNA genes by large-insert library fluorescent in situ hybridization (LIL-FISH).

    Science.gov (United States)

    Leveau, Johan H J; Gerards, Saskia; de Boer, Wietse; van Veen, Johannes A

    2004-09-01

    We assessed the utility of fluorescent in situ hybridization (FISH) in the screening of clone libraries of (meta)genomic or environmental DNA for the presence and expression of bacterial ribosomal RNA (rRNA) genes. To establish proof-of-principle, we constructed a fosmid-based library in Escherichia coli of large-sized genomic DNA fragments of the mycophagous soil bacterium Collimonas fungivorans, and hybridized 768 library clones with the Collimonas-specific fluorescent probe CTE998-1015. Critical to the success of thi