WorldWideScience

Sample records for include drugs targeting

  1. Drug-Target Kinetics in Drug Discovery.

    Science.gov (United States)

    Tonge, Peter J

    2018-01-17

    The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

  2. Magnetic targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Timothy Wiedmann

    2009-10-01

    Full Text Available Lung cancer is the most common cause of death from cancer in both men and women. Treatment by intravenous or oral administration of chemotherapy agents results in serious and often treatment-limiting side effects. Delivery of drugs directly to the lung by inhalation of an aerosol holds the promise of achieving a higher concentration in the lung with lower blood levels. To further enhance the selective lung deposition, it may be possible to target deposition by using external magnetic fields to direct the delivery of drug coupled to magnetic particles. Moreover, alternating magnetic fields can be used to induce particle heating, which in turn controls the drug release rate with the appropriate thermal sensitive material.With this goal, superparamagetic nanoparticles (SPNP were prepared and characterized, and enhanced magnetic deposition was demonstrated in vitro and in vivo. SPNPs were also incorporated into a lipid-based/SPNP aerosol formulation, and drug release was shown to be controlled by thermal activation. Because of the inherent imaging potential of SPNPs, this use of nanotechnology offers the possibility of coupling the diagnosis of lung cancer to drug release, which perhaps will ultimately provide the “magic bullet” that Paul Ehrlich originally sought.

  3. Kidney–targeted drug delivery systems

    Directory of Open Access Journals (Sweden)

    Peng Zhou

    2014-02-01

    Full Text Available Kidney-targeted drug delivery systems represent a promising technology to improve drug efficacy and safety in the treatment of renal diseases. In this review, we summarize the strategies that have been employed to develop kidney-targeted drug delivery systems. We also describe how macromolecular carriers and prodrugs play crucial roles in targeting drugs to particular target cells in the kidney. New technologies render it possible to create renal targeting conjugates and other delivery systems including nanoparticles and liposomes present promising strategies to achieve the goal of targeting drugs to the kidney.

  4. Drug delivery device including electrolytic pump

    KAUST Repository

    Foulds, Ian G.

    2016-03-31

    Systems and methods are provided for a drug delivery device and use of the device for drug delivery. In various aspects, the drug delivery device combines a “solid drug in reservoir” (SDR) system with an electrolytic pump. In various aspects an improved electrolytic pump is provided including, in particular, an improved electrolytic pump for use with a drug delivery device, for example an implantable drug delivery device. A catalytic reformer can be incorporated in a periodically pulsed electrolytic pump to provide stable pumping performance and reduced actuation cycle.

  5. Nanotechnology based targeted drug delivery.

    Science.gov (United States)

    Ruggiero, Carmelina; Pastorino, Laura; Herrera, Oscar L

    2010-01-01

    NANOTECHNOLOGY is having a great impact on many industrial applications, such as manufacturing, semiconductors, nanostructured materials and biotechnology. As relates to the latter, nanobiotechnology focuses on the ability to work at the molecular and atomic level to fabricate structures combining biological materials and synthetic materials, taking into account engineering, physics, chemistry, genomics and proteomics. The main goals relate to biosensors, nanosized microchips, and more generally to medical applications at the molecular level. Nanotechnology has been recently extensively applied to treatment and diagnosis of diseases and the new term nanomedicine has been introduced, for which several definitions have so far been proposed [1]-[3] which focus on the use of engineered nano-devices and nanostructures for diagnosis and treatment. One of the key aspects of nanomedicine is targeted drug delivery by nanoscale drug carriers. At present, 95 % of all new potential therapeutics have poor pharmaco kinetics and biopharmaceutical properties, there is therefore a great need to develop drug delivery [4] systems that convey the therapeutically active molecules only to the site of action, without affecting other organs and tissues [5]. This allows to lower required doses of drugs and to increase their therapeutic indices and safety profiles. It is possible to fabricate nanoparticles or nanocapsules with different properties as relates to drug encapsulation and release. A great amount of nanoscale systems for drug delivery has been investigated; they include liposomes, dendrimers, quantum dots, nanotubes, polymeric biodegradable nanoparticles and nanocapsules [6].

  6. Pharmacogenomics of GPCR Drug Targets

    DEFF Research Database (Denmark)

    Hauser, Alexander Sebastian; Chavali, Sreenivas; Masuho, Ikuo

    2018-01-01

    Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health. Although 108 G-protein-coupled receptors (GPCRs) are the targets of 475 (∼34%) Food and Drug Administration (FDA)-approved drugs...... and account for a global sales volume of over 180 billion US dollars annually, the prevalence of genetic variation among GPCRs targeted by drugs is unknown. By analyzing data from 68,496 individuals, we find that GPCRs targeted by drugs show genetic variation within functional regions such as drug......- and effector-binding sites in the human population. We experimentally show that certain variants of μ-opioid and Cholecystokinin-A receptors could lead to altered or adverse drug response. By analyzing UK National Health Service drug prescription and sales data, we suggest that characterizing GPCR variants...

  7. Targeted drugs in radiation therapy

    International Nuclear Information System (INIS)

    Favaudon, V.; Hennequin, C.; Hennequin, C.

    2004-01-01

    New drugs aiming at the development of targeted therapies have been assayed in combination with ionizing radiation over the past few years. The rationale of this concept comes from the fact that the cytotoxic potential of targeted drugs is limited, thus requiring concomitant association with a cytotoxic agent for the eradication of tumor cells. Conversely a low level of cumulative toxicity is expected from targeted drugs. Most targeted drugs act through inhibition of post-translational modifications of proteins, such as dimerization of growth factor receptors, prenylation reactions, or phosphorylation of tyrosine or serine-threonine residues. Many systems involving the proteasome, neo-angiogenesis promoters, TGF-β, cyclooxygenase or the transcription factor NF-κB, are currently under investigation in hopes they will allow a control of cell proliferation, apoptosis, cell cycle progression, tumor angiogenesis and inflammation. A few drugs have demonstrated an antitumor potential in particular phenotypes. In most instances, however, radiation-drug interactions proved to be strictly additive in terms of cell growth inhibition or induced cell death. Strong potentiation of the response to radiotherapy is expected to require interaction with DNA repair mechanisms. (authors)

  8. Polymeric micelles for drug targeting.

    Science.gov (United States)

    Mahmud, Abdullah; Xiong, Xiao-Bing; Aliabadi, Hamidreza Montazeri; Lavasanifar, Afsaneh

    2007-11-01

    Polymeric micelles are nano-delivery systems formed through self-assembly of amphiphilic block copolymers in an aqueous environment. The nanoscopic dimension, stealth properties induced by the hydrophilic polymeric brush on the micellar surface, capacity for stabilized encapsulation of hydrophobic drugs offered by the hydrophobic and rigid micellar core, and finally a possibility for the chemical manipulation of the core/shell structure have made polymeric micelles one of the most promising carriers for drug targeting. To date, three generations of polymeric micellar delivery systems, i.e. polymeric micelles for passive, active and multifunctional drug targeting, have arisen from research efforts, with each subsequent generation displaying greater specificity for the diseased tissue and/or targeting efficiency. The present manuscript aims to review the research efforts made for the development of each generation and provide an assessment on the overall success of polymeric micellar delivery system in drug targeting. The emphasis is placed on the design and development of ligand modified, stimuli responsive and multifunctional polymeric micelles for drug targeting.

  9. Other targeted drugs in melanoma.

    Science.gov (United States)

    González-Cao, María; Rodón, Jordi; Karachaliou, Niki; Sánchez, Jesús; Santarpia, Mariacarmela; Viteri, Santiago; Pilotto, Sara; Teixidó, Cristina; Riso, Aldo; Rosell, Rafael

    2015-10-01

    Targeted therapy drugs are developed against specific molecular alterations on cancer cells. Because they are "targeted" to the tumor, these therapies are more effective and better tolerated than conventional therapies such as chemotherapy. In the last decade, great advances have been made in understanding of melanoma biology and identification of molecular mechanisms involved in malignant transformation of cells. The identification of oncogenic mutated kinases involved in this process provides an opportunity for development of new target therapies. The dependence of melanoma on BRAF-mutant kinase has provided an opportunity for development of mutation-specific inhibitors with high activity and excellent tolerance that are now being used in clinical practice. This marked a new era in the treatment of metastatic melanoma and much research is now ongoing to identify other "druggable" kinases and transduction signaling networking. It is expected that in the near future the spectrum of target drugs for melanoma treatment will increase. Herein, we review the most relevant potential novel drugs for melanoma treatment based on preclinical data and the results of early clinical trials.

  10. Targeted Delivery of Protein Drugs by Nanocarriers

    Directory of Open Access Journals (Sweden)

    Antonella Battisti

    2010-03-01

    Full Text Available Recent advances in biotechnology demonstrate that peptides and proteins are the basis of a new generation of drugs. However, the transportation of protein drugs in the body is limited by their high molecular weight, which prevents the crossing of tissue barriers, and by their short lifetime due to immuno response and enzymatic degradation. Moreover, the ability to selectively deliver drugs to target organs, tissues or cells is a major challenge in the treatment of several human diseases, including cancer. Indeed, targeted delivery can be much more efficient than systemic application, while improving bioavailability and limiting undesirable side effects. This review describes how the use of targeted nanocarriers such as nanoparticles and liposomes can improve the pharmacokinetic properties of protein drugs, thus increasing their safety and maximizing the therapeutic effect.

  11. Drug target ontology to classify and integrate drug discovery data.

    Science.gov (United States)

    Lin, Yu; Mehta, Saurabh; Küçük-McGinty, Hande; Turner, John Paul; Vidovic, Dusica; Forlin, Michele; Koleti, Amar; Nguyen, Dac-Trung; Jensen, Lars Juhl; Guha, Rajarshi; Mathias, Stephen L; Ursu, Oleg; Stathias, Vasileios; Duan, Jianbin; Nabizadeh, Nooshin; Chung, Caty; Mader, Christopher; Visser, Ubbo; Yang, Jeremy J; Bologa, Cristian G; Oprea, Tudor I; Schürer, Stephan C

    2017-11-09

    model for druggable targets including various related information such as protein, gene, protein domain, protein structure, binding site, small molecule drug, mechanism of action, protein tissue localization, disease association, and many other types of information. DTO will further facilitate the otherwise challenging integration and formal linking to biological assays, phenotypes, disease models, drug poly-pharmacology, binding kinetics and many other processes, functions and qualities that are at the core of drug discovery. The first version of DTO is publically available via the website http://drugtargetontology.org/ , Github ( http://github.com/DrugTargetOntology/DTO ), and the NCBO Bioportal ( http://bioportal.bioontology.org/ontologies/DTO ). The long-term goal of DTO is to provide such an integrative framework and to populate the ontology with this information as a community resource.

  12. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress

    NARCIS (Netherlands)

    Lammers, Twan Gerardus Gertudis Maria; Kiessling, F.; Hennink, W.E.; Storm, Gerrit

    2012-01-01

    Abstract Many different systems and strategies have been evaluated for drug targeting to tumors over the years. Routinely used systems include liposomes, polymers, micelles, nanoparticles and antibodies, and examples of strategies are passive drug targeting, active drug targeting to cancer cells,

  13. Drug Repurposing: Far Beyond New Targets for Old Drugs

    DEFF Research Database (Denmark)

    Oprea, Tudor; Mestres, J.

    2012-01-01

    Repurposing drugs requires finding novel therapeutic indications compared to the ones for which they were already approved. This is an increasingly utilized strategy for finding novel medicines, one that capitalizes on previous investments while derisking clinical activities. This approach...... is of interest primarily because we continue to face significant gaps in the drug–target interactions matrix and to accumulate safety and efficacy data during clinical studies. Collecting and making publicly available as much data as possible on the target profile of drugs offer opportunities for drug...... repurposing, but may limit the commercial applications by patent applications. Certain clinical applications may be more feasible for repurposing than others because of marked differences in side effect tolerance. Other factors that ought to be considered when assessing drug repurposing opportunities include...

  14. The drug target genes show higher evolutionary conservation than non-target genes.

    Science.gov (United States)

    Lv, Wenhua; Xu, Yongdeng; Guo, Yiying; Yu, Ziqi; Feng, Guanglong; Liu, Panpan; Luan, Meiwei; Zhu, Hongjie; Liu, Guiyou; Zhang, Mingming; Lv, Hongchao; Duan, Lian; Shang, Zhenwei; Li, Jin; Jiang, Yongshuai; Zhang, Ruijie

    2016-01-26

    Although evidence indicates that drug target genes share some common evolutionary features, there have been few studies analyzing evolutionary features of drug targets from an overall level. Therefore, we conducted an analysis which aimed to investigate the evolutionary characteristics of drug target genes. We compared the evolutionary conservation between human drug target genes and non-target genes by combining both the evolutionary features and network topological properties in human protein-protein interaction network. The evolution rate, conservation score and the percentage of orthologous genes of 21 species were included in our study. Meanwhile, four topological features including the average shortest path length, betweenness centrality, clustering coefficient and degree were considered for comparison analysis. Then we got four results as following: compared with non-drug target genes, 1) drug target genes had lower evolutionary rates; 2) drug target genes had higher conservation scores; 3) drug target genes had higher percentages of orthologous genes and 4) drug target genes had a tighter network structure including higher degrees, betweenness centrality, clustering coefficients and lower average shortest path lengths. These results demonstrate that drug target genes are more evolutionarily conserved than non-drug target genes. We hope that our study will provide valuable information for other researchers who are interested in evolutionary conservation of drug targets.

  15. Drug-induced regulation of target expression

    DEFF Research Database (Denmark)

    Iskar, Murat; Campillos, Monica; Kuhn, Michael

    2010-01-01

    . In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We...... further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention....

  16. Drug target ontology to classify and integrate drug discovery data

    DEFF Research Database (Denmark)

    Lin, Yu; Mehta, Saurabh; Küçük-McGinty, Hande

    2017-01-01

    characteristics. DTO has been implemented in the IDG user interface Portal, Pharos and the TIN-X explorer of protein target disease relationships. CONCLUSIONS: DTO was built based on the need for a formal semantic model for druggable targets including various related information such as protein, gene, protein...... domain, protein structure, binding site, small molecule drug, mechanism of action, protein tissue localization, disease association, and many other types of information. DTO will further facilitate the otherwise challenging integration and formal linking to biological assays, phenotypes, disease models......BACKGROUND: One of the most successful approaches to develop new small molecule therapeutics has been to start from a validated druggable protein target. However, only a small subset of potentially druggable targets has attracted significant research and development resources. The Illuminating...

  17. Drug and enzyme targeting. Methods in enzymology. Volume 112

    International Nuclear Information System (INIS)

    Widder, K.J.; Green, R.

    1985-01-01

    In evaluating methods of drug and enzyme targeting, studies are included which discuss microencapsulation techniques and the preparation and purification of various drug conjugates and radiopharmaceuticals, which can be used as a carrier that either releases the drug more slowly or targets the drug more selectively on the desired tissue. Separate abstracts have been prepared for five chapters of this volume for inclusion in the Energy Data Base

  18. Trends in GPCR drug discovery: new agents, targets and indications

    DEFF Research Database (Denmark)

    Hauser, Alexander Sebastian; Gloriam, David E.; Attwood, Misty M.

    2017-01-01

    G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals...... current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially...... novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders...

  19. Target based drug design - a reality in virtual sphere.

    Science.gov (United States)

    Verma, Saroj; Prabhakar, Yenamandra S

    2015-01-01

    The target based drug design approaches are a series of computational procedures, including visualization tools, to support the decision systems of drug design/discovery process. In the essence of biological targets shaping the potential lead/drug molecules, this review presents a comprehensive position of different components of target based drug design which include target identification, protein modeling, molecular dynamics simulations, binding/catalytic sites identification, docking, virtual screening, fragment based strategies, substructure treatment of targets in tackling drug resistance, in silico ADMET, structural vaccinology, etc along with the key issues involved therein and some well investigated case studies. The concepts and working of these procedures are critically discussed to arouse interest and to advance the drug research.

  20. Targeted cancer therapy; nanotechnology approaches for overcoming drug resistance.

    Science.gov (United States)

    Gao, Yan; Shen, Jacson K; Milane, Lara; Hornicek, Francis J; Amiji, Mansoor M; Duan, Zhenfeng

    2015-01-01

    Recent advances in cancer molecular biology have resulted in parallel and unprecedented progress in the development of targeted cancer therapy. Targeted therapy can provide higher efficacy and lower toxicity than conventional chemotherapy for cancer. However, like traditional chemotherapy, molecularly targeted cancer therapy also faces the challenge of drug resistance. Multiple mechanisms are responsible for chemotherapy resistance in tumors, including over-expression of efflux transporters, somatic alterations of drug targets, deregulation of apoptosis, and numerous pharmacokinetic issues. Nanotechnology based approaches are proving to be efficacious in overcoming drug resistance in cancer. Combination of targeted therapies with nanotechnology approaches is a promising strategy to overcome targeted therapy drug resistance in cancer treatment. This review discusses the mechanisms of targeted drug resistance in cancer and discusses nanotechnology approaches to circumvent this resistance.

  1. Screening for Novel Drug Targets in Cancer

    NARCIS (Netherlands)

    Nijwening, J.H.

    2012-01-01

    Most cancer drugs are not specific enough, causing unwanted side effects and recurrence of treated tumors. Some modern cancer drugs, the so-called targeted therapeutics, specifically target tumor cells, while leaving normal and healthy cells unharmed. The aim of the research described in this thesis

  2. Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

    Directory of Open Access Journals (Sweden)

    Avinaba Mukherjee

    2016-03-01

    Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

  3. Mitosis as an anti-cancer drug target.

    Science.gov (United States)

    Salmela, Anna-Leena; Kallio, Marko J

    2013-10-01

    Suppression of cell proliferation by targeting mitosis is one potential cancer intervention. A number of existing chemotherapy drugs disrupt mitosis by targeting microtubule dynamics. While efficacious, these drugs have limitations, i.e. neuropathy, unpredictability and development of resistance. In order to overcome these issues, a great deal of effort has been spent exploring novel mitotic targets including Polo-like kinase 1, Aurora kinases, Mps1, Cenp-E and KSP/Eg5. Here we summarize the latest developments in the discovery and clinical evaluation of new mitotic drug targets.

  4. Polymer carriers for targeted drug delivery and controlled drug release

    Czech Academy of Sciences Publication Activity Database

    Ulbrich, Karel; Pechar, Michal; Etrych, Tomáš; Jelínková, Markéta; Kovář, Marek; Říhová, Blanka

    2003-01-01

    Roč. 10, č. 1 (2003), s. 3-4 ISSN 1211-5894 R&D Projects: GA ČR GA305/02/1425; GA AV ČR IAA4050201 Institutional research plan: CEZ:AV0Z5020903; CEZ:AV0Z4050913 Keywords : HPMA copolymers * drug targeting * drug delivery Subject RIV: CD - Macromolecular Chemistry

  5. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress.

    Science.gov (United States)

    Lammers, Twan; Kiessling, Fabian; Hennink, Wim E; Storm, Gert

    2012-07-20

    Many different systems and strategies have been evaluated for drug targeting to tumors over the years. Routinely used systems include liposomes, polymers, micelles, nanoparticles and antibodies, and examples of strategies are passive drug targeting, active drug targeting to cancer cells, active drug targeting to endothelial cells and triggered drug delivery. Significant progress has been made in this area of research both at the preclinical and at the clinical level, and a number of (primarily passively tumor-targeted) nanomedicine formulations have been approved for clinical use. Significant progress has also been made with regard to better understanding the (patho-) physiological principles of drug targeting to tumors. This has led to the identification of several important pitfalls in tumor-targeted drug delivery, including I) overinterpretation of the EPR effect; II) poor tumor and tissue penetration of nanomedicines; III) misunderstanding of the potential usefulness of active drug targeting; IV) irrational formulation design, based on materials which are too complex and not broadly applicable; V) insufficient incorporation of nanomedicine formulations in clinically relevant combination regimens; VI) negligence of the notion that the highest medical need relates to metastasis, and not to solid tumor treatment; VII) insufficient integration of non-invasive imaging techniques and theranostics, which could be used to personalize nanomedicine-based therapeutic interventions; and VIII) lack of (efficacy analyses in) proper animal models, which are physiologically more relevant and more predictive for the clinical situation. These insights strongly suggest that besides making ever more nanomedicine formulations, future efforts should also address some of the conceptual drawbacks of drug targeting to tumors, and that strategies should be developed to overcome these shortcomings. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. The target landscape of clinical kinase drugs.

    Science.gov (United States)

    Klaeger, Susan; Heinzlmeir, Stephanie; Wilhelm, Mathias; Polzer, Harald; Vick, Binje; Koenig, Paul-Albert; Reinecke, Maria; Ruprecht, Benjamin; Petzoldt, Svenja; Meng, Chen; Zecha, Jana; Reiter, Katrin; Qiao, Huichao; Helm, Dominic; Koch, Heiner; Schoof, Melanie; Canevari, Giulia; Casale, Elena; Depaolini, Stefania Re; Feuchtinger, Annette; Wu, Zhixiang; Schmidt, Tobias; Rueckert, Lars; Becker, Wilhelm; Huenges, Jan; Garz, Anne-Kathrin; Gohlke, Bjoern-Oliver; Zolg, Daniel Paul; Kayser, Gian; Vooder, Tonu; Preissner, Robert; Hahne, Hannes; Tõnisson, Neeme; Kramer, Karl; Götze, Katharina; Bassermann, Florian; Schlegl, Judith; Ehrlich, Hans-Christian; Aiche, Stephan; Walch, Axel; Greif, Philipp A; Schneider, Sabine; Felder, Eduard Rudolf; Ruland, Juergen; Médard, Guillaume; Jeremias, Irmela; Spiekermann, Karsten; Kuster, Bernhard

    2017-12-01

    Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  7. MODELING OF TARGETED DRUG DELIVERY PART II. MULTIPLE DRUG ADMINISTRATION

    Directory of Open Access Journals (Sweden)

    A. V. Zaborovskiy

    2017-01-01

    Full Text Available In oncology practice, despite significant advances in early cancer detection, surgery, radiotherapy, laser therapy, targeted therapy, etc., chemotherapy is unlikely to lose its relevance in the near future. In this context, the development of new antitumor agents is one of the most important problems of cancer research. In spite of the importance of searching for new compounds with antitumor activity, the possibilities of the “old” agents have not been fully exhausted. Targeted delivery of antitumor agents can give them a “second life”. When developing new targeted drugs and their further introduction into clinical practice, the change in their pharmacodynamics and pharmacokinetics plays a special role. The paper describes a pharmacokinetic model of the targeted drug delivery. The conditions under which it is meaningful to search for a delivery vehicle for the active substance were described. Primary screening of antitumor agents was undertaken to modify them for the targeted delivery based on underlying assumptions of the model.

  8. Nanomedicine: Drug Delivery Systems and Nanoparticle Targeting

    International Nuclear Information System (INIS)

    Youn, Hye Won; Kang, Keon Wook; Chung, Jun Key; Lee, Dong Soo

    2008-01-01

    Applications of nanotechnology in the medical field have provided the fundamentals of tremendous improvement in precise diagnosis and customized therapy. Recent advances in nanomedicine have led to establish a new concept of theragnosis, which utilizes nanomedicines as a therapeutic and diagnostic tool at the same time. The development of high affinity nanoparticles with large surface area and functional groups multiplies diagnostic and therapeutic capacities. Considering the specific conditions related to the disease of individual patient, customized therapy requires the identification of disease target at the cellular and molecular level for reducing side effects and enhancing therapeutic efficiency. Well-designed nanoparticles can minimize unnecessary exposure of cytotoxic drugs and maximize targeted localization of administrated drugs. This review will focus on major pharmaceutical nanomaterials and nanoparticles as key components of designing and surface engineering for targeted theragnostic drug development

  9. Injected nanocrystals for targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Yi Lu

    2016-03-01

    Full Text Available Nanocrystals are pure drug crystals with sizes in the nanometer range. Due to the advantages of high drug loading, platform stability, and ease of scaling-up, nanocrystals have been widely used to deliver poorly water-soluble drugs. Nanocrystals in the blood stream can be recognized and sequestered as exogenous materials by mononuclear phagocytic system (MPS cells, leading to passive accumulation in MPS-rich organs, such as liver, spleen and lung. Particle size, morphology and surface modification affect the biodistribution of nanocrystals. Ligand conjugation and stimuli-responsive polymers can also be used to target nanocrystals to specific pathogenic sites. In this review, the progress on injected nanocrystals for targeted drug delivery is discussed following a brief introduction to nanocrystal preparation methods, i.e., top-down and bottom-up technologies.

  10. Degradable Polymersomes for Targeted Drug Delivery

    Science.gov (United States)

    Petersen, Matthew Alan

    Chemotherapy today is often accompanied by major side effects due to delivery of toxic drugs to healthy tissue in addition to diseased cells. Targeted drug delivery offers the possibility of minimizing these side effects by specific delivery to cancer cells using targeted nanocarriers that enhance drug accumulation in tumors and facilitate target-specific cellular uptake. Polymersomes, vesicles self-assembled from polymeric amphiphiles, are an attractive targeted vehicle, as they are capable of encapsulating both hydrophobic and hydrophilic drugs, have lengthy circulation times in vivo, and can employ degradable functionality for triggered release of payload and clearance from the body. This thesis reports on efforts to enhance the capabilities of degradable polymersomes for targeted delivery. First, targeting functionality is incorporated into polymersomes of the block copolymer poly(ethylene oxide)-b-poly(gamma-methyl-epsilon-caprolactone) by incorporating the reactive vinyl sulfone group into the amphiphile's hydrophilic terminus, allowing site-selective reaction with cysteine-functionalized targeting peptides following self-assembly. The performance of targeted delivery using this polymersome is then evaluated in vitro. Binding and delivery to model cell lines for targeted and bystander cells is tracked using nontargeted polymersomes and compared to that for polymersomes using a high- or low-affinity ligand. Polymer degradation is also tracked both in simple media and during cellular delivery. Finally, a new monomer is developed incorporating acid-labile acetal functionality into a cyclic polyester. The polymerization of this monomer to two distinct polymers is also characterized and the degradation behavior of both polymers evaluated.

  11. Molecularly targeted drugs for metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    Cheng YD

    2013-11-01

    Full Text Available Ying-dong Cheng, Hua Yang, Guo-qing Chen, Zhi-cao Zhang Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China Abstract: The survival rate of patients with metastatic colorectal cancer (mCRC has significantly improved with applications of molecularly targeted drugs, such as bevacizumab, and led to a substantial improvement in the overall survival rate. These drugs are capable of specifically targeting the inherent abnormal pathways in cancer cells, which are potentially less toxic than traditional nonselective chemotherapeutics. In this review, the recent clinical information about molecularly targeted therapy for mCRC is summarized, with specific focus on several of the US Food and Drug Administration-approved molecularly targeted drugs for the treatment of mCRC in the clinic. Progression-free and overall survival in patients with mCRC was improved greatly by the addition of bevacizumab and/or cetuximab to standard chemotherapy, in either first- or second-line treatment. Aflibercept has been used in combination with folinic acid (leucovorin–fluorouracil–irinotecan (FOLFIRI chemotherapy in mCRC patients and among patients with mCRC with wild-type KRAS, the outcomes were significantly improved by panitumumab in combination with folinic acid (leucovorin–fluorouracil–oxaliplatin (FOLFOX or FOLFIRI. Because of the new preliminary studies, it has been recommended that regorafenib be used with FOLFOX or FOLFIRI as first- or second-line treatment of mCRC chemotherapy. In summary, an era of new opportunities has been opened for treatment of mCRC and/or other malignancies, resulting from the discovery of new selective targeting drugs. Keywords: metastatic colorectal cancer (mCRC, antiangiogenic drug, bevacizumab, aflibercept, regorafenib, cetuximab, panitumumab, clinical trial, molecularly targeted therapy

  12. P-glycoprotein targeted nanoscale drug carriers

    KAUST Repository

    Li, Wengang

    2013-02-01

    Multi-drug resistance (MDR) is a trend whereby tumor cells exposed to one cytotoxic agent develop cross-resistance to a range of structurally and functionally unrelated compounds. P -glycoprotein (P -gp) efflux pump is one of the mostly studied drug carrying processes that shuttle the drugs out of tumor cells. Thus, P -gp inhibitors have attracted a lot of attention as they can stop cancer drugs from being pumped out of target cells with the consumption of ATP. Using quantitive structure activity relationship (QSAR), we have successfully synthesized a series of novel P -gp inhibitors. The obtained dihydropyrroloquinoxalines series were fully characterized and then tested against bacterial and tumor assays with over-expressed P -gps. All compounds were bioactive especially compound 1c that had enhanced antibacterial activity. Furthermore, these compounds were utilized as targeting vectors to direct drug delivery vehicles such as silica nanoparticles (SNPs) to cancerous Hela cells with over expressed P -gps. Cell uptake studies showed a successful accumulation of these decorated SNPs in tumor cells compared to undecorated SNPs. The results obtained show that dihydropyrroloquinoxalines constitute a promising drug candidate for targeting cancers with MDR. Copyright © 2013 American Scientific Publishers All rights reserved.

  13. Pharmacotherapy of obesity: emerging drugs and targets.

    Science.gov (United States)

    Chakrabarti, Ranjan

    2009-02-01

    Obesity and its associated morbidities are the effects of imbalance between energy intake and expenditure. Present drugs either regulate food intake by acting on neural circuits or reduce nutrient absorption from gut. These approaches have shown moderate success, with several safety concerns, leaving an unmet need for effective and safe therapy for obesity. To provide a brief background on obesity, summarize approved drugs and give an overview of emerging therapeutic targets, their potential benefits and disadvantages. A review based on information available from medical literature. Potential anti-obesity targets investigated can be classified into five broad categories: i) decreasing appetite through central action; ii) increasing metabolic rate or affecting metabolism through peripheral action; iii) modulating gut peptide receptors; iv) modulating targets to affect overall cardiometabolic parameters; and v) combination therapies directed against several targets.

  14. Targeting molecular networks for drug research

    Directory of Open Access Journals (Sweden)

    José Pedro Pinto

    2014-06-01

    Full Text Available The study of molecular networks has recently moved into the limelight of biomedical research. While it has certainly provided us with plenty of new insights into cellular mechanisms, the challenge now is how to modify or even restructure these networks. This is especially true for human diseases, which can be regarded as manifestations of distorted states of molecular networks. Of the possible interventions for altering networks, the use of drugs is presently the most feasible. In this mini-review, we present and discuss some exemplary approaches of how analysis of molecular interaction networks can contribute to pharmacology (e.g., by identifying new drug targets or prediction of drug side effects, as well as listing pointers to relevant resources and software to guide future research. We also outline recent progress in the use of drugs for in vitro reprogramming of cells, which constitutes an example par excellence for altering molecular interaction networks with drugs.

  15. Nanoparticles for intracellular-targeted drug delivery

    International Nuclear Information System (INIS)

    Paulo, Cristiana S O; Pires das Neves, Ricardo; Ferreira, Lino S

    2011-01-01

    Nanoparticles (NPs) are very promising for the intracellular delivery of anticancer and immunomodulatory drugs, stem cell differentiation biomolecules and cell activity modulators. Although initial studies in the area of intracellular drug delivery have been performed in the delivery of DNA, there is an increasing interest in the use of other molecules to modulate cell activity. Herein, we review the latest advances in the intracellular-targeted delivery of short interference RNA, proteins and small molecules using NPs. In most cases, the drugs act at different cellular organelles and therefore the drug-containing NPs should be directed to precise locations within the cell. This will lead to the desired magnitude and duration of the drug effects. The spatial control in the intracellular delivery might open new avenues to modulate cell activity while avoiding side-effects.

  16. Trends in GPCR drug discovery: new agents, targets and indications.

    Science.gov (United States)

    Hauser, Alexander S; Attwood, Misty M; Rask-Andersen, Mathias; Schiöth, Helgi B; Gloriam, David E

    2017-12-01

    G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.

  17. Drug targeting to the diseased liver

    NARCIS (Netherlands)

    Poelstra, Klaas; Prakash, Jai; Beljaars, Leonie

    2012-01-01

    Many serious liver diseases affecting millions of people world-wide cannot be treated despite many efforts which warrants a search for new therapeutic strategies. Potent drugs may not be effective enough in vivo or exhibit adverse effects and enhanced delivery into the target cells may improve this

  18. Bacterial proteases, untapped antimicrobial drug targets.

    Science.gov (United States)

    Culp, Elizabeth; Wright, Gerard D

    2017-04-01

    Bacterial proteases are an extensive collection of enzymes that have vital roles in cell viability, stress response and pathogenicity. Although their perturbation clearly offers the potential for antimicrobial drug development, both as traditional antibiotics and anti-virulence drugs, they are not yet the target of any clinically used therapeutics. Here we describe the potential for and recent progress in the development of compounds targeting bacterial proteases with a focus on AAA+ family proteolytic complexes and signal peptidases (SPs). Caseinolytic protease (ClpP) belongs to the AAA+ family of proteases, a group of multimeric barrel-shaped complexes whose activity is tightly regulated by associated AAA+ ATPases. The opportunity for chemical perturbation of these complexes is demonstrated by compounds targeting ClpP for inhibition, activation or perturbation of its associated ATPase. Meanwhile, SPs are also a proven antibiotic target. Responsible for the cleavage of targeting peptides during protein secretion, both type I and type II SPs have been successfully targeted by chemical inhibitors. As the threat of pan-antibiotic resistance continues to grow, these and other bacterial proteases offer an arsenal of novel antibiotic targets ripe for development.

  19. Targeted drug discovery for pediatric leukemia

    Directory of Open Access Journals (Sweden)

    Andrew D Napper

    2013-07-01

    Full Text Available Despite dramatic advances in the treatment of pediatric leukemia over the past 50 years, there remain subsets of patients who respond poorly to treatment. Many of the high-risk cases of childhood leukemia with the poorest prognosis have been found to harbor specific genetic signatures, often resulting from chromosomal rearrangements. With increased understanding of the genetic and epigenetic makeup of high-risk pediatric leukemia has come the opportunity to develop targeted therapies that promise to be both more effective and less toxic than current chemotherapy. Of particular importance is an understanding of the interconnections between different targets within the same cancer, and observations of synergy between two different targeted therapies or between a targeted drug and conventional chemotherapy. It has become clear that many cancers are able to circumvent a single specific blockade, and pediatric leukemias are no exception in this regard. This review highlights the most promising approaches to new drugs and drug combinations for high-risk pediatric leukemia. Key biological evidence supporting selection of molecular targets is presented, together with a critical survey of recent progress towards the discovery, pre-clinical development, and clinical study of novel molecular therapeutics.

  20. The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development.

    Science.gov (United States)

    Kunz, Meik; Liang, Chunguang; Nilla, Santosh; Cecil, Alexander; Dandekar, Thomas

    2016-01-01

    The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure-activity relationships.Database URL:http://drumpid.bioapps.biozentrum.uni-wuerzburg.de. © The Author(s) 2016. Published by Oxford University Press.

  1. Targeted proteins for diabetes drug design

    Science.gov (United States)

    Doan Trang Nguyen, Ngoc; Thi Le, Ly

    2012-03-01

    Type 2 diabetes mellitus is a common metabolism disorder characterized by high glucose in the bloodstream, especially in the case of insulin resistance and relative insulin deficiency. Nowadays, it is very common in middle-aged people and involves such dangerous symptoms as increasing risk of stroke, obesity and heart failure. In Vietnam, besides the common treatment of insulin injection, some herbal medication is used but no unified optimum remedy for the disease yet exists and there is no production of antidiabetic drugs in the domestic market yet. In the development of nanomedicine at the present time, drug design is considered as an innovative tool for researchers to study the mechanisms of diseases at the molecular level. The aim of this article is to review some common protein targets involved in type 2 diabetes, offering a new idea for designing new drug candidates to produce antidiabetic drugs against type 2 diabetes for Vietnamese people.

  2. Targeted proteins for diabetes drug design

    International Nuclear Information System (INIS)

    Trang Nguyen, Ngoc Doan; Le, Ly Thi

    2012-01-01

    Type 2 diabetes mellitus is a common metabolism disorder characterized by high glucose in the bloodstream, especially in the case of insulin resistance and relative insulin deficiency. Nowadays, it is very common in middle-aged people and involves such dangerous symptoms as increasing risk of stroke, obesity and heart failure. In Vietnam, besides the common treatment of insulin injection, some herbal medication is used but no unified optimum remedy for the disease yet exists and there is no production of antidiabetic drugs in the domestic market yet. In the development of nanomedicine at the present time, drug design is considered as an innovative tool for researchers to study the mechanisms of diseases at the molecular level. The aim of this article is to review some common protein targets involved in type 2 diabetes, offering a new idea for designing new drug candidates to produce antidiabetic drugs against type 2 diabetes for Vietnamese people. (review)

  3. Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets

    Directory of Open Access Journals (Sweden)

    Suhas Vasaikar

    2016-11-01

    Full Text Available In the past decade, it was observed that the relationship between the emerging New Molecular Entities and the quantum of R&D investment has not been favorable. There might be numerous reasons but few studies stress the introduction of target based drug discovery approach as one of the factors. Although a number of drugs have been developed with an emphasis on a single protein target, yet identification of valid target is complex. The approach focuses on an in vitro single target, which overlooks the complexity of cell and makes process of validation drug targets uncertain. Thus, it is imperative to search for alternatives rather than looking at success stories of target-based drug discovery. It would be beneficial if the drugs were developed to target multiple components. New approaches like reverse engineering and translational research need to take into account both system and target-based approach. This review evaluates the strengths and limitations of known drug discovery approaches and proposes alternative approaches for increasing efficiency against treatment.

  4. Predicting drug-target interaction for new drugs using enhanced similarity measures and super-target clustering.

    Science.gov (United States)

    Shi, Jian-Yu; Yiu, Siu-Ming; Li, Yiming; Leung, Henry C M; Chin, Francis Y L

    2015-07-15

    Predicting drug-target interaction using computational approaches is an important step in drug discovery and repositioning. To predict whether there will be an interaction between a drug and a target, most existing methods identify similar drugs and targets in the database. The prediction is then made based on the known interactions of these drugs and targets. This idea is promising. However, there are two shortcomings that have not yet been addressed appropriately. Firstly, most of the methods only use 2D chemical structures and protein sequences to measure the similarity of drugs and targets respectively. However, this information may not fully capture the characteristics determining whether a drug will interact with a target. Secondly, there are very few known interactions, i.e. many interactions are "missing" in the database. Existing approaches are biased towards known interactions and have no good solutions to handle possibly missing interactions which affect the accuracy of the prediction. In this paper, we enhance the similarity measures to include non-structural (and non-sequence-based) information and introduce the concept of a "super-target" to handle the problem of possibly missing interactions. Based on evaluations on real data, we show that our similarity measure is better than the existing measures and our approach is able to achieve higher accuracy than the two best existing algorithms, WNN-GIP and KBMF2K. Our approach is available at http://web.hku.hk/∼liym1018/projects/drug/drug.html or http://www.bmlnwpu.org/us/tools/PredictingDTI_S2/METHODS.html. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Emerging migraine treatments and drug targets

    DEFF Research Database (Denmark)

    Olesen, Jes; Ashina, Messoud

    2011-01-01

    Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5....... Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development...

  6. Meningococcal disease and future drug targets

    DEFF Research Database (Denmark)

    Gammelgaard, L K; Colding, H; Hartzen, S H

    2011-01-01

    -host interactions are key determinants of the clinical course and risk of fatal outcome. Accordingly, successful treatment of severe meningococcal disease requires not only antibiotics but also adjuvants targeting the released endotoxins and the host immune/inflammatory responses. This review highlights the most...... recent data and current knowledge on molecular mechanisms of meningococcal disease and explains how host immune responses ultimately may aggravate neuropathology and the clinical prognosis. Within this context, particular importance is paid to the endotoxic components that provide potential drug targets...

  7. Coating nanoparticles with cell membranes for targeted drug delivery.

    Science.gov (United States)

    Gao, Weiwei; Zhang, Liangfang

    2015-01-01

    Targeted delivery allows drug molecules to preferentially accumulate at the sites of action and thus holds great promise to improve therapeutic index. Among various drug-targeting approaches, nanoparticle-based delivery systems offer some unique strengths and have achieved exciting preclinical and clinical results. Herein, we aim to provide a review on the recent development of cell membrane-coated nanoparticle system, a new class of biomimetic nanoparticles that combine both the functionalities of cellular membranes and the engineering flexibility of synthetic nanomaterials for effective drug delivery and novel therapeutics. This review is particularly focused on novel designs of cell membrane-coated nanoparticles as well as their underlying principles that facilitate the purpose of drug targeting. Three specific areas are highlighted, including: (i) cell membrane coating to prolong nanoparticle circulation, (ii) cell membrane coating to achieve cell-specific targeting and (iii) cell membrane coating for immune system targeting. Overall, cell membrane-coated nanoparticles have emerged as a novel class of targeted nanotherapeutics with strong potentials to improve on drug delivery and therapeutic efficacy for treatment of various diseases.

  8. Emerging migraine treatments and drug targets

    DEFF Research Database (Denmark)

    Olesen, Jes; Ashina, Messoud

    2011-01-01

    Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5....... Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development....... The greatest need is for new prophylactic drugs, and it seems likely that such compounds will be developed in the coming decade....

  9. Drug target residence time: a misleading concept.

    Science.gov (United States)

    Folmer, Rutger H A

    2018-01-01

    Since the importance of drug target residence time was first highlighted more 10 years ago, slow binding kinetics has received much attention in the drug discovery literature, and indeed within pharmaceutical research. However, the residence concept as presented in most papers is supported by rather misleading simulations and arguments, and by examples where compounds are taken out of their pharmacokinetic context. Moreover, fast association is typically more desirable than slow, and advantages of long residence time, notably a potential disconnect between pharmacodynamics (PD) and pharmacokinetics (PK), would be partially or completely offset by slow on-rate. Therefore, plain potency is likely a better predictor of drug development success than is residence time. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Genomes2Drugs: identifies target proteins and lead drugs from proteome data.

    LENUS (Irish Health Repository)

    Toomey, David

    2009-01-01

    BACKGROUND: Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins\\/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and\\/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. METHODOLOGY\\/PRINCIPAL FINDINGS: To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i) homologous to previously crystallized proteins or (ii) targets of known drugs, but are (iii) not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. CONCLUSIONS\\/SIGNIFICANCE: Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under \\'change-of-application\\' patents.

  11. Genomes2Drugs: identifies target proteins and lead drugs from proteome data.

    Directory of Open Access Journals (Sweden)

    David Toomey

    Full Text Available BACKGROUND: Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. METHODOLOGY/PRINCIPAL FINDINGS: To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i homologous to previously crystallized proteins or (ii targets of known drugs, but are (iii not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. CONCLUSIONS/SIGNIFICANCE: Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under 'change-of-application' patents.

  12. Histone as future drug target for malaria.

    Science.gov (United States)

    Rawat, D S; Lumb, V; Sharma, Y D; Pasha, S T; Singh, G

    2007-06-01

    Malaria continues to be a major cause of mortality and morbidity in tropical countries and affecting around 100 countries of the world. As per WHO estimates, 300-500 million are being infected and 1-3 million deaths annually due to malaria. With the emerging knowledge about genome sequence of all the three counterparts involved in the disease of malaria, the parasite Plasmodium, vector Anopheles and host Homo sapien have helped the scientists to understand interactions between them. Simultaneous advancement in technology further improves the prospects to discover new targets for vaccines and drugs. Though the malaria vaccine is still far away in this situation there is need to develop a potent and affordable drug(s). Histones are the key protein of chromatin and play an important role in DNA packaging, replication and gene expression. They also show frequent post-translation modifications. The specific combinations of these posttranslational modifications are thought to alter chromatin structure by forming epigenetic bar codes that specify either transient or heritable patterns of genome function. Chromatin regulators and upstream pathways are therefore seen as promising targets for development of therapeutic drugs.

  13. Functional genomics and cancer drug target discovery.

    Science.gov (United States)

    Moody, Susan E; Boehm, Jesse S; Barbie, David A; Hahn, William C

    2010-06-01

    The recent development of technologies for whole-genome sequencing, copy number analysis and expression profiling enables the generation of comprehensive descriptions of cancer genomes. However, although the structural analysis and expression profiling of tumors and cancer cell lines can allow the identification of candidate molecules that are altered in the malignant state, functional analyses are necessary to confirm such genes as oncogenes or tumor suppressors. Moreover, recent research suggests that tumor cells also depend on synthetic lethal targets, which are not mutated or amplified in cancer genomes; functional genomics screening can facilitate the discovery of such targets. This review provides an overview of the tools available for the study of functional genomics, and discusses recent research involving the use of these tools to identify potential novel drug targets in cancer.

  14. Prediction of potential drug targets based on simple sequence properties

    Directory of Open Access Journals (Sweden)

    Lai Luhua

    2007-09-01

    Full Text Available Abstract Background During the past decades, research and development in drug discovery have attracted much attention and efforts. However, only 324 drug targets are known for clinical drugs up to now. Identifying potential drug targets is the first step in the process of modern drug discovery for developing novel therapeutic agents. Therefore, the identification and validation of new and effective drug targets are of great value for drug discovery in both academia and pharmaceutical industry. If a protein can be predicted in advance for its potential application as a drug target, the drug discovery process targeting this protein will be greatly speeded up. In the current study, based on the properties of known drug targets, we have developed a sequence-based drug target prediction method for fast identification of novel drug targets. Results Based on simple physicochemical properties extracted from protein sequences of known drug targets, several support vector machine models have been constructed in this study. The best model can distinguish currently known drug targets from non drug targets at an accuracy of 84%. Using this model, potential protein drug targets of human origin from Swiss-Prot were predicted, some of which have already attracted much attention as potential drug targets in pharmaceutical research. Conclusion We have developed a drug target prediction method based solely on protein sequence information without the knowledge of family/domain annotation, or the protein 3D structure. This method can be applied in novel drug target identification and validation, as well as genome scale drug target predictions.

  15. Functional differentiation of cytotoxic cancer drugs and targeted cancer therapeutics.

    Science.gov (United States)

    Winkler, Gian C; Barle, Ester Lovsin; Galati, Giuseppe; Kluwe, William M

    2014-10-01

    There is no nationally or internationally binding definition of the term "cytotoxic drug" although this term is used in a variety of regulations for pharmaceutical development and manufacturing of drugs as well as in regulations for protecting medical personnel from occupational exposure in pharmacy, hospital, and other healthcare settings. The term "cytotoxic drug" is frequently used as a synonym for any and all oncology or antineoplastic drugs. Pharmaceutical companies generate and receive requests for assessments of the potential hazards of drugs regularly - including cytotoxicity. This publication is intended to provide functional definitions that help to differentiate between generically-cytotoxic cancer drugs of significant risk to normal human tissues, and targeted cancer therapeutics that pose much lesser risks. Together with specific assessments, it provides comprehensible guidance on how to assess the relevant properties of cancer drugs, and how targeted therapeutics discriminate between cancer and normal cells. The position of several regulatory agencies in the long-term is clearly to regulate all drugs regardless of classification, according to scientific risk based data. Despite ongoing discussions on how to replace the term "cytotoxic drugs" in current regulations, it is expected that its use will continue for the near future. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. New approaches to targeted drug delivery to tumour cells

    International Nuclear Information System (INIS)

    Severin, E S

    2015-01-01

    Basic approaches to the design of targeted drugs for the treatment of human malignant tumours have been considered. The stages of the development of these approaches have been described in detail and theoretically substantiated, and basic experimental results have been reported. Considerable attention is paid to the general characteristic of nanopharmacological drugs and to the description of mechanisms of cellular interactions with nanodrugs. The potentialities and limitations of application of nanodrugs for cancer therapy and treatment of other diseases have been considered. The use of nanodrugs conjugated with vector molecules seems to be the most promising trend of targeted therapy of malignant tumours. The bibliography includes 122 references

  17. External triggering and triggered targeting strategies for drug delivery

    Science.gov (United States)

    Wang, Yanfei; Kohane, Daniel S.

    2017-06-01

    Drug delivery systems that are externally triggered to release drugs and/or target tissues hold considerable promise for improving the treatment of many diseases by minimizing nonspecific toxicity and enhancing the efficacy of therapy. These drug delivery systems are constructed from materials that are sensitive to a wide range of external stimuli, including light, ultrasound, electrical and magnetic fields, and specific molecules. The responsiveness conferred by these materials allows the release of therapeutics to be triggered on demand and remotely by a physician or patient. In this Review, we describe the rationales for such systems and the types of stimuli that can be deployed, and provide an outlook for the field.

  18. Emerging migraine treatments and drug targets

    DEFF Research Database (Denmark)

    Olesen, Jes; Ashina, Messoud

    2011-01-01

    Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5......-hydroxytrypamine (5-HT)(1F) receptor agonists, which are in late-stage development. Nitric oxide antagonists are also in development. New forms of administration of sumatriptan might improve efficacy and reduce side effects. Botulinum toxin A has recently been approved for the prophylaxis of chronic migraine....... Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development...

  19. Structure and organization of drug-target networks: insights from genomic approaches for drug discovery.

    Science.gov (United States)

    Janga, Sarath Chandra; Tzakos, Andreas

    2009-12-01

    Recent years have seen an explosion in the amount of "omics" data and the integration of several disciplines, which has influenced all areas of life sciences including that of drug discovery. Several lines of evidence now suggest that the traditional notion of "one drug-one protein" for one disease does not hold any more and that treatment for most complex diseases can best be attempted using polypharmacological approaches. In this review, we formalize the definition of a drug-target network by decomposing it into drug, target and disease spaces and provide an overview of our understanding in recent years about its structure and organizational principles. We discuss advances made in developing promiscuous drugs following the paradigm of polypharmacology and reveal their advantages over traditional drugs for targeting diseases such as cancer. We suggest that drug-target networks can be decomposed to be studied at a variety of levels and argue that such network-based approaches have important implications in understanding disease phenotypes and in accelerating drug discovery. We also discuss the potential and scope network pharmacology promises in harnessing the vast amount of data from high-throughput approaches for therapeutic advantage.

  20. NSAIDs: Old Drugs Reveal New Anticancer Targets

    Directory of Open Access Journals (Sweden)

    Gary A. Piazza

    2010-05-01

    Full Text Available There is compelling evidence that nonsteroidal anti-inflammatory drugs (NSAIDs and cyclooxygenase-2 selective inhibitors have antineoplastic activity, but toxicity from cyclooxygenase (COX inhibition and the suppression of physiologically important prostaglandins limits their use for cancer chemoprevention. Previous studies as reviewed here suggest that the mechanism for their anticancer properties does not require COX inhibition, but instead involves an off-target effect. In support of this possibility, recent molecular modeling studies have shown that the NSAID sulindac can be chemically modified to selectively design out its COX-1 and COX-2 inhibitory activity. Unexpectedly, certain derivatives that were synthesized based on in silico modeling displayed increased potency to inhibit tumor cell growth. Other experiments have shown that sulindac can inhibit phosphodiesterase to increase intracellular cyclic GMP levels and that this activity is closely associated with its ability to selectively induce apoptosis of tumor cells. Together, these studies suggest that COX-independent mechanisms can be targeted to develop safer and more efficacious drugs for cancer chemoprevention.

  1. Intermittent claudication: new targets for drug development.

    Science.gov (United States)

    Brass, Eric P

    2013-07-01

    Peripheral artery disease (PAD) is the result of extensive atherosclerosis in the arterial supply to the lower extremities. PAD is associated with increased systemic cardiovascular morbidity and mortality as well as substantial disability due to walking impairment. Claudication is the classic symptom of leg pain with walking that is relieved by rest, but patients with PAD without typical claudication also have a walking limitation. Treatment of the patient with PAD is directed towards reducing cardiovascular risk and improving exercise capacity. The pathophysiology of the physical impairment is complex as changes in the muscle distal to the arterial stenoses contribute to the limitations. Current treatment options to improve exercise performance have limitations emphasizing the need for new pharmacotherapies for this highly prevalent condition. The multifactorial contributors to the exercise impairment in PAD suggest potential targets for novel drug therapies. Advances in understanding angiogenesis make pharmacologic revascularization possible. However, ensuring that new blood vessels develop in a distribution relevant to the clinical impairment remains a challenge. Skeletal muscle metabolism and its regulation are altered in patients with PAD and strategies to improve the efficient oxidation of fuel substrates may improve muscle function. PAD is associated with increased oxidative stress which may result in injury to the muscle microvasculature and myocyte. Minimizing this oxidative stress by enhancing cellular defense mechanisms, administration of anti-inflammatory agents or by providing antioxidants, could prevent oxidative injury. Given the central role of atherosclerosis in the flow limitation, therapies to induce regression of atherosclerotic lesions could result in improved blood flow and oxygen delivery. Drugs targeting the distribution of blood flow in the microcirculatory environment of the muscle have the potential to better match oxygen delivery with

  2. Multi-target drugs: the trend of drug research and development.

    Science.gov (United States)

    Lu, Jin-Jian; Pan, Wei; Hu, Yuan-Jia; Wang, Yi-Tao

    2012-01-01

    Summarizing the status of drugs in the market and examining the trend of drug research and development is important in drug discovery. In this study, we compared the drug targets and the market sales of the new molecular entities approved by the U.S. Food and Drug Administration from January 2000 to December 2009. Two networks, namely, the target-target and drug-drug networks, have been set up using the network analysis tools. The multi-target drugs have much more potential, as shown by the network visualization and the market trends. We discussed the possible reasons and proposed the rational strategies for drug research and development in the future.

  3. Increasing the structural coverage of tuberculosis drug targets.

    Science.gov (United States)

    Baugh, Loren; Phan, Isabelle; Begley, Darren W; Clifton, Matthew C; Armour, Brianna; Dranow, David M; Taylor, Brandy M; Muruthi, Marvin M; Abendroth, Jan; Fairman, James W; Fox, David; Dieterich, Shellie H; Staker, Bart L; Gardberg, Anna S; Choi, Ryan; Hewitt, Stephen N; Napuli, Alberto J; Myers, Janette; Barrett, Lynn K; Zhang, Yang; Ferrell, Micah; Mundt, Elizabeth; Thompkins, Katie; Tran, Ngoc; Lyons-Abbott, Sally; Abramov, Ariel; Sekar, Aarthi; Serbzhinskiy, Dmitri; Lorimer, Don; Buchko, Garry W; Stacy, Robin; Stewart, Lance J; Edwards, Thomas E; Van Voorhis, Wesley C; Myler, Peter J

    2015-03-01

    High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus "homolog-rescue" strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD 85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Leveraging human genetics to guide drug target discovery.

    Science.gov (United States)

    Stitziel, Nathan O; Kathiresan, Sekar

    2017-07-01

    Identifying appropriate molecular targets is a critical step in drug development. Despite many advantages, the traditional tools of observational epidemiology and cellular or animal models of disease can be misleading in identifying causal pathways likely to lead to successful therapeutics. Here, we review some favorable aspects of human genetics studies that have the potential to accelerate drug target discovery. These include using genetic studies to identify pathways relevant to human disease, leveraging human genetics to discern causal relationships between biomarkers and disease, and studying genetic variation in humans to predict the potential efficacy and safety of inhibitory compounds aimed at molecular targets. We present some examples taken from studies of plasma lipids and coronary artery disease to highlight how human genetics can accelerate therapeutics development. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Telomerase – future drug target enzyme?

    Directory of Open Access Journals (Sweden)

    Tomaž Langerholc

    2012-06-01

    Full Text Available Eucaryotic chromosome endings (telomeres replication problem was solved in the 1980’s by discovery of the telomerase enzyme. The Nobel Prize in Physiology or Medicine was awarded in 2009 for the discovery of telomerase. Altered telomerase expression in cancer, and human dream of eternal youth have accelerated the development of pharmacological telomerase inhibitors and activators. However, after 15 years of development they are still not available on the market. In the present article we reviewed pharmacological agents that target telomerase activity, which have entered clinical trials. Current drugs in development are mostly not intended to be used alone, as telomerase inhibitors under clinical trials are used in combination with the existing chemotherapeutics and anti-telomerase vaccines in combination with immuno-stimulants. Apart from cancer and aging, there are other diseases linked to deregulated activity of telomerase/telomeres and we also discuss technical and legal problems that researchers encounter in developing anti-telomerase therapy. Given the pace of development, first anti-telomerase drugs might appear on the market in the next 5 years.

  6. Genetic Approaches To Identifying Novel Osteoporosis Drug Targets.

    Science.gov (United States)

    Brommage, Robert

    2015-10-01

    During the past two decades effective drugs for treating osteoporosis have been developed, including anti-resorptives inhibiting bone resorption (estrogens, the SERM raloxifene, four bisphosphonates, RANKL inhibitor denosumab) and the anabolic bone forming daily injectable peptide teriparatide. Two potential drugs (odanacatib and romosozumab) are in late stage clinical development. The most pressing unmet need is for orally active anabolic drugs. This review describes the basic biological studies involved in developing these drugs, including the animal models employed for osteoporosis drug development. The genomics revolution continues to identify potential novel osteoporosis drug targets. Studies include human GWAS studies and identification of mutant genes in subjects having abnormal bone mass, mouse QTL and gene knockouts, and gene expression studies. Multiple lines of evidence indicate that Wnt signaling plays a major role in regulating bone formation and continued study of this complex pathway is likely to lead to key discoveries. In addition to the classic Wnt signaling targets DKK1 and sclerostin, LRP4, LRP5/LRP6, SFRP4, WNT16, and NOTUM can potentially be targeted to modulate Wnt signaling. Next-generation whole genome and exome sequencing, RNA-sequencing and CRISPR/CAS9 gene editing are new experimental techniques contributing to understanding the genome. The International Knockout Mouse Consortium efforts to knockout and phenotype all mouse genes are poised to accelerate. Accumulating knowledge will focus attention on readily accessible databases (Big Data). Efforts are underway by the International Bone and Mineral Society to develop an annotated Skeletome database providing information on all genes directly influencing bone mass, architecture, mineralization or strength. © 2015 Wiley Periodicals, Inc.

  7. Application of targeting nano-drug for neoplasms

    International Nuclear Information System (INIS)

    Fan Yongzeng; Yuan Gengbiao

    2010-01-01

    With the rise of nano science and technology, more and more researchers will take attention to application of nano-drugs in the biomedical field. The current focus of concern is that a target of nano-drugs linked specificity immunoreactive substances combine to tumor cells for diagnosis and treatment by physical, chemical and biological synthesis methods in based on nano-drugs. This paper mainly reviewed the concept of nano-drug and development of nano-drug targeting research. (authors)

  8. Recent advances in targeted drug therapy for hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    FAN Yongqiang

    2018-02-01

    Full Text Available More and more clinical trials have proved the efficacy of targeted drugs in the treatment of hepatocellular carcinoma (HCC. With the development of science and technology, more and more targeted drugs have appeared. In recent years, targeted drugs such as regorafenib and ramucirumab have shown great potential in related clinical trials. In addition, there are ongoing clinical trials for second-line candidate drugs, such as c-Met inhibitors tivantinib and cabozantinib and a VEGFR-2 inhibitor ramucirumab. This article summarizes the advances in targeted drug therapy for HCC and related trial data, which provides a reference for further clinical trials and treatment.

  9. Drug target identification using side-effect similarity

    DEFF Research Database (Denmark)

    Campillos, Monica; Kuhn, Michael; Gavin, Anne-Claude

    2008-01-01

    Targets for drugs have so far been predicted on the basis of molecular or cellular features, for example, by exploiting similarity in chemical structure or in activity across cell lines. We used phenotypic side-effect similarities to infer whether two drugs share a target. Applied to 746 marketed...... drugs, a network of 1018 side effect-driven drug-drug relations became apparent, 261 of which are formed by chemically dissimilar drugs from different therapeutic indications. We experimentally tested 20 of these unexpected drug-drug relations and validated 13 implied drug-target relations by in vitro...... binding assays, of which 11 reveal inhibition constants equal to less than 10 micromolar. Nine of these were tested and confirmed in cell assays, documenting the feasibility of using phenotypic information to infer molecular interactions and hinting at new uses of marketed drugs....

  10. The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective.

    Science.gov (United States)

    Li, Ying Hong; Wang, Pan Pan; Li, Xiao Xu; Yu, Chun Yan; Yang, Hong; Zhou, Jin; Xue, Wei Wei; Tan, Jun; Zhu, Feng

    2016-01-01

    The human kinome is one of the most productive classes of drug target, and there is emerging necessity for treating complex diseases by means of polypharmacology (multi-target drugs and combination products). However, the advantages of the multi-target drugs and the combination products are still under debate. A comparative analysis between FDA approved multi-target drugs and combination products, targeting the human kinome, was conducted by mapping targets onto the phylogenetic tree of the human kinome. The approach of network medicine illustrating the drug-target interactions was applied to identify popular targets of multi-target drugs and combination products. As identified, the multi-target drugs tended to inhibit target pairs in the human kinome, especially the receptor tyrosine kinase family, while the combination products were able to against targets of distant homology relationship. This finding asked for choosing the combination products as a better solution for designing drugs aiming at targets of distant homology relationship. Moreover, sub-networks of drug-target interactions in specific disease were generated, and mechanisms shared by multi-target drugs and combination products were identified. In conclusion, this study performed an analysis between approved multi-target drugs and combination products against the human kinome, which could assist the discovery of next generation polypharmacology.

  11. Deep-Learning-Based Drug-Target Interaction Prediction.

    Science.gov (United States)

    Wen, Ming; Zhang, Zhimin; Niu, Shaoyu; Sha, Haozhi; Yang, Ruihan; Yun, Yonghuan; Lu, Hongmei

    2017-04-07

    Identifying interactions between known drugs and targets is a major challenge in drug repositioning. In silico prediction of drug-target interaction (DTI) can speed up the expensive and time-consuming experimental work by providing the most potent DTIs. In silico prediction of DTI can also provide insights about the potential drug-drug interaction and promote the exploration of drug side effects. Traditionally, the performance of DTI prediction depends heavily on the descriptors used to represent the drugs and the target proteins. In this paper, to accurately predict new DTIs between approved drugs and targets without separating the targets into different classes, we developed a deep-learning-based algorithmic framework named DeepDTIs. It first abstracts representations from raw input descriptors using unsupervised pretraining and then applies known label pairs of interaction to build a classification model. Compared with other methods, it is found that DeepDTIs reaches or outperforms other state-of-the-art methods. The DeepDTIs can be further used to predict whether a new drug targets to some existing targets or whether a new target interacts with some existing drugs.

  12. Killing cancer cells by targeted drug-carrying phage nanomedicines

    Directory of Open Access Journals (Sweden)

    Yacoby Iftach

    2008-04-01

    Full Text Available Abstract Background Systemic administration of chemotherapeutic agents, in addition to its anti-tumor benefits, results in indiscriminate drug distribution and severe toxicity. This shortcoming may be overcome by targeted drug-carrying platforms that ferry the drug to the tumor site while limiting exposure to non-target tissues and organs. Results We present a new form of targeted anti-cancer therapy in the form of targeted drug-carrying phage nanoparticles. Our approach is based on genetically-modified and chemically manipulated filamentous bacteriophages. The genetic manipulation endows the phages with the ability to display a host-specificity-conferring ligand. The phages are loaded with a large payload of a cytotoxic drug by chemical conjugation. In the presented examples we used anti ErbB2 and anti ERGR antibodies as targeting moieties, the drug hygromycin conjugated to the phages by a covalent amide bond, or the drug doxorubicin conjugated to genetically-engineered cathepsin-B sites on the phage coat. We show that targeting of phage nanomedicines via specific antibodies to receptors on cancer cell membranes results in endocytosis, intracellular degradation, and drug release, resulting in growth inhibition of the target cells in vitro with a potentiation factor of >1000 over the corresponding free drugs. Conclusion The results of the proof-of concept study presented here reveal important features regarding the potential of filamentous phages to serve as drug-delivery platform, on the affect of drug solubility or hydrophobicity on the target specificity of the platform and on the effect of drug release mechanism on the potency of the platform. These results define targeted drug-carrying filamentous phage nanoparticles as a unique type of antibody-drug conjugates.

  13. Nonstructural Proteins of Alphavirus—Potential Targets for Drug Development

    Directory of Open Access Journals (Sweden)

    Farhana Abu Bakar

    2018-02-01

    Full Text Available Alphaviruses are enveloped, positive single-stranded RNA viruses, typically transmitted by arthropods. They often cause arthralgia or encephalitic diseases in infected humans and there is currently no targeted antiviral treatment available. The re-emergence of alphaviruses in Asia, Europe, and the Americas over the last decade, including chikungunya and o’nyong’nyong viruses, have intensified the search for selective inhibitors. In this review, we highlight key molecular determinants within the alphavirus replication complex that have been identified as viral targets, focusing on their structure and functionality in viral dissemination. We also summarize recent structural data of these viral targets and discuss how these could serve as templates to facilitate structure-based drug design and development of small molecule inhibitors.

  14. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

    Directory of Open Access Journals (Sweden)

    Yoon-Dong Park

    2016-08-01

    Full Text Available Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development.

  15. Emerging drugs for axial spondyloarthritis including ankylosing spondylitis.

    Science.gov (United States)

    Busquets-Perez, Noemi; Marzo-Ortega, Helena; Emery, Paul

    2013-03-01

    Only non-steroidal anti-inflammatories (NSAIDs) and TNF inhibitors (TNFi) are effective in ankylosing spondylitis (AS). However, not all patients successfully respond to these drugs and a subset may have contraindications to their use. In the last decade, an earlier diagnosis of AS has been achieved due to the increasing availability of MRI. This has led to prompt treatment initiation with improved outcomes. NSAIDs and TNFi are the current treatments for AS which lead to sustained clinical responses in the long term. Recent studies have shown other potential biomarkers in AS, such as the IL-17/IL-23 axis. This has translated into the development of new drugs which interfere with these pathways, such as apremilast and secukinumab, which have shown efficacy in early clinical trials. AS carries considerable short- and long-term disabilities. Anti-TNF-α therapies reduce pain, improve function and decrease inflammation as seen by MRI. New treatment options are being developed which may prove efficacious on those patients not responding to anti-TNF. The ultimate research goal should focus on treatments to prevent and stop new bone formation.

  16. Large-scale prediction of drug-target relationships

    DEFF Research Database (Denmark)

    Kuhn, Michael; Campillos, Mónica; González, Paula

    2008-01-01

    , but also provides a more global view on drug-target relations. Here we review recent attempts to apply large-scale computational analyses to predict novel interactions of drugs and targets from molecular and cellular features. In this context, we quantify the family-dependent probability of two proteins...... to bind the same ligand as function of their sequence similarity. We finally discuss how phenotypic data could help to expand our understanding of the complex mechanisms of drug action....

  17. Magnetic polymer nanospheres for anticancer drug targeting

    International Nuclear Information System (INIS)

    JurIkova, A; Csach, K; Koneracka, M; Zavisova, V; Tomasovicova, N; Lancz, G; Kopcansky, P; Timko, M; Miskuf, J; Muckova, M

    2010-01-01

    Poly(D,L-lactide-co-glycolide) polymer (PLGA) nanospheres loaded with biocom-patible magnetic fluid as a magnetic carrier and anticancer drug Taxol were prepared by the modified nanoprecipitation method with size of 200-250 nm in diameter. The PLGA polymer was utilized as a capsulation material due to its biodegradability and biocompatibility. Taxol as an important anticancer drug was chosen for its significant role against a wide range of tumours. Thermal properties of the drug-polymer system were characterized using thermal analysis methods. It was determined the solubility of Taxol in PLGA nanospheres. Magnetic properties investigated using SQUID magnetometry showed superparamagnetism of the prepared magnetic polymer nanospheres.

  18. Targeted electrohydrodynamic printing for micro-reservoir drug delivery systems

    International Nuclear Information System (INIS)

    Hwang, Tae Heon; Kim, Jin Bum; Yang, Da Som; Ryu, WonHyoung; Park, Yong-il

    2013-01-01

    Microfluidic drug delivery systems consisting of a drug reservoir and microfluidic channels have shown the possibility of simple and robust modulation of drug release rate. However, the difficulty of loading a small quantity of drug into drug reservoirs at a micro-scale limited further development of such systems. Electrohydrodynamic (EHD) printing was employed to fill micro-reservoirs with controlled amount of drugs in the range of a few hundreds of picograms to tens of micrograms with spatial resolution of as small as 20 µm. Unlike most EHD systems, this system was configured in combination with an inverted microscope that allows in situ targeting of drug loading at micrometer scale accuracy. Methylene blue and rhodamine B were used as model drugs in distilled water, isopropanol and a polymer solution of a biodegradable polymer and dimethyl sulfoxide (DMSO). Also tetracycline-HCl/DI water was used as actual drug ink. The optimal parameters of EHD printing to load an extremely small quantity of drug into microscale drug reservoirs were investigated by changing pumping rates, the strength of an electric field and drug concentration. This targeted EHD technique was used to load drugs into the microreservoirs of PDMS microfluidic drug delivery devices and their drug release performance was demonstrated in vitro. (paper)

  19. NCI-MATCH Trial Links Targeted Drugs to Mutations

    Science.gov (United States)

    Investigators for the nationwide trial, NCI-MATCH: Molecular Analysis for Therapy Choice, announced that the trial will seek to determine whether targeted therapies for people whose tumors have specific gene mutations will be effective regardless of their cancer type. NCI-MATCH will incorporate more than 20 different study drugs or drug combinations, each targeting a specific gene mutation, in order to match each patient in the trial with a therapy that targets a molecular abnormality in their tumor.

  20. Drug target mining and analysis of the Chinese tree shrew for pharmacological testing.

    Directory of Open Access Journals (Sweden)

    Feng Zhao

    Full Text Available The discovery of new drugs requires the development of improved animal models for drug testing. The Chinese tree shrew is considered to be a realistic candidate model. To assess the potential of the Chinese tree shrew for pharmacological testing, we performed drug target prediction and analysis on genomic and transcriptomic scales. Using our pipeline, 3,482 proteins were predicted to be drug targets. Of these predicted targets, 446 and 1,049 proteins with the highest rank and total scores, respectively, included homologs of targets for cancer chemotherapy, depression, age-related decline and cardiovascular disease. Based on comparative analyses, more than half of drug target proteins identified from the tree shrew genome were shown to be higher similarity to human targets than in the mouse. Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets. We developed an effective pipeline and search strategy for drug target prediction and the evaluation of model-based target identification for drug testing. This work provides useful information for future studies of the Chinese tree shrew as a source of novel targets for drug discovery research.

  1. SuperTarget and Matador: resources for exploring drug-target relationships.

    Science.gov (United States)

    Günther, Stefan; Kuhn, Michael; Dunkel, Mathias; Campillos, Monica; Senger, Christian; Petsalaki, Evangelia; Ahmed, Jessica; Urdiales, Eduardo Garcia; Gewiess, Andreas; Jensen, Lars Juhl; Schneider, Reinhard; Skoblo, Roman; Russell, Robert B; Bourne, Philip E; Bork, Peer; Preissner, Robert

    2008-01-01

    The molecular basis of drug action is often not well understood. This is partly because the very abundant and diverse information generated in the past decades on drugs is hidden in millions of medical articles or textbooks. Therefore, we developed a one-stop data warehouse, SuperTarget that integrates drug-related information about medical indication areas, adverse drug effects, drug metabolization, pathways and Gene Ontology terms of the target proteins. An easy-to-use query interface enables the user to pose complex queries, for example to find drugs that target a certain pathway, interacting drugs that are metabolized by the same cytochrome P450 or drugs that target the same protein but are metabolized by different enzymes. Furthermore, we provide tools for 2D drug screening and sequence comparison of the targets. The database contains more than 2500 target proteins, which are annotated with about 7300 relations to 1500 drugs; the vast majority of entries have pointers to the respective literature source. A subset of these drugs has been annotated with additional binding information and indirect interactions and is available as a separate resource called Matador. SuperTarget and Matador are available at http://insilico.charite.de/supertarget and http://matador.embl.de.

  2. New Drugs and Treatment Targets in Psoriasis

    DEFF Research Database (Denmark)

    Kofoed, Kristian; Skov, Lone; Zachariae, Claus

    2015-01-01

    , and phosphodiesterase inhibitors. We review published clinical trials, and conference abstracts presented during the last years, concerned with new drugs under development for the treatment of psoriasis. In conclusion, our psoriasis armamentarium will be filled with several new effective therapeutic options the coming...... years. We need to be aware of the limitations of drug safety data when selecting new novel treatments. Monitoring and clinical registries are still important tools....

  3. Predicting the Reliability of Drug-target Interaction Predictions with Maximum Coverage of Target Space.

    Science.gov (United States)

    Peón, Antonio; Naulaerts, Stefan; Ballester, Pedro J

    2017-06-19

    Many computational methods to predict the macromolecular targets of small organic molecules have been presented to date. Despite progress, target prediction methods still have important limitations. For example, the most accurate methods implicitly restrict their predictions to a relatively small number of targets, are not systematically validated on drugs (whose targets are harder to predict than those of non-drug molecules) and often lack a reliability score associated with each predicted target. Here we present a systematic validation of ligand-centric target prediction methods on a set of clinical drugs. These methods exploit a knowledge-base covering 887,435 known ligand-target associations between 504,755 molecules and 4,167 targets. Based on this dataset, we provide a new estimate of the polypharmacology of drugs, which on average have 11.5 targets below IC 50 10 µM. The average performance achieved across clinical drugs is remarkable (0.348 precision and 0.423 recall, with large drug-dependent variability), especially given the unusually large coverage of the target space. Furthermore, we show how a sparse ligand-target bioactivity matrix to retrospectively validate target prediction methods could underestimate prospective performance. Lastly, we present and validate a first-in-kind score capable of accurately predicting the reliability of target predictions.

  4. Orphan nuclear receptors, excellent targets of drug discovery.

    Science.gov (United States)

    Shi, Yanhong

    2006-11-01

    To date, the pharmaceutical industry has placed a considerable amount of interest in the discovery of drug targets and diagnostics. One of the most challenging areas of drug discovery today is the search for novel receptor-ligand pairs. Nuclear receptors comprise a large superfamily of ligand-dependent transcription factors that regulate the expression of genes critical for a variety of biological processes, including development, growth, differentiation, and homeostasis. Orphan nuclear receptors, for which the ligands are not yet identified, represent the most ancient component of the nuclear receptor superfamily. Orphan nuclear receptors not only offer a unique system to uncover novel signaling pathways that impact human health, but also provide excellent targets of drug discoveries for a variety of human diseases. This review highlights advances made on ligand identification for orphan nuclear receptors using transgenic mouse models, cell-based screening, direct binding, structure-based assays, and computer-aided virtual screening. With rapid advances in combinatorial chemistry and high throughput screening, along with other modern technologies, this field promises a bountiful harvest.

  5. Vibrio cholerae infection, novel drug targets and phage therapy.

    Science.gov (United States)

    Fazil, Mobashar Hussain Urf Turabe; Singh, Durg V

    2011-10-01

    Vibrio cholerae is the causative agent of the diarrheal disease cholera. Although antibiotic therapy shortens the duration of diarrhea, excessive use has contributed to the emergence of antibiotic resistance in V. cholerae. Mobile genetic elements have been shown to be largely responsible for the shift of drug resistance genes in bacteria, including some V. cholerae strains. Quorum sensing communication systems are used for interaction among bacteria and for sensing environmental signals. Sequence analysis of the ctxB gene of toxigenic V. cholerae strains demonstrated its presence in multiple cholera toxin genotypes. Moreover, bacteriophage that lyse the bacterium have been reported to modulate epidemics by decreasing the required infectious dose of the bacterium. In this article, we will briefly discuss the disease, its clinical manifestation, antimicrobial resistance and the novel approaches to locate drug targets to treat cholera.

  6. Target-mediated drug disposition with drug-drug interaction, Part I: single drug case in alternative formulations.

    Science.gov (United States)

    Koch, Gilbert; Jusko, William J; Schropp, Johannes

    2017-02-01

    Target-mediated drug disposition (TMDD) describes drug binding with high affinity to a target such as a receptor. In application TMDD models are often over-parameterized and quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are essential to reduce the number of parameters. However, implementation of such approximations becomes difficult for TMDD models with drug-drug interaction (DDI) mechanisms. Hence, alternative but equivalent formulations are necessary for QE or QSS approximations. To introduce and develop such formulations, the single drug case is reanalyzed. This work opens the route for straightforward implementation of QE or QSS approximations of DDI TMDD models. The manuscript is the first part to introduce DDI TMDD models with QE or QSS approximations.

  7. Exploring Drug Targets in Isoprenoid Biosynthetic Pathway for Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Tabish Qidwai

    2014-01-01

    Full Text Available Emergence of rapid drug resistance to existing antimalarial drugs in Plasmodium falciparum has created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.

  8. Biodegradable polymers for targeted delivery of anti-cancer drugs.

    Science.gov (United States)

    Doppalapudi, Sindhu; Jain, Anjali; Domb, Abraham J; Khan, Wahid

    2016-06-01

    Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy. This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered. Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.

  9. Targeted drugs in small-cell lung cancer.

    Science.gov (United States)

    Santarpia, Mariacarmela; Daffinà, Maria Grazia; Karachaliou, Niki; González-Cao, Maria; Lazzari, Chiara; Altavilla, Giuseppe; Rosell, Rafael

    2016-02-01

    In contrast to non-small-cell lung cancer (NSCLC), few advances have been made in systemic treatment of small-cell lung cancer (SCLC) in recent years. Most patients are diagnosed with extensive stage disease and are commonly treated with platinum-based chemotherapy which, although attaining high initial objective responses, has a limited impact on survival. Due to the dismal prognosis of SCLC, novel and more effective treatment strategies are urgently needed. A deeper characterization of the genomic landscape of SCLC has led to the development of rational and promising targeted agents. However, despite a large number of clinical trials, results have been disappointing and there are still no approved targeted drugs for SCLC. Recent comprehensive genomic studies suggest SCLC is a heterogeneous disease, characterized by genomic alterations targeting a broad variety of genes, including those involved in transcription regulation and chromatin modification which seem to be a hallmark of this specific lung cancer subtype. Current research efforts are focusing on further understanding of the cellular and molecular abnormalities underlying SCLC development, progression and resistance to chemotherapy. Unraveling the genomic complexity of SCLC could be the key to optimize existing treatments, including chemotherapy and radiotherapy, and for identifying those patients most likely to benefit from selected targeted therapeutic approaches.

  10. Novel drugs targeting Toll-like receptors for antiviral therapy.

    Science.gov (United States)

    Patel, Mira C; Shirey, Kari Ann; Pletneva, Lioubov M; Boukhvalova, Marina S; Garzino-Demo, Alfredo; Vogel, Stefanie N; Blanco, Jorge Cg

    2014-09-01

    Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved 'pathogen-associated molecular patterns' of invading microbes, including viruses. The activation of TLRs establishes antiviral innate immune responses and coordinates the development of long-lasting adaptive immunity in order to control viral pathogenesis. However, microbe-induced damage to host tissues may release 'danger-associated molecular patterns' that also activate TLRs, leading to an overexuberant inflammatory response and, ultimately, to tissue damage. Thus, TLRs have proven to be promising targets as therapeutics for the treatment of viral infections that result in inflammatory damage or as adjuvants in order to enhance the efficacy of vaccines. Here, we explore recent advances in TLR biology with a focus on novel drugs that target TLRs (agonists and antagonists) for antiviral therapy.

  11. 34 CFR 86.100 - What must the IHE's drug prevention program include?

    Science.gov (United States)

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false What must the IHE's drug prevention program include? 86.100 Section 86.100 Education Office of the Secretary, Department of Education DRUG AND ALCOHOL ABUSE PREVENTION Institutions of Higher Education § 86.100 What must the IHE's drug prevention program include? The IHE's drug prevention program must, a...

  12. loaded, colon-targeted drug delivery system

    African Journals Online (AJOL)

    controlled delivery of 5-flurouracil (5-FU) in cancer patients. Method: Nine different miCAP formulations were prepared ... osmotically-controlled devices, pro-drug systems,. pH-dependent devices, and systems in which the ..... are very useful tools in the investigation of the thermal properties of miCAPs, and they provide.

  13. Target mediated drug disposition with drug-drug interaction, Part II: competitive and uncompetitive cases.

    Science.gov (United States)

    Koch, Gilbert; Jusko, William J; Schropp, Johannes

    2017-02-01

    We present competitive and uncompetitive drug-drug interaction (DDI) with target mediated drug disposition (TMDD) equations and investigate their pharmacokinetic DDI properties. For application of TMDD models, quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are necessary to reduce the number of parameters. To realize those approximations of DDI TMDD models, we derive an ordinary differential equation (ODE) representation formulated in free concentration and free receptor variables. This ODE formulation can be straightforward implemented in typical PKPD software without solving any non-linear equation system arising from the QE or QSS approximation of the rapid binding assumptions. This manuscript is the second in a series to introduce and investigate DDI TMDD models and to apply the QE or QSS approximation.

  14. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .

  15. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

  16. Predicting selective drug targets in cancer through metabolic networks

    Science.gov (United States)

    Folger, Ori; Jerby, Livnat; Frezza, Christian; Gottlieb, Eyal; Ruppin, Eytan; Shlomi, Tomer

    2011-01-01

    The interest in studying metabolic alterations in cancer and their potential role as novel targets for therapy has been rejuvenated in recent years. Here, we report the development of the first genome-scale network model of cancer metabolism, validated by correctly identifying genes essential for cellular proliferation in cancer cell lines. The model predicts 52 cytostatic drug targets, of which 40% are targeted by known, approved or experimental anticancer drugs, and the rest are new. It further predicts combinations of synthetic lethal drug targets, whose synergy is validated using available drug efficacy and gene expression measurements across the NCI-60 cancer cell line collection. Finally, potential selective treatments for specific cancers that depend on cancer type-specific downregulation of gene expression and somatic mutations are compiled. PMID:21694718

  17. Neuroinflammation in Alzheimer's disease: different molecular targets and potential therapeutic agents including curcumin.

    Science.gov (United States)

    Ray, Balmiki; Lahiri, Debomoy K

    2009-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly. Deposition of amyloid beta plaque and associated neuroinflammation are the major hallmarks of AD. Whereas reactive oxygen species (ROS) and activated microglial cells contribute to neuronal loss, nuclear factor kappaB and apolipoprotein E participate in inflammatory process of AD. Current FDA approved drugs provide only symptomatic relief in AD. For broad spectrum of activity, some natural products are also being tested. Turmeric is used as an anti-inflammatory medicine in various regions of Asia. Curcumin, which is a yellow colored polyphenol compound present in turmeric, showed anti-inflammatory properties. Herein, we discuss the neurobiological and neuroinflammatory pathways of AD, evaluate different molecular targets and potential therapeutic agents, including curcumin, for the treatment of AD.

  18. Magnetically responsive microparticles for targeted drug and radionuclide delivery

    International Nuclear Information System (INIS)

    Kaminski, M. D.; Ghebremeskel, A. N.; Nunez, L.; Kasza, K. E.; Chang, F.; Chien, T.-H.; Fisher, P. F.; Eastman, J. A.; Rosengart, A. J.; McDonald, L.; Xie, Y.; Johns, L.; Pytel, P.; Hafeli, U. O.

    2004-01-01

    We are currently investigating the use of magnetic particles--polymeric-based spheres containing dispersed magnetic nanocrystalline phases--for the precise delivery of drugs via the human vasculature. According to this review, meticulously prepared magnetic drug targeting holds promise as a safe and effective method of delivering drugs to specific organ, tissue or cellular targets. We have critically examined the wide range of approaches in the design and implementation of magnetic-particle-based drug delivery systems to date, including magnetic particle preparation, drug encapsulation, biostability, biocompatibility, toxicity, magnetic field designs, and clinical trials. However, we strongly believe that there are several limitations with past developments that need to be addressed to enable significant strides in the field. First, particle size has to be carefully chosen. Micrometer-sized magnetic particles are better attracted over a distance than nanometer sized magnetic particles by a constant magnetic field gradient, and particle sizes up to 1 (micro)m show a much better accumulation with no apparent side effects in small animal models, since the smallest blood vessels have an inner diameter of 5-7 (micro)m. Nanometer-sized particles <70 nm will accumulate in organ fenestrations despite an effective surface stabilizer. To be suitable for future human applications, our experimental approach synthesizes the magnetic drug carrier according to specific predefined outcome metrics: monodisperse population in a size range of 100 nm to 1.0 (micro)m, non-toxic, with appropriate magnetic properties, and demonstrating successful in vitro and in vivo tests. Another important variable offering possible improvement is surface polarity, which is expected to prolong particle half-life in circulation and modify biodistribution and stability of drugs in the body. The molecules in the blood that are responsible for enhancing the uptake of particles by the reticuloendothelial

  19. A Computational Drug Repositioning Approach for Targeting Oncogenic Transcription Factors

    OpenAIRE

    Gayvert, Kaitlyn; Dardenne, Etienne; Cheung, Cynthia; Boland, Mary Regina; Lorberbaum, Tal; Wanjala, Jackline; Chen, Yu; Rubin, Mark; Tatonetti, Nicholas P.; Rickman, David; Elemento, Olivier

    2016-01-01

    Mutations in transcription factors (TFs) genes are frequently observed in tumors, often leading to aberrant transcriptional activity. Unfortunately, TFs are often considered undruggable due to the absence of targetable enzymatic activity. To address this problem, we developed CRAFTT, a Computational drug-Repositioning Approach For Targeting Transcription factor activity. CRAFTT combines ChIP-seq with drug-induced expression profiling to identify small molecules that can specifically perturb T...

  20. Cyclic nucleotide metabolism including nitric oxide and phosphodiesterase-related targets in the lower urinary tract.

    Science.gov (United States)

    Uckert, Stefan; Kuczyk, Markus A

    2011-01-01

    The clinical data on the use of the orally active phosphodiesterase (PDE) type 5 inhibitors sildenafil (VIAGRA™), vardenafil (LEVITRA™), and tadalafil (CIALIS™) for the treatment of male erectile dysfunction have boosted research activities on the physiology and pharmacology of the organs of the lower urinary tract (LUT). This includes both intracellular signal transduction in the prostate, urinary bladder (detrusor), and urethra, as well as central brain and spinal cord pathways controlling the function of the LUT. Such efforts provided the basis for the development of new therapeutic modalities into the management of dysfunctions/ syndromes of the LUT, some of which are already offered to the patients. The pharmacological treatment of the overactive bladder and the so-called benign prostatic syndrome, including LUT symptomatology and bladder outlet obstruction secondary to benign prostatic enlargement, has primarily focused on selective, orally available drugs acting by influencing intracellular regulatory mechanisms. These agents are regarded efficacious, have a fast onset of drug action in the target tissue and an improved effect-to-side-effect ratio. Better understanding of the functional significance of proteins related to cyclic nucleotide-dependent pathways, such as nitric oxide synthase, cytosolic and membrane-bound guanylyl cyclases, PDE isoenzymes and cyclic AMP- and cyclic GMP-binding protein kinases, the relative distribution in tissues of the LUT, and the consequences for urogenital function, seems to be of particular interest in order to identify new or more selective pharmacological approaches to manage disorders of the LUT. The present review focuses on cyclic nucleotide-related targets involved in the control of the function of the bladder, prostate, and urethra and the significance of those proteins in the process of evolving new pharmacological options for the treatment of LUT symptoms secondary to benign prostatic hyperplasia as well as

  1. Synthetic LDL as targeted drug delivery vehicle

    Science.gov (United States)

    Forte, Trudy M [Berkeley, CA; Nikanjam, Mina [Richmond, CA

    2012-08-28

    The present invention provides a synthetic LDL nanoparticle comprising a lipid moiety and a synthetic chimeric peptide so as to be capable of binding the LDL receptor. The synthetic LDL nanoparticle of the present invention is capable of incorporating and targeting therapeutics to cells expressing the LDL receptor for diseases associated with the expression of the LDL receptor such as central nervous system diseases. The invention further provides methods of using such synthetic LDL nanoparticles.

  2. Ex vivo investigation of magnetically targeted drug delivery system

    International Nuclear Information System (INIS)

    Yoshida, Y.; Fukui, S.; Fujimoto, S.; Mishima, F.; Takeda, S.; Izumi, Y.; Ohtani, S.; Fujitani, Y.; Nishijima, S.

    2007-01-01

    In conventional systemic drug delivery the drug is administered by intravenous injection; it then travels to the heart from where it is pumped to all regions of the body. When the drug is aimed at a small target region, this method is extremely inefficient and leads to require much larger doses than those being necessary. In order to overcome this problem a number of targeted drug delivery methods are developed. One of these, magnetically targeted drug delivery system (MT-DDS) will be a promising way, which involves binding a drug to small biocompatible magnetic particles, injecting these into the blood stream and using a high gradient magnetic field to pull them out of suspension in the target region. In the present paper, we describe an ex vivo experimental work. It is also reported that navigation and accumulation test of the magnetic particles in the Y-shaped glass tube was performed in order to examine the threshold of the magnetic force for accumulation. It is found that accumulation of the magnetic particles was succeeded in the blood vessel when a permanent magnet was placed at the vicinity of the blood vessel. This result indicates the feasibility of the magnetically drug targeting in the blood vessel

  3. Drug-Target Interaction Prediction with Graph Regularized Matrix Factorization.

    Science.gov (United States)

    Ezzat, Ali; Zhao, Peilin; Wu, Min; Li, Xiao-Li; Kwoh, Chee-Keong

    2017-01-01

    Experimental determination of drug-target interactions is expensive and time-consuming. Therefore, there is a continuous demand for more accurate predictions of interactions using computational techniques. Algorithms have been devised to infer novel interactions on a global scale where the input to these algorithms is a drug-target network (i.e., a bipartite graph where edges connect pairs of drugs and targets that are known to interact). However, these algorithms had difficulty predicting interactions involving new drugs or targets for which there are no known interactions (i.e., "orphan" nodes in the network). Since data usually lie on or near to low-dimensional non-linear manifolds, we propose two matrix factorization methods that use graph regularization in order to learn such manifolds. In addition, considering that many of the non-occurring edges in the network are actually unknown or missing cases, we developed a preprocessing step to enhance predictions in the "new drug" and "new target" cases by adding edges with intermediate interaction likelihood scores. In our cross validation experiments, our methods achieved better results than three other state-of-the-art methods in most cases. Finally, we simulated some "new drug" and "new target" cases and found that GRMF predicted the left-out interactions reasonably well.

  4. Nanoparticle functionalization for brain targeting drug delivery and diagnostic

    DEFF Research Database (Denmark)

    Gomes, Maria João; Mendes, Bárbara; Martins, Susana

    2016-01-01

    carriers to cross the BBB and achieve brain, and their functionalization strategies are described; and finally the delivery of nanoparticles to the target moiety, as diagnostics or therapeutics. Therefore, this chapter is focused on how the nanoparticle surface may be functionalized for drug delivery......-mediated drug transport across the BBB, where nanoparticles take advantage of physiological receptor-mediated transport processes....

  5. Targeted drug delivery to magnetic implants for therapeutic applications

    International Nuclear Information System (INIS)

    Yellen, Benjamin B.; Forbes, Zachary G.; Halverson, Derek S.; Fridman, Gregory; Barbee, Kenneth A.; Chorny, Michael; Levy, Robert; Friedman, Gary

    2005-01-01

    A new method for locally targeted drug delivery is proposed that employs magnetic implants placed directly in the cardiovascular system to attract injected magnetic carriers. Theoretical simulations and experimental results support the assumption that using magnetic implants in combination with externally applied magnetic field will optimize the delivery of magnetic drug to selected sites within a subject

  6. Prediction of drug-target interactions for drug repositioning only based on genomic expression similarity.

    Directory of Open Access Journals (Sweden)

    Kejian Wang

    Full Text Available Small drug molecules usually bind to multiple protein targets or even unintended off-targets. Such drug promiscuity has often led to unwanted or unexplained drug reactions, resulting in side effects or drug repositioning opportunities. So it is always an important issue in pharmacology to identify potential drug-target interactions (DTI. However, DTI discovery by experiment remains a challenging task, due to high expense of time and resources. Many computational methods are therefore developed to predict DTI with high throughput biological and clinical data. Here, we initiatively demonstrate that the on-target and off-target effects could be characterized by drug-induced in vitro genomic expression changes, e.g. the data in Connectivity Map (CMap. Thus, unknown ligands of a certain target can be found from the compounds showing high gene-expression similarity to the known ligands. Then to clarify the detailed practice of CMap based DTI prediction, we objectively evaluate how well each target is characterized by CMap. The results suggest that (1 some targets are better characterized than others, so the prediction models specific to these well characterized targets would be more accurate and reliable; (2 in some cases, a family of ligands for the same target tend to interact with common off-targets, which may help increase the efficiency of DTI discovery and explain the mechanisms of complicated drug actions. In the present study, CMap expression similarity is proposed as a novel indicator of drug-target interactions. The detailed strategies of improving data quality by decreasing the batch effect and building prediction models are also effectively established. We believe the success in CMap can be further translated into other public and commercial data of genomic expression, thus increasing research productivity towards valid drug repositioning and minimal side effects.

  7. Glial cells as drug targets: What does it take?

    Science.gov (United States)

    Möller, Thomas; Boddeke, Hendrikus W G M

    2016-10-01

    The last two decades have brought a significant increase in our understanding of glial biology and glial contribution to CNS disease. Yet, despite the fact that glial cells make up the majority of CNS cells, no drug specifically targeting glial cells is on the market. Given the long development times of CNS drugs, on average over 12 years, this is not completely surprising. However, there is increasing interest from academia and industry to exploit glial targets to develop drugs for the benefit of patients with currently limited or no therapeutic options. CNS drug development has a high attrition rate and has encountered many challenges. It seems unlikely that developing drugs against glial targets would be any less demanding. However, the knowledge generated in traditional CNS drug discovery teaches valuable lessons, which could enable the glial community to accelerate the cycle time from basic discovery to drug development. In this review we will discuss steps necessary to bring a "glial target idea" to a clinical development program. GLIA 2016;64:1742-1754. © 2016 Wiley Periodicals, Inc.

  8. A Computational Drug Repositioning Approach for Targeting Oncogenic Transcription Factors

    Directory of Open Access Journals (Sweden)

    Kaitlyn M. Gayvert

    2016-06-01

    Full Text Available Mutations in transcription factor (TF genes are frequently observed in tumors, often leading to aberrant transcriptional activity. Unfortunately, TFs are often considered undruggable due to the absence of targetable enzymatic activity. To address this problem, we developed CRAFTT, a computational drug-repositioning approach for targeting TF activity. CRAFTT combines ChIP-seq with drug-induced expression profiling to identify small molecules that can specifically perturb TF activity. Application to ENCODE ChIP-seq datasets revealed known drug-TF interactions, and a global drug-protein network analysis supported these predictions. Application of CRAFTT to ERG, a pro-invasive, frequently overexpressed oncogenic TF, predicted that dexamethasone would inhibit ERG activity. Dexamethasone significantly decreased cell invasion and migration in an ERG-dependent manner. Furthermore, analysis of electronic medical record data indicates a protective role for dexamethasone against prostate cancer. Altogether, our method provides a broadly applicable strategy for identifying drugs that specifically modulate TF activity.

  9. Di/tri-peptide transporters as drug delivery targets

    DEFF Research Database (Denmark)

    Nielsen, C U; Brodin, Birger

    2003-01-01

    , and the transporters thus belong to the Proton-dependent Oligopeptide Transporter (POT)-family. The transporters are not drug targets per se, however due to their uniquely broad substrate specificity; they have proved to be relevant drug targets at the level of drug transport. Drug molecules such as oral active beta......Two human di/tri-peptide transporters, hPepT1 and hPepT2 have been identified and functionally characterized. In the small intestine hPepT1 is exclusively expressed, whereas both PepT1 and PepT2 are expressed in the proximal tubule. The transport via di/tri-peptide transporters is proton-dependent....../tri-peptide transporters from vesicular storages 3) changes in gene transcription/mRNA stability. The aim of the present review is to discuss physiological, patho-physiological and drug-induced regulation of di/tri-peptide transporter mediated transport....

  10. Nanostructured materials for selective recognition and targeted drug delivery

    International Nuclear Information System (INIS)

    Kotrotsiou, O; Kotti, K; Dini, E; Kammona, O; Kiparissides, C

    2005-01-01

    Selective recognition requires the introduction of a molecular memory into a polymer matrix in order to make it capable of rebinding an analyte with a very high specificity. In addition, targeted drug delivery requires drug-loaded vesicles which preferentially localize to the sites of injury and avoid uptake into uninvolved tissues. The rapid evolution of nanotechnology is aiming to fulfill the goal of selective recognition and optimal drug delivery through the development of molecularly imprinted polymeric (MIP) nanoparticles, tailor-made for a diverse range of analytes (e.g., pharmaceuticals, pesticides, amino acids, etc.) and of nanostructured targeted drug carriers (e.g., liposomes and micelles) with increased circulation lifetimes. In the present study, PLGA microparticles containing multilamellar vesicles (MLVs), and MIP nanoparticles were synthesized to be employed as drug carriers and synthetic receptors respectively

  11. In silico structure-based approaches to discover protein-protein interaction-targeting drugs.

    Science.gov (United States)

    Shin, Woong-Hee; Christoffer, Charles W; Kihara, Daisuke

    2017-12-01

    A core concept behind modern drug discovery is finding a small molecule that modulates a function of a target protein. This concept has been successfully applied since the mid-1970s. However, the efficiency of drug discovery is decreasing because the druggable target space in the human proteome is limited. Recently, protein-protein interaction (PPI) has been identified asan emerging target space for drug discovery. PPI plays a pivotal role in biological pathways including diseases. Current human interactome research suggests that the number of PPIs is between 130,000 and 650,000, and only a small number of them have been targeted as drug targets. For traditional drug targets, in silico structure-based methods have been successful in many cases. However, their performance suffers on PPI interfaces because PPI interfaces are different in five major aspects: From a geometric standpoint, they have relatively large interface regions, flat geometry, and the interface surface shape tends to fluctuate upon binding. Also, their interactions are dominated by hydrophobic atoms, which is different from traditional binding-pocket-targeted drugs. Finally, PPI targets usually lack natural molecules that bind to the target PPI interface. Here, we first summarize characteristics of PPI interfaces and their known binders. Then, we will review existing in silico structure-based approaches for discovering small molecules that bind to PPI interfaces. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Drug treatment and novel drug target against Cryptosporidium

    Directory of Open Access Journals (Sweden)

    Gargala G.

    2008-09-01

    Full Text Available Cryptosporidiosis emergence triggered the screening of many compounds for potential anti-cryptosporidial activity in which the majority were ineffective. The outbreak of cryptosporidiosis which occurred in Milwaukee in 1993 was not only the first significant emergence of Cryptosporidium spp. as a major human pathogen but also a huge waterborne outbreak thickening thousands of people from a major city in North America. Since then, outbreaks of cryptosporidiosis are regularly occurring throughout the world. New drugs against this parasite became consequently urgently needed. Among the most commonly used treatments against cryptosporidiosis are paromomycin, and azithromycin, which are partially effective. Nitazoxanide (NTZ’s effectiveness was demonstrated in vitro, and in vivo using several animal models and finally in clinical trials. It significantly shortened the duration of diarrhea and decreased mortality in adults and in malnourished children. NTZ is not effective without an appropriate immune response. In AIDS patients, combination therapy restoring immunity along with antimicrobial treatment of Cryptosporidium infection is necessary. Recent investigations focused on the potential of molecular-based immunotherapy against this parasite. Others tested the effects of probiotic bacteria, but were unable to demonstrate eradication of C. parvum. New synthetic isoflavone derivatives demonstrated excellent activity against C. parvum in vitro and in a gerbil model of infection. Newly synthesized nitroor non nitro- thiazolide compounds, derived from NTZ, have been recently shown to be at least as effective as NTZ against C. parvum in vitro development and are promising new therapeutic agents.

  13. Drug-target interaction prediction from PSSM based evolutionary information.

    Science.gov (United States)

    Mousavian, Zaynab; Khakabimamaghani, Sahand; Kavousi, Kaveh; Masoudi-Nejad, Ali

    2016-01-01

    The labor-intensive and expensive experimental process of drug-target interaction prediction has motivated many researchers to focus on in silico prediction, which leads to the helpful information in supporting the experimental interaction data. Therefore, they have proposed several computational approaches for discovering new drug-target interactions. Several learning-based methods have been increasingly developed which can be categorized into two main groups: similarity-based and feature-based. In this paper, we firstly use the bi-gram features extracted from the Position Specific Scoring Matrix (PSSM) of proteins in predicting drug-target interactions. Our results demonstrate the high-confidence prediction ability of the Bigram-PSSM model in terms of several performance indicators specifically for enzymes and ion channels. Moreover, we investigate the impact of negative selection strategy on the performance of the prediction, which is not widely taken into account in the other relevant studies. This is important, as the number of non-interacting drug-target pairs are usually extremely large in comparison with the number of interacting ones in existing drug-target interaction data. An interesting observation is that different levels of performance reduction have been attained for four datasets when we change the sampling method from the random sampling to the balanced sampling. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Orexin Receptor Targets for Anti-Relapse Medication Development in Drug Addiction

    Directory of Open Access Journals (Sweden)

    Ronald E. See

    2011-06-01

    Full Text Available Drug addiction is a chronic illness characterized by high rates of relapse. Relapse to drug use can be triggered by re-exposure to drug-associated cues, stressful events, or the drug itself after a period of abstinence. Pharmacological intervention to reduce the impact of relapse-instigating factors offers a promising target for addiction treatment. Growing evidence has implicated an important role of the orexin/hypocretin system in drug reward and drug-seeking, including animal models of relapse. Here, we review the evidence for the role of orexins in modulating reward and drug-seeking in animal models of addiction and the potential for orexin receptors as specific targets for anti-relapse medication approaches.

  15. Carrier-free, functionalized pure drug nanorods as a novel cancer-targeted drug delivery platform

    Science.gov (United States)

    Li, Yanan; Yang, Yinlong; An, Feifei; Liu, Zhuang; Zhang, Xiujuan; Zhang, Xiaohong

    2013-01-01

    A one-dimensional drug delivery system (1D DDS) is highly attractive since it has distinct advantages such as enhanced drug efficiency and better pharmacokinetics. However, drugs in 1D DDSs are all encapsulated in inert carriers, and problems such as low drug loading content and possible undesirable side effects caused by the carriers remain a serious challenge. In this paper, a novel, carrier-free, pure drug nanorod-based, tumor-targeted 1D DDS has been developed. Drugs are first prepared as nanorods and then surface functionalized to achieve excellent water dispersity and stability. The resulting drug nanorods show enhanced internalization rates mainly through energy-dependent endocytosis, with the shape-mediated nanorod (NR) diffusion process as a secondary pathway. The multiple endocytotic mechanisms lead to significantly improved drug efficiency of functionalized NRs with nearly ten times higher cytotoxicity than those of free molecules and unfunctionalized NRs. A targeted drug delivery system can be readily achieved through surface functionalization with targeting group linked amphipathic surfactant, which exhibits significantly enhanced drug efficacy and discriminates between cell lines with high selectivity. These results clearly show that this tumor-targeting DDS demonstrates high potential toward specific cancer cell lines.

  16. Carrier-free, functionalized pure drug nanorods as a novel cancer-targeted drug delivery platform

    International Nuclear Information System (INIS)

    Li Yanan; An Feifei; Zhang Xiaohong; Yang Yinlong; Liu Zhuang; Zhang Xiujuan

    2013-01-01

    A one-dimensional drug delivery system (1D DDS) is highly attractive since it has distinct advantages such as enhanced drug efficiency and better pharmacokinetics. However, drugs in 1D DDSs are all encapsulated in inert carriers, and problems such as low drug loading content and possible undesirable side effects caused by the carriers remain a serious challenge. In this paper, a novel, carrier-free, pure drug nanorod-based, tumor-targeted 1D DDS has been developed. Drugs are first prepared as nanorods and then surface functionalized to achieve excellent water dispersity and stability. The resulting drug nanorods show enhanced internalization rates mainly through energy-dependent endocytosis, with the shape-mediated nanorod (NR) diffusion process as a secondary pathway. The multiple endocytotic mechanisms lead to significantly improved drug efficiency of functionalized NRs with nearly ten times higher cytotoxicity than those of free molecules and unfunctionalized NRs. A targeted drug delivery system can be readily achieved through surface functionalization with targeting group linked amphipathic surfactant, which exhibits significantly enhanced drug efficacy and discriminates between cell lines with high selectivity. These results clearly show that this tumor-targeting DDS demonstrates high potential toward specific cancer cell lines. (paper)

  17. Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition.

    Science.gov (United States)

    Raja, Srikumar M; Desale, Swapnil S; Mohapatra, Bhopal; Luan, Haitao; Soni, Kruti; Zhang, Jinjin; Storck, Matthew A; Feng, Dan; Bielecki, Timothy A; Band, Vimla; Cohen, Samuel M; Bronich, Tatiana K; Band, Hamid

    2016-03-01

    Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance receptor

  18. Ribosomal targets for antibiotic drug discovery

    Energy Technology Data Exchange (ETDEWEB)

    Blanchard, Scott C.; Feldman, Michael Brian; Wang, Leyi; Doudna Cate, James H.; Pulk, Arto; Altman, Roger B.; Wasserman, Michael R

    2016-09-13

    The present invention relates to methods to identify molecules that binds in the neomycin binding pocket of a bacterial ribosome using structures of an intact bacterial ribosome that reveal how the ribosome binds tRNA in two functionally distinct states, determined by x-ray crystallography. One state positions tRNA in the peptidyl-tRNA binding site. The second, a fully rotated state, is stabilized by ribosome recycling factor (RRF) and binds tRNA in a highly bent conformation in a hybrid peptidyl/exit (P/E) site. Additionally, the invention relates to various assays, including single-molecule assay for ribosome recycling, and methods to identify compounds that interfere with ribosomal function by detecting newly identified intermediate FRET states using known and novel FRET pairs on the ribosome. The invention also provides vectors and compositions with an N-terminally tagged S13 protein.

  19. Large-scale prediction of drug-target interactions using protein sequences and drug topological structures

    Energy Technology Data Exchange (ETDEWEB)

    Cao Dongsheng [Research Center of Modernization of Traditional Chinese Medicines, Central South University, Changsha 410083 (China); Liu Shao [Xiangya Hospital, Central South University, Changsha 410008 (China); Xu Qingsong [School of Mathematical Sciences and Computing Technology, Central South University, Changsha 410083 (China); Lu Hongmei; Huang Jianhua [Research Center of Modernization of Traditional Chinese Medicines, Central South University, Changsha 410083 (China); Hu Qiannan [Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, and Wuhan University School of Pharmaceutical Sciences, Wuhan 430071 (China); Liang Yizeng, E-mail: yizeng_liang@263.net [Research Center of Modernization of Traditional Chinese Medicines, Central South University, Changsha 410083 (China)

    2012-11-08

    Highlights: Black-Right-Pointing-Pointer Drug-target interactions are predicted using an extended SAR methodology. Black-Right-Pointing-Pointer A drug-target interaction is regarded as an event triggered by many factors. Black-Right-Pointing-Pointer Molecular fingerprint and CTD descriptors are used to represent drugs and proteins. Black-Right-Pointing-Pointer Our approach shows compatibility between the new scheme and current SAR methodology. - Abstract: The identification of interactions between drugs and target proteins plays a key role in the process of genomic drug discovery. It is both consuming and costly to determine drug-target interactions by experiments alone. Therefore, there is an urgent need to develop new in silico prediction approaches capable of identifying these potential drug-target interactions in a timely manner. In this article, we aim at extending current structure-activity relationship (SAR) methodology to fulfill such requirements. In some sense, a drug-target interaction can be regarded as an event or property triggered by many influence factors from drugs and target proteins. Thus, each interaction pair can be represented theoretically by using these factors which are based on the structural and physicochemical properties simultaneously from drugs and proteins. To realize this, drug molecules are encoded with MACCS substructure fingerings representing existence of certain functional groups or fragments; and proteins are encoded with some biochemical and physicochemical properties. Four classes of drug-target interaction networks in humans involving enzymes, ion channels, G-protein-coupled receptors (GPCRs) and nuclear receptors, are independently used for establishing predictive models with support vector machines (SVMs). The SVM models gave prediction accuracy of 90.31%, 88.91%, 84.68% and 83.74% for four datasets, respectively. In conclusion, the results demonstrate the ability of our proposed method to predict the drug-target

  20. Novel Drugs that Target ErbB2

    Science.gov (United States)

    2012-05-01

    drugs including curcumin , arsenic trioxide, non-steroidal anti-inflammatory drugs, and triterpenoids such as celastrol, 2-cyano-1,12-dioxooleana-1,9...and tumors. These include curcumin , arsenic trioxide, tolfenamic acid and structurally related nonsteroidal anti-inflammatory drugs, BA, and...Jutooru I, Chintharlapalli S, Papineni S, Smith R, 3rd, Li X, et al. Curcumin decreases specificity protein expression in bladder cancer cells

  1. Targeting DNA repair systems in antitubercular drug development.

    Science.gov (United States)

    Minias, Alina; Brzostek, Anna; Dziadek, Jaroslaw

    2018-01-28

    Infections with Mycobacterium tuberculosis, the causative agent of tuberculosis, are difficult to treat using currently available chemotherapeutics. Clinicians agree on the urgent need for novel drugs to treat tuberculosis. In this mini review, we summarize data that prompts the consideration of DNA repair-associated proteins as targets for the development of new antitubercular compounds. We discuss data, including gene expression data, that highlight the importance of DNA repair genes during the pathogenic cycle as well as after exposure to antimicrobials currently in use. Specifically, we report experiments on determining the essentiality of DNA repair-related genes. We report the availability of protein crystal structures and summarize discovered protein inhibitors. Further, we describe phenotypes of available gene mutants of M. tuberculosis and model organisms Mycobacterium bovis and Mycobacterium smegmatis. We summarize experiments regarding the role of DNA repair-related proteins in pathogenesis and virulence performed both in vitro and in vivo during the infection of macrophages and animals. We detail the role of DNA repair genes in acquiring mutations, which influence the rate of drug resistance acquisition. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. Multifunctional Nanoparticles for Drug Delivery Applications Imaging, Targeting, and Delivery

    CERN Document Server

    Prud'homme, Robert

    2012-01-01

    This book clearly demonstrates the progression of nanoparticle therapeutics from basic research to applications. Unlike other books covering nanoparticles used in medical applications, Multifunctional Nanoparticles for Drug Delivery Applications presents the medical challenges that can be reduced or even overcome by recent advances in nanoscale drug delivery. Each chapter highlights recent progress in the design and engineering of select multifunctional nanoparticles with topics covering targeting, imaging, delivery, diagnostics, and therapy.

  3. An efficient targeted drug delivery through apotransferrin loaded nanoparticles.

    Science.gov (United States)

    Krishna, Athuluri Divakar Sai; Mandraju, Raj Kumar; Kishore, Golla; Kondapi, Anand Kumar

    2009-10-02

    Cancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin. Apotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano) have diameters of 25-50 etam, which increase to 60-80 etam upon direct loading of drug (direct-nano), and showed further increase in dimension (75-95 etam) in conjugated nanoparticles (conj-nano). The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a) localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus) (b) pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c) the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in regression of hepatocellular carcinoma with negligible

  4. Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics

    Science.gov (United States)

    2014-01-01

    Background The demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. Results We use this approach to prioritize genes as drug target candidates in a set of ER + breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER + breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process. Conclusions Influence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use. PMID:24495353

  5. Current drug treatments targeting dopamine D3 receptor.

    Science.gov (United States)

    Leggio, Gian Marco; Bucolo, Claudio; Platania, Chiara Bianca Maria; Salomone, Salvatore; Drago, Filippo

    2016-09-01

    Dopamine receptors (DR) have been extensively studied, but only in recent years they became object of investigation to elucidate the specific role of different subtypes (D1R, D2R, D3R, D4R, D5R) in neural transmission and circuitry. D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D2R and D4R) differ in signal transduction, binding profile, localization in the central nervous system and physiological effects. D3R is involved in a number of pathological conditions, including schizophrenia, Parkinson's disease, addiction, anxiety, depression and glaucoma. Development of selective D3R ligands has been so far challenging, due to the high sequence identity and homology shared by D2R and D3R. As a consequence, despite a rational design of selective DR ligands has been carried out, none of currently available medicines selectively target a given D2-like receptor subtype. The availability of the D3R ligand [(11)C]-(+)-PHNO for positron emission tomography studies in animal models as well as in humans, allows researchers to estimate the expression of D3R in vivo; displacement of [(11)C]-(+)-PHNO binding by concurrent drug treatments is used to estimate the in vivo occupancy of D3R. Here we provide an overview of studies indicating D3R as a target for pharmacological therapy, and a review of market approved drugs endowed with significant affinity at D3R that are used to treat disorders where D3R plays a relevant role. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Identifying problematic drugs based on the characteristics of their targets.

    Science.gov (United States)

    Lopes, Tiago J S; Shoemaker, Jason E; Matsuoka, Yukiko; Kawaoka, Yoshihiro; Kitano, Hiroaki

    2015-01-01

    Identifying promising compounds during the early stages of drug development is a major challenge for both academia and the pharmaceutical industry. The difficulties are even more pronounced when we consider multi-target pharmacology, where the compounds often target more than one protein, or multiple compounds are used together. Here, we address this problem by using machine learning and network analysis to process sequence and interaction data from human proteins to identify promising compounds. We used this strategy to identify properties that make certain proteins more likely to cause harmful effects when targeted; such proteins usually have domains commonly found throughout the human proteome. Additionally, since currently marketed drugs hit multiple targets simultaneously, we combined the information from individual proteins to devise a score that quantifies the likelihood of a compound being harmful to humans. This approach enabled us to distinguish between approved and problematic drugs with an accuracy of 60-70%. Moreover, our approach can be applied as soon as candidate drugs are available, as demonstrated with predictions for more than 5000 experimental drugs. These resources are available at http://sourceforge.net/projects/psin/.

  7. Identifying problematic drugs based on the characteristics of their targets

    Directory of Open Access Journals (Sweden)

    Tiago Jose eDa Silva Lopes

    2015-09-01

    Full Text Available Identifying promising compounds during the early stages of drug development is a major challenge for both academia and the pharmaceutical industry. The difficulties are even more pronounced when we consider multi-target pharmacology, where the compounds often target more than one protein, or multiple compounds are used together. Here, we address this problem by using machine learning and network analysis to process sequence and interaction data from human proteins to identify promising compounds. We used this strategy to identify properties that make certain proteins more likely to cause harmful effects when targeted; such proteins usually have domains commonly found throughout the human proteome. Additionally, since currently marketed drugs hit multiple targets simultaneously, we combined the information from individual proteins to devise a score that quantifies the likelihood of a compound being harmful to humans. This approach enabled us to distinguish between approved and problematic drugs with an accuracy of 60%¬–70%. Moreover, our approach can be applied as soon as candidate drugs are available, as demonstrated with predictions for more than 5000 experimental drugs. These resources are available at http://sourceforge.net/projects/psin/.

  8. The concept of focused magnet for targeted drug delivery

    International Nuclear Information System (INIS)

    Kopcansky, P.; Timko, M.; Hnatic, M.; Vala, M.; Arzumanyan, G.M.; Ajryan, E.A.; Jancurova, L.; Jadlovsky, J.; Chovanak, J.

    2009-01-01

    A special focused magnet, designed for the use in the magnetic targeted drug delivery system, was constructed. The theoretical calculation of the adhesion condition for a magnetic fluid drop in magnetic field with obtained design showed that the constructed focused magnet generates a sufficient magnetic force for the capture of a magnetic drop on the vessel wall and can be used 2.5-3 cm deeper in an organism compared with the prism permanent magnet which could enable the non-invasivity of the magnetic drug targeting procedure. The maximal values for the magnetic field and gradient of the magnetic field are 0.38 T and 101 T/m

  9. Multifunctional Bacteria-Driven Microswimmers for Targeted Active Drug Delivery.

    Science.gov (United States)

    Park, Byung-Wook; Zhuang, Jiang; Yasa, Oncay; Sitti, Metin

    2017-09-26

    High-performance, multifunctional bacteria-driven microswimmers are introduced using an optimized design and fabrication method for targeted drug delivery applications. These microswimmers are made of mostly single Escherichia coli bacterium attached to the surface of drug-loaded polyelectrolyte multilayer (PEM) microparticles with embedded magnetic nanoparticles. The PEM drug carriers are 1 μm in diameter and are intentionally fabricated with a more viscoelastic material than the particles previously studied in the literature. The resulting stochastic microswimmers are able to swim at mean speeds of up to 22.5 μm/s. They can be guided and targeted to specific cells, because they exhibit biased and directional motion under a chemoattractant gradient and a magnetic field, respectively. Moreover, we demonstrate the microswimmers delivering doxorubicin anticancer drug molecules, encapsulated in the polyelectrolyte multilayers, to 4T1 breast cancer cells under magnetic guidance in vitro. The results reveal the feasibility of using these active multifunctional bacteria-driven microswimmers to perform targeted drug delivery with significantly enhanced drug transfer, when compared with the passive PEM microparticles.

  10. Targeted and non-targeted drug screening in whole blood by UHPLC-TOF-MS with data-independent acquisition

    DEFF Research Database (Denmark)

    Mollerup, Christian Brinch; Dalsgaard, Petur Weihe; Mardal, Marie

    2017-01-01

    of peaks to inspect by three orders of magnitude, down to four peaks per DUID sample. The screening allowed for tentative identification of metabolites and drugs not included in the initial screening, and three drugs and thirteen metabolites were tentatively identified in the authentic DUID samples......High-resolution mass spectrometry (HRMS) is widely used for the drug screening of biological samples in clinical and forensic laboratories. With the continuous addition of new psychoactive substances (NPS), keeping such methods updated is challenging. HRMS allows for combined targeted and non......-targeted screening; first, peaks are identified by software algorithms, and identifications are based on reference standard data. Remaining unknown peaks are attempted identified with in silico and literature data. However, several thousand peaks remain where most are unidentifiable or uninteresting in drug...

  11. PDTD: a web-accessible protein database for drug target identification

    Directory of Open Access Journals (Sweden)

    Gao Zhenting

    2008-02-01

    Full Text Available Abstract Background Target identification is important for modern drug discovery. With the advances in the development of molecular docking, potential binding proteins may be discovered by docking a small molecule to a repository of proteins with three-dimensional (3D structures. To complete this task, a reverse docking program and a drug target database with 3D structures are necessary. To this end, we have developed a web server tool, TarFisDock (Target Fishing Docking http://www.dddc.ac.cn/tarfisdock, which has been used widely by others. Recently, we have constructed a protein target database, Potential Drug Target Database (PDTD, and have integrated PDTD with TarFisDock. This combination aims to assist target identification and validation. Description PDTD is a web-accessible protein database for in silico target identification. It currently contains >1100 protein entries with 3D structures presented in the Protein Data Bank. The data are extracted from the literatures and several online databases such as TTD, DrugBank and Thomson Pharma. The database covers diverse information of >830 known or potential drug targets, including protein and active sites structures in both PDB and mol2 formats, related diseases, biological functions as well as associated regulating (signaling pathways. Each target is categorized by both nosology and biochemical function. PDTD supports keyword search function, such as PDB ID, target name, and disease name. Data set generated by PDTD can be viewed with the plug-in of molecular visualization tools and also can be downloaded freely. Remarkably, PDTD is specially designed for target identification. In conjunction with TarFisDock, PDTD can be used to identify binding proteins for small molecules. The results can be downloaded in the form of mol2 file with the binding pose of the probe compound and a list of potential binding targets according to their ranking scores. Conclusion PDTD serves as a comprehensive and

  12. Leptin signaling molecular actions and drug target in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Jiang N

    2014-11-01

    Full Text Available Nan Jiang,1,* Rongtong Sun,2,* Qing Sun3 1Shandong University School of Medicine, Jinan, Shandong Province, People’s Republic of China; 2Weihai Municipal Hospital, Weihai, Shandong Province, People’s Republic of China; 3Department of Pathology, QianFoShan Hospital Affiliated to Shandong University, Jinan, Shandong Province, People’s Republic of China *These authors contributed equally to this work Abstract: Previous reports indicate that over 13 different tumors, including hepatocellular carcinoma (HCC, are related to obesity. Obesity-associated inflammatory, metabolic, and endocrine mediators, as well as the functioning of the gut microbiota, are suspected to contribute to tumorigenesis. In obese people, proinflammatory cytokines/chemokines including tumor necrosis factor-alpha, interleukin (IL-1 and IL-6, insulin and insulin-like growth factors, adipokines, plasminogen activator inhibitor-1, adiponectin, and leptin are found to play crucial roles in the initiation and development of cancer. The cytokines induced by leptin in adipose tissue or tumor cells have been intensely studied. Leptin-induced signaling pathways are critical for biological functions such as adiposity, energy balance, endocrine function, immune reaction, and angiogenesis as well as oncogenesis. Leptin is an activator of cell proliferation and anti-apoptosis in several cell types, and an inducer of cancer stem cells; its critical roles in tumorigenesis are based on its oncogenic, mitogenic, proinflammatory, and pro-angiogenic actions. This review provides an update of the pathological effects of leptin signaling with special emphasis on potential molecular mechanisms and therapeutic targeting, which could potentially be used in future clinical settings. In addition, leptin-induced angiogenic ability and molecular mechanisms in HCC are discussed. The stringent binding affinity of leptin and its receptor Ob-R, as well as the highly upregulated expression of both

  13. Leveraging big data to transform target selection and drug discovery.

    Science.gov (United States)

    Chen, B; Butte, A J

    2016-03-01

    The advances of genomics, sequencing, and high throughput technologies have led to the creation of large volumes of diverse datasets for drug discovery. Analyzing these datasets to better understand disease and discover new drugs is becoming more common. Recent open data initiatives in basic and clinical research have dramatically increased the types of data available to the public. The past few years have witnessed successful use of big data in many sectors across the whole drug discovery pipeline. In this review, we will highlight the state of the art in leveraging big data to identify new targets, drug indications, and drug response biomarkers in this era of precision medicine. © 2015 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  14. Potential of magnetic nanoparticles for targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Yang HW

    2012-08-01

    Full Text Available Hung-Wei Yang,1,2 Mu-Yi Hua,1 Hao-Li Liu,3 Chiung-Yin Huang,2 Kuo-Chen Wei21Molecular Medicine Research Center, Department of Chemical and Materials Engineering, Chang Gung University, 2Department of Neurosurgery, Chang Gung University and Memorial Hospital, 3Department of Electrical Engineering, Chang Gung University, Taoyuan, TaiwanAbstract: Nanoparticles (NPs play an important role in the molecular diagnosis, treatment, and monitoring of therapeutic outcomes in various diseases. Their nanoscale size, large surface area, unique capabilities, and negligible side effects make NPs highly effective for biomedical applications such as cancer therapy, thrombolysis, and molecular imaging. In particular, nontoxic superparamagnetic magnetic NPs (MNPs with functionalized surface coatings can conjugate chemotherapeutic drugs or be used to target ligands/proteins, making them useful for drug delivery, targeted therapy, magnetic resonance imaging, transfection, and cell/protein/DNA separation. To optimize the therapeutic efficacy of MNPs for a specific application, three issues must be addressed. First, the efficacy of magnetic targeting/guidance is dependent on particle magnetization, which can be controlled by adjusting the reaction conditions during synthesis. Second, the tendency of MNPs to aggregate limits their therapeutic use in vivo; surface modifications to produce high positive or negative charges can reduce this tendency. Finally, the surface of MNPs can be coated with drugs which can be rapidly released after injection, resulting in targeting of low doses of the drug. Drugs therefore need to be conjugated to MNPs such that their release is delayed and their thermal stability enhanced. This chapter describes the creation of nanocarriers with a high drug-loading capacity comprised of a high-magnetization MNP core and a shell of aqueous, stable, conducting polyaniline derivatives and their applications in cancer therapy. It further summarizes some

  15. GPCR homomers and heteromers: a better choice as targets for drug development than GPCR monomers?

    Science.gov (United States)

    Casadó, Vicent; Cortés, Antoni; Mallol, Josefa; Pérez-Capote, Kamil; Ferré, Sergi; Lluis, Carmen; Franco, Rafael; Canela, Enric I

    2009-11-01

    G protein-coupled receptors (GPCR) are targeted by many therapeutic drugs marketed to fight against a variety of diseases. Selection of novel lead compounds are based on pharmacological parameters obtained assuming that GPCR are monomers. However, many GPCR are expressed as dimers/oligomers. Therefore, drug development may consider GPCR as homo- and hetero-oligomers. A two-state dimer receptor model is now available to understand GPCR operation and to interpret data obtained from drugs interacting with dimers, and even from mixtures of monomers and dimers. Heteromers are distinct entities and therefore a given drug is expected to have different affinities and different efficacies depending on the heteromer. All these concepts would lead to broaden the therapeutic potential of drugs targeting GPCRs, including receptor heteromer-selective drugs with a lower incidence of side effects, or to identify novel pharmacological profiles using cell models expressing receptor heteromers.

  16. Prediction of Drug-Target Interactions and Drug Repositioning via Network-Based Inference

    Science.gov (United States)

    Jiang, Jing; Lu, Weiqiang; Li, Weihua; Liu, Guixia; Zhou, Weixing; Huang, Jin; Tang, Yun

    2012-01-01

    Drug-target interaction (DTI) is the basis of drug discovery and design. It is time consuming and costly to determine DTI experimentally. Hence, it is necessary to develop computational methods for the prediction of potential DTI. Based on complex network theory, three supervised inference methods were developed here to predict DTI and used for drug repositioning, namely drug-based similarity inference (DBSI), target-based similarity inference (TBSI) and network-based inference (NBI). Among them, NBI performed best on four benchmark data sets. Then a drug-target network was created with NBI based on 12,483 FDA-approved and experimental drug-target binary links, and some new DTIs were further predicted. In vitro assays confirmed that five old drugs, namely montelukast, diclofenac, simvastatin, ketoconazole, and itraconazole, showed polypharmacological features on estrogen receptors or dipeptidyl peptidase-IV with half maximal inhibitory or effective concentration ranged from 0.2 to 10 µM. Moreover, simvastatin and ketoconazole showed potent antiproliferative activities on human MDA-MB-231 breast cancer cell line in MTT assays. The results indicated that these methods could be powerful tools in prediction of DTIs and drug repositioning. PMID:22589709

  17. 3-D MDT with spherical targets by bilinear interpolation for determining blood velocity profiles including the vessel wall effect

    Science.gov (United States)

    Choomphon-anomakhun, Natthaphon; Natenapit, Mayuree

    2018-02-01

    A numerical simulation of three-dimensional (3-D) implant assisted-magnetic drug targeting (IA-MDT) using ferromagnetic spherical targets, including the effect from the vessel wall on the blood flow, is presented. The targets were implanted within arterioles and subjected to an externally uniform applied magnetic field in order to increase the effectiveness of targeting magnetic drug carrier particles (MDCPs). The capture area (As) of the MDCPs was determined by inspection of the particle trajectories simulated from the particle equations of motion. The blood flow velocities at any particle position around the target were obtained by applying bilinear interpolation to the numerical blood velocity data. The effects on As of the type of ferromagnetic materials in the targets and MDCPs, average blood flow rates, mass fraction of the ferromagnetic material in the MDCPs, average radii of MDCPs (Rp) and the externally applied magnetic field strength (μ0H0) were evaluated. Furthermore, the appropriate μ0H0 and Rp for the IA-MDT design is suggested. In the case of the SS409 target and magnetite MDCPs, dimensionless capture areas ranging from 4.1- to 12.4 and corresponding to particle capture efficiencies of 31-94% were obtained with Rp ranging from 100- to 500 nm, weight fraction of 80%, μ0H0 of 0.6 T and an average blood flow rate of 0.01 ms-1. In addition, the more general 3-D modelling of IA-MDT in this work is applicable to IA-MDT using spherical targets implanted within blood vessels for both laminar and potential blood flows including the wall effect.

  18. Identification of putative drug targets for human sperm-egg interaction defect using protein network approach.

    Science.gov (United States)

    Sabetian, Soudabeh; Shamsir, Mohd Shahir

    2015-07-18

    Sperm-egg interaction defect is a significant cause of in-vitro fertilization failure for infertile cases. Numerous molecular interactions in the form of protein-protein interactions mediate the sperm-egg membrane interaction process. Recent studies have demonstrated that in addition to experimental techniques, computational methods, namely protein interaction network approach, can address protein-protein interactions between human sperm and egg. Up to now, no drugs have been detected to treat sperm-egg interaction disorder, and the initial step in drug discovery research is finding out essential proteins or drug targets for a biological process. The main purpose of this study is to identify putative drug targets for human sperm-egg interaction deficiency and consider if the detected essential proteins are targets for any known drugs using protein-protein interaction network and ingenuity pathway analysis. We have created human sperm-egg protein interaction networks with high confidence, including 106 nodes and 415 interactions. Through topological analysis of the network with calculation of some metrics, such as connectivity and betweenness centrality, we have identified 13 essential proteins as putative drug targets. The potential drug targets are from integrins, fibronectins, epidermal growth factor receptors, collagens and tetraspanins protein families. We evaluated these targets by ingenuity pathway analysis, and the known drugs for the targets have been detected, and the possible effective role of the drugs on sperm-egg interaction defect has been considered. These results showed that the drugs ocriplasmin (Jetrea©), gefitinib (Iressa©), erlotinib hydrochloride (Tarceva©), clingitide, cetuximab (Erbitux©) and panitumumab (Vectibix©) are possible candidates for efficacy testing for the treatment of sperm-egg interaction deficiency. Further experimental validation can be carried out to confirm these results. We have identified the first potential list of

  19. Dihydroorotate dehydrogenase: A drug target for the development of antimalarials.

    Science.gov (United States)

    Singh, Anju; Maqbool, Mudasir; Mobashir, Mohammad; Hoda, Nasimul

    2017-01-05

    Malaria is a critical human disease with extensive exploration yet unestablished due to occurrence of frequent drug resistance. This aspect of malaria pharmacology calls for the introduction of new antimalarial. The drugs reported till date targeted different stages of the parasites in order to stop their growth and proliferation. Beside this, various drugs that could inhibit the imperative enzymes of the parasite have also been reported. Amid them, dihydroorotate dehydrogenase (DHODH) has a key worth. DHODH is involved in the de novo pyrimidine biosynthesis of the malarial parasite which acts as a primary source of energy for its survival. Since life of the parasite utterly depends on pyrimidine biosynthesis, so it can be used as an apt drug target for malaria eradication. In addition to this, DHODH is also present in human and their active sites have significant structural dissimilarities, so the development of selective inhibitors may prove to be a milestone in search of new antimalarials. Inhibitors of human DHODH have been used to treat autoimmune diseases such as, rheumatoid arthritis or multiple sclerosis and have been investigated in the treatment of cancer, viral diseases, as well as in plant pathology. Here, we have reviewed the important role of DHODH as a viable drug target against malaria, its importance for the survival of the parasite, and DHODH inhibitors reported so far. The rate of success of the reported DHODH inhibitors and further required improvements have also been accounted. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  20. DIHYDROFOLATE REDUCTASE AS A VERSATILE DRUG TARGET IN HEALTHCARE

    Directory of Open Access Journals (Sweden)

    Naira Rashid

    2016-09-01

    Full Text Available Dihydrofolate reductase is one of the important enzymes for thymidylate and purine synthesis. It has been used as a drug target for treatment of various diseases. A large number of pharmaceutical drugs have been designed to inhibit the activity of dihydrofolate reductase. However, over the period of time some organisms have developed resistance against some of these drugs. There is also a chance of cross reactivity for these drugs, as they may target the dihydrofolate reductase enzyme of other organisms. Although using NMR spectroscopy, phylogenetic sequence analysis, comparative sequence analysis between dihydrofolate enzymes of various organisms and molecular modeling studies, a lot has been unraveled about the difference in the structure of this enzyme in various organisms, yet there is a need for deeper understanding of these differences so as to design drugs that are specific to their targets and reduce the chance for cross reactivity. The dihydrofolate enzyme can also be explored for treatment of various other diseases that are associated with the folate cycle.

  1. Drug interactions with solid tumour-targeted therapies.

    Science.gov (United States)

    Thomas-Schoemann, Audrey; Blanchet, Benoit; Bardin, Christophe; Noé, Gaëlle; Boudou-Rouquette, Pascaline; Vidal, Michel; Goldwasser, François

    2014-01-01

    Drug interactions are an on-going concern in the treatment of cancer, especially when targeted therapies, such as tyrosine kinase inhibitors (TKI) or mammalian target of rapamycin (mTOR) inhibitors, are being used. The emergence of elderly patients and/or patients with both cancer and other chronic co-morbidities leads to polypharmacy. Therefore, the risk of drug-drug interactions (DDI) becomes a clinically relevant issue, all the more so as TKIs and mTOR inhibitors are essentially metabolised by cytochrome P450 enzymes. These DDIs can result in variability in anticancer drug exposure, thus favouring the selection of resistant cellular clones or the occurrence of toxicity. This review provides a comprehensive overview of DDIs that involve targeted therapies approved by the FDA for the treatment of solid tumours for more than 3 years (sorafenib, sunitinib, erlotinib, gefitinib, imatinib, lapatinib, everolimus, temsirolimus) and medicinal herb or drugs. This review also provides some guidelines to help oncologists and pharmacists in their clinical practice. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. Efficient CRM197-mediated drug targeting to monocytes

    NARCIS (Netherlands)

    Schenk, Geert J.; Haasnoot, P. C. Joost; Centlivre, Mireille; Legrand, Nicolas; Rip, Jaap; de Boer, Albertus G.; Berkhout, Ben

    2012-01-01

    Efficient delivery of drugs to specific cellular reservoirs is of particular importance for therapeutics that are not able to pass cellular barriers and that may have unwanted side effects in off-target tissues. Heparin-binding epidermal growth factor (HB-EGF) is expressed on leukocytes and may be

  3. Glial cells as drug targets : What does it take?

    NARCIS (Netherlands)

    Moller, Thomas; Boddeke, Hendrikus W. G. M.

    2016-01-01

    The last two decades have brought a significant increase in our understanding of glial biology and glial contribution to CNS disease. Yet, despite the fact that glial cells make up the majority of CNS cells, no drug specifically targeting glial cells is on the market. Given the long development

  4. Anticancer Drugs Targeting the Mitochondrial Electron Transport Chain

    Czech Academy of Sciences Publication Activity Database

    Rohlena, Jakub; Dong, L.-F.; Ralph, S.J.; Neužil, Jiří

    2011-01-01

    Roč. 15, č. 12 (2011), s. 2951-2974 ISSN 1523-0864 R&D Projects: GA AV ČR(CZ) KAN200520703 Institutional research plan: CEZ:AV0Z50520701 Keywords : Targets for anticancer drugs * mitochondrial electron transport chain * mitocans Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 8.456, year: 2011

  5. Breakable mesoporous silica nanoparticles for targeted drug delivery.

    Science.gov (United States)

    Maggini, Laura; Cabrera, Ingrid; Ruiz-Carretero, Amparo; Prasetyanto, Eko A; Robinet, Eric; De Cola, Luisa

    2016-04-07

    "Pop goes the particle". Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery.

  6. Breakable mesoporous silica nanoparticles for targeted drug delivery

    Science.gov (United States)

    Maggini, Laura; Cabrera, Ingrid; Ruiz-Carretero, Amparo; Prasetyanto, Eko A.; Robinet, Eric; de Cola, Luisa

    2016-03-01

    ``Pop goes the particle''. Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery.``Pop goes the particle''. Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery. Electronic supplementary information (ESI) available: Full experimental procedures, additional SEM and TEM images of particles, complete UV-Vis and PL-monitored characterization of the breakdown of

  7. Aptamer-Mediated Polymeric Vehicles for Enhanced Cell-Targeted Drug Delivery.

    Science.gov (United States)

    Tan, Kei X; Danquah, Michael K; Sidhu, Amandeep; Yon, Lau Sie; Ongkudon, Clarence M

    2018-02-08

    The search for smart delivery systems for enhanced pre-clinical and clinical pharmaceutical delivery and cell targeting continues to be a major biomedical research endeavor owing to differences in the physicochemical characteristics and physiological effects of drug molecules, and this affects the delivery mechanisms to elicit maximum therapeutic effects. Targeted drug delivery is a smart evolution essential to address major challenges associated with conventional drug delivery systems. These challenges mostly result in poor pharmacokinetics due to the inability of the active pharmaceutical ingredients to specifically act on malignant cells thus, causing poor therapeutic index and toxicity to surrounding normal cells. Aptamers are oligonucleotides with engineered affinities to bind specifically to their cognate targets. Aptamers have gained significant interests as effective targeting elements for enhanced therapeutic delivery as they can be generated to specifically bind to wide range of targets including proteins, peptides, ions, cells and tissues. Notwithstanding, effective delivery of aptamers as therapeutic vehicles is challenged by cell membrane electrostatic repulsion, endonuclease degradation, low pH cleavage, and binding conformation stability. The application of molecularly engineered biodegradable and biocompatible polymeric particles with tunable features such as surface area and chemistry, particulate size distribution and toxicity creates opportunities to develop smart aptamer-mediated delivery systems for controlled drug release. This article discusses opportunities for particulate aptamer-drug formulations to advance current drug delivery modalities by navigating active ingredients through cellular and biomolecular traffic to target sites for sustained and controlled release at effective therapeutic dosages while minimizing systemic cytotoxic effects. A proposal for a novel drug-polymer-aptamer-polymer (DPAP) design of aptamer-drug formulation with

  8. Prediction of Human Drug Targets and Their Interactions Using Machine Learning Methods: Current and Future Perspectives.

    Science.gov (United States)

    Nath, Abhigyan; Kumari, Priyanka; Chaube, Radha

    2018-01-01

    Identification of drug targets and drug target interactions are important steps in the drug-discovery pipeline. Successful computational prediction methods can reduce the cost and time demanded by the experimental methods. Knowledge of putative drug targets and their interactions can be very useful for drug repurposing. Supervised machine learning methods have been very useful in drug target prediction and in prediction of drug target interactions. Here, we describe the details for developing prediction models using supervised learning techniques for human drug target prediction and their interactions.

  9. Targeted drug delivery using temperature-sensitive liposomes

    International Nuclear Information System (INIS)

    Magin, R.L.; Niesman, M.R.

    1984-01-01

    Liposomes are receiving considerable attention as vehicles for selective drug delivery. One method of targeting liposomal contents involves the combination of local hyperthermia with temperature-sensitive liposomes. Such liposomes have been used to increase the uptake of methotrexate and cis-platinum into locally heated mouse tumors. However, additional information is needed on the mechanism of liposome drug release and the physiologic deposition of liposomes in vivo before clinical trails are begun. Current research is directed at studying the encapsulation and release of water soluble drugs from temperature-sensitive liposomes. The influence of liposome size, structure, and composition on the rapid release in plasma of cytosine arabinoside, cis-platinum, and the radiation sensitizer SR-2508 are described. These results demonstrate potential applications for temperature-sensitive liposomes in selective drug delivery

  10. Carbon Nanotubes: An Emerging Drug Carrier for Targeting Cancer Cells

    Science.gov (United States)

    Bhattacharya, Shiv Sankar; Mishra, Arun Kumar; Verma, Navneet; Verma, Anurag; Pandit, Jayanta Kumar

    2014-01-01

    During recent years carbon nanotubes (CNTs) have been attracted by many researchers as a drug delivery carrier. CNTs are the third allotropic form of carbon-fullerenes which were rolled into cylindrical tubes. To be integrated into the biological systems, CNTs can be chemically modified or functionalised with therapeutically active molecules by forming stable covalent bonds or supramolecular assemblies based on noncovalent interactions. Owing to their high carrying capacity, biocompatibility, and specificity to cells, various cancer cells have been explored with CNTs for evaluation of pharmacokinetic parameters, cell viability, cytotoxicty, and drug delivery in tumor cells. This review attempts to highlight all aspects of CNTs which render them as an effective anticancer drug carrier and imaging agent. Also the potential application of CNT in targeting metastatic cancer cells by entrapping biomolecules and anticancer drugs has been covered in this review. PMID:24872894

  11. Structural genomics of infectious disease drug targets: the SSGCID

    International Nuclear Information System (INIS)

    Stacy, Robin; Begley, Darren W.; Phan, Isabelle; Staker, Bart L.; Van Voorhis, Wesley C.; Varani, Gabriele; Buchko, Garry W.; Stewart, Lance J.; Myler, Peter J.

    2011-01-01

    An introduction and overview of the focus, goals and overall mission of the Seattle Structural Genomics Center for Infectious Disease (SSGCID) is given. The Seattle Structural Genomics Center for Infectious Disease (SSGCID) is a consortium of researchers at Seattle BioMed, Emerald BioStructures, the University of Washington and Pacific Northwest National Laboratory that was established to apply structural genomics approaches to drug targets from infectious disease organisms. The SSGCID is currently funded over a five-year period by the National Institute of Allergy and Infectious Diseases (NIAID) to determine the three-dimensional structures of 400 proteins from a variety of Category A, B and C pathogens. Target selection engages the infectious disease research and drug-therapy communities to identify drug targets, essential enzymes, virulence factors and vaccine candidates of biomedical relevance to combat infectious diseases. The protein-expression systems, purified proteins, ligand screens and three-dimensional structures produced by SSGCID constitute a valuable resource for drug-discovery research, all of which is made freely available to the greater scientific community. This issue of Acta Crystallographica Section F, entirely devoted to the work of the SSGCID, covers the details of the high-throughput pipeline and presents a series of structures from a broad array of pathogenic organisms. Here, a background is provided on the structural genomics of infectious disease, the essential components of the SSGCID pipeline are discussed and a survey of progress to date is presented

  12. Pericyte-targeting drug delivery and tissue engineering

    Directory of Open Access Journals (Sweden)

    Kang E

    2016-05-01

    Full Text Available Eunah Kang,1 Jong Wook Shin2 1School of Chemical Engineering and Material Science, 2Division of Allergic and Pulmonary Medicine, Department of Internal Medicine, College of Medicine, Chung-Ang University, Dongjak-Gu, Seoul, South Korea Abstract: Pericytes are contractile mural cells that wrap around the endothelial cells of capillaries and venules. Depending on the triggers by cellular signals, pericytes have specific functionality in tumor microenvironments, properties of potent stem cells, and plasticity in cellular pathology. These features of pericytes can be activated for the promotion or reduction of angiogenesis. Frontier studies have exploited pericyte-targeting drug delivery, using pericyte-specific peptides, small molecules, and DNA in tumor therapy. Moreover, the communication between pericytes and endothelial cells has been applied to the induction of vessel neoformation in tissue engineering. Pericytes may prove to be a novel target for tumor therapy and tissue engineering. The present paper specifically reviews pericyte-specific drug delivery and tissue engineering, allowing insight into the emerging research targeting pericytes. Keywords: pericytes, pericyte-targeting drug delivery, tissue engineering, platelet-derived growth factor, angiogenesis, vascular remodeling

  13. Functionalized mesoporous silicon for targeted-drug-delivery.

    Science.gov (United States)

    Tabasi, Ozra; Falamaki, Cavus; Khalaj, Zahra

    2012-10-01

    The present work concerns a preliminary step in the production of anticancer drug loaded porous silicon (PSi) for targeted-drug-delivery applications. A successful procedure for the covalent attachment of folic acid, polyethylene glycol (PEG) and doxorubicin to hydrophilic mesoporous silicon layers is presented. A systematic approach has been followed to obtain the optimal composition of the N,N'-dicyclohexylcarbodiimide (DCC)/N-hydroxysuccimide (NHS) in dimethylsulfoxide (DMSO) solution for the surface activation process of the undecylenic acid (UD) grafted molecules to take place with minimal undesired byproduct formation. The effect of reactant concentration and kind of solvent (aqueous or DMSO) on the attachment of folic acid to the activated PSi layer has been investigated. The covalent attachment of the doxorubicin molecules to the PSi layer functionalized with folic acid and PEG is discussed. The drug release kinetics as a function of pH has been studied. The functionalized PSi particles show a high cytotoxicity compared to the equivalent amount of free drug. Cell toxicity tests show clearly that the incorporation of folate molecules increases substantially the toxicity of the loaded PSi particles. Accordingly this new functionalized PSi may be considered a proper candidate for targeted drug delivery. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. A review on target drug delivery: magnetic microspheres

    Directory of Open Access Journals (Sweden)

    Amit Chandna

    2013-01-01

    Magnetic microsphere is newer approach in pharmaceutical field. Magnetic microspheres as an alternative to traditional radiation methods which use highly penetrating radiation that is absorbed throughout the body. Its use is limited by toxicity and side effects. The aim of the specific targeting is to enhance the efficiency of drug delivery & at the same time to reduce the toxicity & side effects. This kind of delivery system is very much important which localises the drug to the disease site. In this larger amount of freely circulating drug can be replaced by smaller amount of magnetically targeted drug. Magnetic carriers receive magnetic responses to a magnetic field from incorporated materials that are used for magnetic microspheres are chitosan, dextran etc. magnetic microspheres can be prepared from a variety of carrier material. One of the most utilized is serum albumin from human or other appropriate species. Drug release from albumin microspheres can be sustained or controlled by various stabilization procedures generally involving heat or chemical cross-linking of the protein carrier matrix.

  15. [Data-mining characteristics of adverse drug reactions and pharmacovi-gilance of Chinese patent drugs including Aconitum herbs].

    Science.gov (United States)

    Zhang, Xiao-Meng; Li, Fan; Zhang, Bing; Chen, Xiao-Fen; Piao, Jing-Zhu

    2018-01-01

    The common Aconitum herbs in clinical application mainly include Aconiti Radix(Chuanwu), Aconiti Kusnezoffii Radix(Caowu) and Aconiti Lateralis Radix Praeparaia(Fuzi), all of which have toxicity. Therefore, the safety of using Chinese patent drugs including Aconitum herbs has become an hot topic in clinical controversy. Based on the data-mining methods, this study explored the characteristics and causes of adverse drug reactions/events (ADR/ADE) of the Chinese patent drugs including Aconitum, in order to provide pharmacovigilance and rational drug use suggestions for clinical application. The detailed ADR/ADE reports about the Chinese patent drugs including Aconitum herbs were retrieved in the domestic literature databases since 1984 to now. The information extraction and data-mining were conducted based on the platforms of Microsoft office Excel 2016, Clementine 12.0 and Cytoscape 3.3.0. Finally, 78 detailed ADR/ADE reports involving a total of 30 varieties were included. 92.31% ADR/ADE were surely or likely led by the Chinese patent drugs including Aconitum, mostly involving multiple system/organ damages with good prognosis, and even 1 case of death. The incidence of included ADRs/ADEs was associated with various factors such as the patient idiosyncratic, drug toxicity, as well as clinical medication. The patient age was most closely related to ADR/ADEs, and those aged from 60 to 69 were more easily suffered from the ADRs/ADEs of Chinese patent drugs including Aconitum. The probability of ADR/ADEs for the drugs including Chuanwu or Caowu was greater than that of Fuzi, and the using beyond the instructions dose was the most important potential safety hazard in the clinical medication process. For the regular and characteristics of ADR/ADEs led by Chinese patent drugs including Aconitum, special attention shall be paid to the elder patients or with the patients with allergies; strictly control the dosage and course of treatment, strengthen the safety medication

  16. Chronic neuropathic pain: mechanisms, drug targets and measurement

    DEFF Research Database (Denmark)

    Finnerup, Nanna Brix; Sindrup, Søren H.; Jensen, Troels Staehelin

    2007-01-01

    Neuropathic pain is common in many diseases or injuries of the peripheral or central nervous system, and has a substantial impact on quality of life and mood. Lesions of the nervous system may lead to potentially irreversible changes and imbalance between excitatory and inhibitory systems...... to assess various symptoms and signs in neuropathic pain and knowledge of drug mechanisms are prerequisites for pursuing this approach. The present review summarizes mechanisms of neuropathic pain, targets of currently used drugs, and measures used in neuropathic pain trials....

  17. An efficient targeted drug delivery through apotransferrin loaded nanoparticles.

    Directory of Open Access Journals (Sweden)

    Athuluri Divakar Sai Krishna

    Full Text Available BACKGROUND: Cancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin. METHODOLOGY/PRINCIPAL FINDINGS: Apotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano have diameters of 25-50 etam, which increase to 60-80 etam upon direct loading of drug (direct-nano, and showed further increase in dimension (75-95 etam in conjugated nanoparticles (conj-nano. The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus (b pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in

  18. Mining predicted essential genes of Brugia malayi for nematode drug targets.

    Directory of Open Access Journals (Sweden)

    Sanjay Kumar

    Full Text Available We report results from the first genome-wide application of a rational drug target selection methodology to a metazoan pathogen genome, the completed draft sequence of Brugia malayi, a parasitic nematode responsible for human lymphatic filariasis. More than 1.5 billion people worldwide are at risk of contracting lymphatic filariasis and onchocerciasis, a related filarial disease. Drug treatments for filariasis have not changed significantly in over 20 years, and with the risk of resistance rising, there is an urgent need for the development of new anti-filarial drug therapies. The recent publication of the draft genomic sequence for B. malayi enables a genome-wide search for new drug targets. However, there is no functional genomics data in B. malayi to guide the selection of potential drug targets. To circumvent this problem, we have utilized the free-living model nematode Caenorhabditis elegans as a surrogate for B. malayi. Sequence comparisons between the two genomes allow us to map C. elegans orthologs to B. malayi genes. Using these orthology mappings and by incorporating the extensive genomic and functional genomic data, including genome-wide RNAi screens, that already exist for C. elegans, we identify potentially essential genes in B. malayi. Further incorporation of human host genome sequence data and a custom algorithm for prioritization enables us to collect and rank nearly 600 drug target candidates. Previously identified potential drug targets cluster near the top of our prioritized list, lending credibility to our methodology. Over-represented Gene Ontology terms, predicted InterPro domains, and RNAi phenotypes of C. elegans orthologs associated with the potential target pool are identified. By virtue of the selection procedure, the potential B. malayi drug targets highlight components of key processes in nematode biology such as central metabolism, molting and regulation of gene expression.

  19. Drugs and drug delivery systems targeting amyloid-β in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Morgan Robinson

    2015-07-01

    Full Text Available Alzheimer's disease (AD is a devastating neurodegenerative disorder with no cure and limited treatment solutions that are unable to target any of the suspected causes. Increasing evidence suggests that one of the causes of neurodegeneration is the overproduction of amyloid beta (Aβ and the inability of Aβ peptides to be cleared from the brain, resulting in self-aggregation to form toxic oligomers, fibrils and plaques. One of the potential treatment options is to target Aβ and prevent self-aggregation to allow for a natural clearing of the brain. In this paper, we review the drugs and drug delivery systems that target Aβ in relation to Alzheimer's disease. Many attempts have been made to use anti-Aβ targeting molecules capable of targeting Aβ (with much success in vitro and in vivo animal models, but the major obstacle to this technique is the challenge posed by the blood brain barrier (BBB. This highly selective barrier protects the brain from toxic molecules and pathogens and prevents the delivery of most drugs. Therefore novel Aβ aggregation inhibitor drugs will require well thought-out drug delivery systems to deliver sufficient concentrations to the brain.

  20. Iron Deprivation Affects Drug Susceptibilities of Mycobacteria Targeting Membrane Integrity

    Directory of Open Access Journals (Sweden)

    Rahul Pal

    2015-01-01

    Full Text Available Multidrug resistance (MDR acquired by Mycobacterium tuberculosis (MTB through continuous deployment of antitubercular drugs warrants immediate search for novel targets and mechanisms. The ability of MTB to sense and become accustomed to changes in the host is essential for survival and confers the basis of infection. A crucial condition that MTB must surmount is iron limitation, during the establishment of infection, since iron is required by both bacteria and humans. This study focuses on how iron deprivation affects drug susceptibilities of known anti-TB drugs in Mycobacterium smegmatis, a “surrogate of MTB.” We showed that iron deprivation leads to enhanced potency of most commonly used first line anti-TB drugs that could be reverted upon iron supplementation. We explored that membrane homeostasis is disrupted upon iron deprivation as revealed by enhanced membrane permeability and hypersensitivity to membrane perturbing agent leading to increased passive diffusion of drug and TEM images showing detectable differences in cell envelope thickness. Furthermore, iron seems to be indispensable to sustain genotoxic stress suggesting its possible role in DNA repair machinery. Taken together, we for the first time established a link between cellular iron and drug susceptibility of mycobacteria suggesting iron as novel determinant to combat MDR.

  1. Rhamnogalacturonan-I based microcapsules for targeted drug release

    DEFF Research Database (Denmark)

    Svagan, Anna J.; Kusic, Anja; De Gobba, Cristian

    2016-01-01

    Drug targeting to the colon via the oral administration route for local treatment of e.g. inflammatory bowel disease and colonic cancer has several advantages such as needle-free administration and low infection risk. A new source for delivery is plant-polysaccharide based delivery platforms...... such as Rhamnogalacturonan-I (RG-I). In the gastro-intestinal tract the RG-I is only degraded by the action of the colonic microflora. For assessment of potential drug delivery properties, RG-I based microcapsules (~1 μm in diameter) were prepared by an interfacial poly-addition reaction. The cross-linked capsules were...... loaded with a fluorescent dye (model drug). The capsules showed negligible and very little in vitro release when subjected to media simulating gastric and intestinal fluids, respectively. However, upon exposure to a cocktail of commercial RG-I cleaving enzymes, ~ 9 times higher release was observed...

  2. Collagen like peptide bioconjugates for targeted drug delivery applications

    Science.gov (United States)

    Luo, Tianzhi

    the coil/globule conformational transition of the PDEGMEMA building block above its LCST with stabilization of the nanostructures by the hydrophilic CLP. To the best of our knowledge, this is the first report on such assembled nanostructures from collagen-like peptide containing copolymers. Due to the strong propensity for CLPs to bind to natural collagen via strand invasion processes, these nanosized vesicles may be used as drug carriers for targeted delivery. In addition to synthetic polymers, the collagen like peptide is then conjugated with a thermoresponsive elastin-like peptide (ELP). The resulting ELP-CLP diblock conjugates show a remarkable reduction in the inverse transition temperature of the ELP domain, attributed to the anchoring effect of the CLP triple helix. The lower transition temperature of the conjugate enables facile formation of well-defined vesicles at physiological temperature and the unexpected resolubilization of the vesicles at elevated temperatures upon unfolding of the CLP domain. Given the ability of CLPs to modify collagens, this work provides not only a simple and versatile avenue for controlling the inverse transition behavior of elastin-like peptides, but also suggest future opportunities for these thermoresponsive nanostructures in biologically relevant environments. In the last section, the potential of using the ELP-CLP nanoparticles as drug delivery vehicles for targeting collagen containing matrices is evaluated. A sustained release of clinically relevant amount of encapsulated modelled drug is achieved within three weeks, followed by a thermally controlled burst release. As expected, the ELP-CLP nanoparticles show strong retention on collagen substrate, via specific binding through collagen triple helix hybridization. Additionally, cell viability and proliferation studies using fibroblasts and chondrocytes suggest the nanoparticles are non-cytotoxic. Additionally, almost no TNF-alpha expression from macrophages is observed

  3. Chemical Genomics and Emerging DNA Technologies in the Identification of Drug Mechanisms and Drug Targets

    DEFF Research Database (Denmark)

    Olsen, Louise Cathrine Braun; Færgeman, Nils J.

    2012-01-01

    and validate therapeutic targets and to discover drug candidates for rapidly and effectively generating new interventions for human diseases. The recent emergence of genomic technologies and their application on genetically tractable model organisms like Drosophila melanogaster,Caenorhabditis elegans...... critical roles in the genomic age of biological research and drug discovery. In the present review we discuss how simple biological model organisms can be used as screening platforms in combination with emerging genomic technologies to advance the identification of potential drugs and their molecular...... and Saccharomyces cerevisiae have provided momentum to cell biological and biomedical research, particularly in the functional characterization of gene functions and the identification of novel drug targets. We therefore anticipate that chemical genomics and the vast development of genomic technologies will play...

  4. Chemical Genomics and Emerging DNA Technologies in the Identification of Drug Mechanisms and Drug Targets

    DEFF Research Database (Denmark)

    Olsen, Louise Cathrine Braun; Færgeman, Nils J.

    2012-01-01

    and validate therapeutic targets and to discover drug candidates for rapidly and effectively generating new interventions for human diseases. The recent emergence of genomic technologies and their application on genetically tractable model organisms like Drosophila melanogaster,Caenorhabditis elegans...... and Saccharomyces cerevisiae have provided momentum to cell biological and biomedical research, particularly in the functional characterization of gene functions and the identification of novel drug targets. We therefore anticipate that chemical genomics and the vast development of genomic technologies will play...... critical roles in the genomic age of biological research and drug discovery. In the present review we discuss how simple biological model organisms can be used as screening platforms in combination with emerging genomic technologies to advance the identification of potential drugs and their molecular...

  5. Rhamnogalacturonan-I Based Microcapsules for Targeted Drug Release.

    Science.gov (United States)

    Svagan, Anna J; Kusic, Anja; De Gobba, Cristian; Larsen, Flemming H; Sassene, Philip; Zhou, Qi; van de Weert, Marco; Mullertz, Anette; Jørgensen, Bodil; Ulvskov, Peter

    2016-01-01

    Drug targeting to the colon via the oral administration route for local treatment of e.g. inflammatory bowel disease and colonic cancer has several advantages such as needle-free administration and low infection risk. A new source for delivery is plant-polysaccharide based delivery platforms such as Rhamnogalacturonan-I (RG-I). In the gastro-intestinal tract the RG-I is only degraded by the action of the colonic microflora. For assessment of potential drug delivery properties, RG-I based microcapsules (~1 μm in diameter) were prepared by an interfacial poly-addition reaction. The cross-linked capsules were loaded with a fluorescent dye (model drug). The capsules showed negligible and very little in vitro release when subjected to media simulating gastric and intestinal fluids, respectively. However, upon exposure to a cocktail of commercial RG-I cleaving enzymes, ~ 9 times higher release was observed, demonstrating that the capsules can be opened by enzymatic degradation. The combined results suggest a potential platform for targeted drug delivery in the terminal gastro-intestinal tract.

  6. Targeted albumin-based nanoparticles for delivery of amphipathic drugs.

    Science.gov (United States)

    Xu, Rongzuo; Fisher, Michael; Juliano, R L

    2011-05-18

    We report the preparation and physical and biological characterization of human serum albumin-based micelles of approximately 30 nm diameter for the delivery of amphipathic drugs, represented by doxorubicin. The micelles were surface conjugated with cyclic RGD peptides to guide selective delivery to cells expressing the α(v)β(3) integrin. Multiple poly(ethylene glycol)s (PEGs) with molecular weight of 3400 Da were used to form a hydrophilic outer layer, with the inner core formed by albumin conjugated with doxorubicin via disulfide bonds. Additional doxorubicin was physically adsorbed into this core to attain a high drug loading capacity, where each albumin was associated with about 50 doxorubicin molecules. The formed micelles were stable in serum but continuously released doxorubicin when incubated with free thiols at concentrations mimicking the intracellular environment. When incubated with human melanoma cells (M21+) that express the α(v)β(3) integrin, higher uptake and longer retention of doxorubicin was observed with the RGD-targeted micelles than in the case of untargeted control micelles or free doxorubicin. Consequently, the RGD-targeted micelles manifested cytotoxicity at lower doses of drug than control micelles or free drug.

  7. New alginic acid–atenolol microparticles for inhalatory drug targeting

    Energy Technology Data Exchange (ETDEWEB)

    Ceschan, Nazareth Eliana; Bucalá, Verónica [Planta Piloto de Ingeniería Química (PLAPIQUI), CONICET, Universidad Nacional del Sur (UNS), Camino La Carrindanga Km 7, 8000 Bahía Blanca (Argentina); Departamento de Ingeniería Química, UNS, Avenida Alem 1253, 8000 Bahía Blanca (Argentina); Ramírez-Rigo, María Verónica, E-mail: vrrigo@plapiqui.edu.ar [Planta Piloto de Ingeniería Química (PLAPIQUI), CONICET, Universidad Nacional del Sur (UNS), Camino La Carrindanga Km 7, 8000 Bahía Blanca (Argentina); Departamento de Biología, Bioquímica y Farmacia, UNS, San Juan 670, 8000 Bahía Blanca (Argentina)

    2014-08-01

    The inhalatory route allows drug delivery for local or systemic treatments in a noninvasively way. The current tendency of inhalable systems is oriented to dry powder inhalers due to their advantages in terms of stability and efficiency. In this work, microparticles of atenolol (AT, basic antihypertensive drug) and alginic acid (AA, acid biocompatible polyelectrolyte) were obtained by spray drying. Several formulations, varying the relative composition AT/AA and the total solid content of the atomized dispersions, were tested. The powders were characterized by: Fourier Transform Infrared Spectroscopy, Differential Scanning Calorimetry and Powder X-ray Diffraction, while also the following properties were measured: drug load efficiency, flow properties, particles size and density, moisture content, hygroscopicity and morphology. The ionic interaction between AA and AT was demonstrated, then the new chemical entity could improve the drug targeting to the respiratory membrane and increase its time residence due to the mucoadhesive properties of the AA polymeric chains. Powders exhibited high load efficiencies, low moisture contents, adequate mean aerodynamic diameters and high cumulative fraction of respirable particles (lower than 10 μm). - Highlights: • Novel particulate material to target atenolol to the respiratory membrane was developed. • Crumbled microparticles were obtained by spray drying of alginic–atenolol dispersions. • Ionic interaction between alginic acid and atenolol was demonstrated in the product. • Amorphous solids with low moisture content and high load efficiency were produced. • Relationships between the feed formulation and the product characteristics were found.

  8. Dihydrofolate reductase: A potential drug target in trypanosomes and leishmania

    Science.gov (United States)

    Zuccotto, Fabio; Martin, Andrew C. R.; Laskowski, Roman A.; Thornton, Janet M.; Gilbert, Ian H.

    1998-05-01

    Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherapy. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leishmania major dihydrofolate reductase has been published. In this paper, we describe the modelling of Trypanosoma cruzi and Trypanosoma brucei dihydrofolate reductases based on this crystal structure. These structures and models have been used in the comparison of protozoan, bacterial and human enzymes in order to highlight the different features that can be used in the design of selective anti-protozoan agents. Comparison has been made between residues present in the active site, the accessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high degree of similarity between protozoan, human and bacterial dihydrofolate reductase active sites, there are differences that provide potential for selective drug design. In particular, we have identified a set of residues which may be important for selective drug design and identified a larger binding pocket in the protozoan than the human and bacterial enzymes.

  9. High Throughput Screening Methodologies Classified for Major Drug Target Classes According to Target Signaling Pathways

    NARCIS (Netherlands)

    Kool, J.; Lingeman, H.; Niessen, W.M.A.; Irth, H.

    2010-01-01

    Over the years, many different high throughput screening technologies and subsequently follow-up methodologies have been developed. All of these can be categorized, for example according to measurement of analyte classes, assay mechanisms, readout principles, or screening of drug target classes.

  10. Preparation of magnetic nanoparticles and their application to magnetic targeting drug delivery

    International Nuclear Information System (INIS)

    Li Guiping; Wang Yongxian

    2006-01-01

    Magnetic nanoparticles barrier is a novel kind of drug delivery system for magnetic targeting drugs, which can effectively deliver the drug to a tumor target site and increase therapeutic benefit, with the side effects minimized. This article summarizes the most outstanding papers on the of magnetic nanoparticles used as the targeting drug's delivery systems. (authors)

  11. Bacterial Histidine Kinases as Novel Antibacterial Drug Targets

    NARCIS (Netherlands)

    Bem, A.E.; Velikova, N.R.; Pellicer, M.T.; Baarlen, van P.; Marina, A.; Wells, J.M.

    2015-01-01

    Bacterial histidine kinases (HKs) are promising targets for novel antibacterials. Bacterial HKs are part of bacterial two-component systems (TCSs), the main signal transduction pathways in bacteria, regulating various processes including virulence, secretion systems and antibiotic resistance. In

  12. TCGA bladder cancer study reveals potential drug targets

    Science.gov (United States)

    Investigators with TCGA have identified new potential therapeutic targets for a major form of bladder cancer, including important genes and pathways that are disrupted in the disease. They also discovered that, at the molecular level, some subtypes of bla

  13. From drug response profiling to target addiction scoring in cancer cell models

    Directory of Open Access Journals (Sweden)

    Bhagwan Yadav

    2015-10-01

    Full Text Available Deconvoluting the molecular target signals behind observed drug response phenotypes is an important part of phenotype-based drug discovery and repurposing efforts. We demonstrate here how our network-based deconvolution approach, named target addiction score (TAS, provides insights into the functional importance of druggable protein targets in cell-based drug sensitivity testing experiments. Using cancer cell line profiling data sets, we constructed a functional classification across 107 cancer cell models, based on their common and unique target addiction signatures. The pan-cancer addiction correlations could not be explained by the tissue of origin, and only correlated in part with molecular and genomic signatures of the heterogeneous cancer cells. The TAS-based cancer cell classification was also shown to be robust to drug response data resampling, as well as predictive of the transcriptomic patterns in an independent set of cancer cells that shared similar addiction signatures with the 107 cancers. The critical protein targets identified by the integrated approach were also shown to have clinically relevant mutation frequencies in patients with various cancer subtypes, including not only well-established pan-cancer genes, such as PTEN tumor suppressor, but also a number of targets that are less frequently mutated in specific cancer types, including ABL1 oncoprotein in acute myeloid leukemia. An application to leukemia patient primary cell models demonstrated how the target deconvolution approach offers functional insights into patient-specific addiction patterns, such as those indicative of their receptor-type tyrosine-protein kinase FLT3 internal tandem duplication (FLT3-ITD status and co-addiction partners, which may lead to clinically actionable, personalized drug treatment developments. To promote its application to the future drug testing studies, we have made available an open-source implementation of the TAS calculation in the form

  14. Prediction of Effective Drug Combinations by Chemical Interaction, Protein Interaction and Target Enrichment of KEGG Pathways

    Science.gov (United States)

    Chen, Lei; Zheng, Ming-Yue; Zhang, Jian; Feng, Kai-Yan; Cai, Yu-Dong

    2013-01-01

    Drug combinatorial therapy could be more effective in treating some complex diseases than single agents due to better efficacy and reduced side effects. Although some drug combinations are being used, their underlying molecular mechanisms are still poorly understood. Therefore, it is of great interest to deduce a novel drug combination by their molecular mechanisms in a robust and rigorous way. This paper attempts to predict effective drug combinations by a combined consideration of: (1) chemical interaction between drugs, (2) protein interactions between drugs' targets, and (3) target enrichment of KEGG pathways. A benchmark dataset was constructed, consisting of 121 confirmed effective combinations and 605 random combinations. Each drug combination was represented by 465 features derived from the aforementioned three properties. Some feature selection techniques, including Minimum Redundancy Maximum Relevance and Incremental Feature Selection, were adopted to extract the key features. Random forest model was built with its performance evaluated by 5-fold cross-validation. As a result, 55 key features providing the best prediction result were selected. These important features may help to gain insights into the mechanisms of drug combinations, and the proposed prediction model could become a useful tool for screening possible drug combinations. PMID:24083237

  15. Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

    Science.gov (United States)

    2012-10-01

    plants (12), and the chorismate pathway is absent in humans. Therefore, our hypothesis is that these proteins are potential therapeutic targets in...Tyr, and other aromatic compounds (e.g. folate, alkaloids ) (13, 14). Although PSCVT has been previously suggested as a drug target for antibacterials...most research in this field has concentrated on Plasmodium falciparum (antimalarials) and glyphosate resistant plants (12, 15, 16

  16. In silico tools used for compound selection during target-based drug discovery and development.

    Science.gov (United States)

    Caldwell, Gary W

    2015-01-01

    The target-based drug discovery process, including target selection, screening, hit-to-lead (H2L) and lead optimization stage gates, is the most common approach used in drug development. The full integration of in vitro and/or in vivo data with in silico tools across the entire process would be beneficial to R&D productivity by developing effective selection criteria and drug-design optimization strategies. This review focuses on understanding the impact and extent in the past 5 years of in silico tools on the various stage gates of the target-based drug discovery approach. There are a large number of in silico tools available for establishing selection criteria and drug-design optimization strategies in the target-based approach. However, the inconsistent use of in vitro and/or in vivo data integrated with predictive in silico multiparameter models throughout the process is contributing to R&D productivity issues. In particular, the lack of reliable in silico tools at the H2L stage gate is contributing to the suboptimal selection of viable lead compounds. It is suggested that further development of in silico multiparameter models and organizing biologists, medicinal and computational chemists into one team with a single accountable objective to expand the utilization of in silico tools in all phases of drug discovery would improve R&D productivity.

  17. Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs

    Directory of Open Access Journals (Sweden)

    Wanderley de Souza

    2009-01-01

    Full Text Available Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS, which catalyzes the first committed step in sterol biosynthesis, (d allylamines, inhibitors of squalene epoxidase, (e azoles, which inhibit C14α-demethylase, and (f azasterols, which inhibit Δ24(25-sterol methyltransferase (SMT. Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures, and their effects on protozoan structural organization (as evaluted by light and electron microscopy and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take

  18. Application of RNAi to Genomic Drug Target Validation in Schistosomes.

    Directory of Open Access Journals (Sweden)

    Alessandra Guidi

    2015-05-01

    Full Text Available Concerns over the possibility of resistance developing to praziquantel (PZQ, has stimulated efforts to develop new drugs for schistosomiasis. In addition to the development of improved whole organism screens, the success of RNA interference (RNAi in schistosomes offers great promise for the identification of potential drug targets to initiate drug discovery. In this study we set out to contribute to RNAi based validation of putative drug targets. Initially a list of 24 target candidates was compiled based on the identification of putative essential genes in schistosomes orthologous of C. elegans essential genes. Knockdown of Calmodulin (Smp_026560.2 (Sm-Calm, that topped this list, produced a phenotype characterised by waves of contraction in adult worms but no phenotype in schistosomula. Knockdown of the atypical Protein Kinase C (Smp_096310 (Sm-aPKC resulted in loss of viability in both schistosomula and adults and led us to focus our attention on other kinase genes that were identified in the above list and through whole organism screening of known kinase inhibitor sets followed by chemogenomic evaluation. RNAi knockdown of these kinase genes failed to affect adult worm viability but, like Sm-aPKC, knockdown of Polo-like kinase 1, Sm-PLK1 (Smp_009600 and p38-MAPK, Sm-MAPK p38 (Smp_133020 resulted in an increased mortality of schistosomula after 2-3 weeks, an effect more marked in the presence of human red blood cells (hRBC. For Sm-PLK-1 the same effects were seen with the specific inhibitor, BI2536, which also affected viable egg production in adult worms. For Sm-PLK-1 and Sm-aPKC the in vitro effects were reflected in lower recoveries in vivo. We conclude that the use of RNAi combined with culture with hRBC is a reliable method for evaluating genes important for larval development. However, in view of the slow manifestation of the effects of Sm-aPKC knockdown in adults and the lack of effects of Sm-PLK-1 and Sm-MAPK p38 on adult viability

  19. Ultrasound-sensitive nanoparticle aggregates for targeted drug delivery.

    Science.gov (United States)

    Papa, Anne-Laure; Korin, Netanel; Kanapathipillai, Mathumai; Mammoto, Akiko; Mammoto, Tadanori; Jiang, Amanda; Mannix, Robert; Uzun, Oktay; Johnson, Christopher; Bhatta, Deen; Cuneo, Garry; Ingber, Donald E

    2017-09-01

    Here we describe injectable, ultrasound (US)-responsive, nanoparticle aggregates (NPAs) that disintegrate into slow-release, nanoscale, drug delivery systems, which can be targeted to selective sites by applying low-energy US locally. We show that, unlike microbubble based drug carriers which may suffer from stability problems, the properties of mechanical activated NPAs, composed of polymer nanoparticles, can be tuned by properly adjusting the polymer molecular weight, the size of the nanoparticle precursors as well as the percentage of excipient utilized to hold the NPA together. We then apply this concept to practice by fabricating NPAs composed of nanoparticles loaded with Doxorubicin (Dox) and tested their ability to treat tumors via ultrasound activation. Mouse studies demonstrated significantly increased efficiency of tumor targeting of the US-activated NPAs compared to PLGA nanoparticle controls (with or without US applied) or intact NPAs. Importantly, when the Dox-loaded NPAs were injected and exposed to US energy locally, this increased ability to concentrate nanoparticles at the tumor site resulted in a significantly greater reduction in tumor volume compared to tumors treated with a 20-fold higher dose of the free drug. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Physics considerations in targeted anticancer drug delivery by magnetoelectric nanoparticles

    Science.gov (United States)

    Stimphil, Emmanuel; Nagesetti, Abhignyan; Guduru, Rakesh; Stewart, Tiffanie; Rodzinski, Alexandra; Liang, Ping; Khizroev, Sakhrat

    2017-06-01

    In regard to cancer therapy, magnetoelectric nanoparticles (MENs) have proven to be in a class of its own when compared to any other nanoparticle type. Like conventional magnetic nanoparticles, they can be used for externally controlled drug delivery via application of a magnetic field gradient and image-guided delivery. However, unlike conventional nanoparticles, due to the presence of a non-zero magnetoelectric effect, MENs provide a unique mix of important properties to address key challenges in modern cancer therapy: (i) a targeting mechanism driven by a physical force rather than antibody matching, (ii) a high-specificity delivery to enhance the cellular uptake of therapeutic drugs across the cancer cell membranes only, while sparing normal cells, (iii) an externally controlled mechanism to release drugs on demand, and (iv) a capability for image guided precision medicine. These properties separate MEN-based targeted delivery from traditional biotechnology approaches and lay a foundation for the complementary approach of technobiology. The biotechnology approach stems from the underlying biology and exploits bioinformatics to find the right therapy. In contrast, the technobiology approach is geared towards using the physics of molecular-level interactions between cells and nanoparticles to treat cancer at the most fundamental level and thus can be extended to all the cancers. This paper gives an overview of the current state of the art and presents an ab initio model to describe the underlying mechanisms of cancer treatment with MENs from the perspective of basic physics.

  1. Self-assembled peptide-based nanostructures: Smart nanomaterials toward targeted drug delivery.

    Science.gov (United States)

    Habibi, Neda; Kamaly, Nazila; Memic, Adnan; Shafiee, Hadi

    2016-02-01

    Self-assembly of peptides can yield an array of well-defined nanostructures that are highly attractive nanomaterials for many biomedical applications such as drug delivery. Some of the advantages of self-assembled peptide nanostructures over other delivery platforms include their chemical diversity, biocompatibility, high loading capacity for both hydrophobic and hydrophilic drugs, and their ability to target molecular recognition sites. Furthermore, these self-assembled nanostructures could be designed with novel peptide motifs, making them stimuli-responsive and achieving triggered drug delivery at disease sites. The goal of this work is to present a comprehensive review of the most recent studies on self-assembled peptides with a focus on their "smart" activity for formation of targeted and responsive drug-delivery carriers.

  2. Dual responsive PNIPAM–chitosan targeted magnetic nanopolymers for targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Yadavalli, Tejabhiram, E-mail: tejabhiram@gmail.com [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); Ramasamy, Shivaraman [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); School of Physics, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009 (Australia); Chandrasekaran, Gopalakrishnan; Michael, Isaac; Therese, Helen Annal [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); Chennakesavulu, Ramasamy [Department of Pharmacy practice, SRM College of Pharmacy, Chennai 603203 (India)

    2015-04-15

    A dual stimuli sensitive magnetic hyperthermia based drug delivery system has been developed for targeted cancer treatment. Thermosensitive amine terminated poly-N-isopropylacrylamide complexed with pH sensitive chitosan nanoparticles was prepared as the drug carrier. Folic acid and fluorescein were tagged to the nanopolymer complex via N-hydroxysuccinimide and ethyl-3-(3-dimethylaminopropyl)carbodiimide reaction to form a fluorescent and cancer targeting magnetic carrier system. The formation of the polymer complex was confirmed using infrared spectroscopy. Gadolinium doped nickel ferrite nanoparticles prepared by a hydrothermal method were encapsulated in the polymer complex to form a magnetic drug carrier system. The proton relaxation studies on the magnetic carrier system revealed a 200% increase in the T1 proton relaxation rate. These magnetic carriers were loaded with curcumin using solvent evaporation method with a drug loading efficiency of 86%. Drug loaded nanoparticles were tested for their targeting and anticancer properties on four cancer cell lines with the help of MTT assay. The results indicated apoptosis of cancer cell lines within 3 h of incubation. - Highlights: • The use of gadolinium doped nickel ferrite with the suggested doping level. • The use of PNIPMA–chitosan polymer with folic acid and fluorescein as a drug carrier complex. • Magnetic hyperthermia studies of gadolinium doped nickel ferrites are being reported for the first time. • Proton relaxivity studies which indicate the MRI contrasting properties on the reported system are new. • Use of curcumin, a hydrophobic Indian spice as a cancer killing agent inside the reported magnetic polymer complex.

  3. Encapsulation of methotrexate loaded magnetic microcapsules for magnetic drug targeting and controlled drug release

    Energy Technology Data Exchange (ETDEWEB)

    Chakkarapani, Prabu [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli 620024, Tamil Nadu (India); Subbiah, Latha, E-mail: lathasuba2010@gmail.com [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli 620024, Tamil Nadu (India); Palanisamy, Selvamani; Bibiana, Arputha [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli 620024, Tamil Nadu (India); Ahrentorp, Fredrik; Jonasson, Christian; Johansson, Christer [Acreo Swedish ICT AB, Arvid Hedvalls backe 4, SE-411 33 Göteborg (Sweden)

    2015-04-15

    We report on the development and evaluation of methotrexate magnetic microcapsules (MMC) for targeted rheumatoid arthritis therapy. Methotrexate was loaded into CaCO{sub 3}-PSS (poly (sodium 4-styrenesulfonate)) doped microparticles that were coated successively with poly (allylamine hydrochloride) and poly (sodium 4-styrenesulfonate) by layer-by-layer technique. Ferrofluid was incorporated between the polyelectrolyte layers. CaCO{sub 3}-PSS core was etched by incubation with EDTA yielding spherical MMC. The MMC were evaluated for various physicochemical, pharmaceutical parameters and magnetic properties. Surface morphology, crystallinity, particle size, zeta potential, encapsulation efficiency, loading capacity, drug release pattern, release kinetics and AC susceptibility studies revealed spherical particles of ~3 µm size were obtained with a net zeta potential of +24.5 mV, 56% encapsulation and 18.6% drug loading capacity, 96% of cumulative drug release obeyed Hixson-Crowell model release kinetics. Drug excipient interaction, surface area, thermal and storage stability studies for the prepared MMC was also evaluated. The developed MMC offer a promising mode of targeted and sustained release drug delivery for rheumatoid arthritis therapy. - Highlights: • Development of methotrexate magnetic microcapsules (MMC) by layer-by-layer method. • Characterization of physicochemical, pharmaceutical and magnetic properties of MMC. • Multiple layers of alternative polyelectrolytes prolongs methotrexate release time. • MMC is capable for targeted and sustained release rheumatoid arthritis therapy.

  4. Current idea of an algorithm for drug treatment and optimal succession of using targeted drugs

    Directory of Open Access Journals (Sweden)

    D. A. Nosov

    2014-11-01

    Full Text Available The application of targeted and pathogenetically sound medicational approaches could considerably improve the results of therapy in patients with metastatic renal-cell carcinoma (mRCC. To date, VEGF/VEGFR inhibitors continue to remain a basic and most effective drug treatment in patients with mRCC and the choice of a drug for first-line therapy is based on the following factors: disease prognosis, a patient’s general somatic state, and the understanding of immediate therapy goals, anticipated toxicity and tolerability.Most patients develop resistance to VEGFR inhibitors within 6–11 months after treatment initiation. The basis for resistance development may be the following mechanisms: activation of alternative proangiogenic signaling pathways, that of angiogenesis-independent progression pathways, a microenvironment-induced phenotypic change of tumor cells to form their resistance to targeted drugs, and pharmacokinetic and pharmacodynamic changes in the drug itself during therapy. To overcome resistance to VEGFR inhibitors, there are 2 possible options: 1 switching to a drug having another mechanism of action (the mTOR inhibitor everolimus; 2 that to a more selective and potent tyrosine kinase inhibitor (axitinib that selectively affects and suppresses the activityof the same targets – VEGFR (Vascular Endothelial Growth Factor Receptor 1–3. As before, there is scanty convincing evidence for unique benefits in a particular succession of targeted drugs: a VEGFR inhibitor – a VEGFR inhibitor or a VEGFR inhibitor – an mТOR inhibitor. In a number of cases, the succession of prescribing of targeted drugs may be practically determined by clinical criteria, specifically by the possibility of controlling toxic complications that may be typical for VEFGR inhibitors and may accumulate in case of their successive use. It must be also remembered that VEGFR inhibitors may be successfully reused in patients who have received second- or

  5. Current idea of an algorithm for drug treatment and optimal succession of using targeted drugs

    Directory of Open Access Journals (Sweden)

    D. A. Nosov

    2014-01-01

    Full Text Available The application of targeted and pathogenetically sound medicational approaches could considerably improve the results of therapy in patients with metastatic renal-cell carcinoma (mRCC. To date, VEGF/VEGFR inhibitors continue to remain a basic and most effective drug treatment in patients with mRCC and the choice of a drug for first-line therapy is based on the following factors: disease prognosis, a patient’s general somatic state, and the understanding of immediate therapy goals, anticipated toxicity and tolerability.Most patients develop resistance to VEGFR inhibitors within 6–11 months after treatment initiation. The basis for resistance development may be the following mechanisms: activation of alternative proangiogenic signaling pathways, that of angiogenesis-independent progression pathways, a microenvironment-induced phenotypic change of tumor cells to form their resistance to targeted drugs, and pharmacokinetic and pharmacodynamic changes in the drug itself during therapy. To overcome resistance to VEGFR inhibitors, there are 2 possible options: 1 switching to a drug having another mechanism of action (the mTOR inhibitor everolimus; 2 that to a more selective and potent tyrosine kinase inhibitor (axitinib that selectively affects and suppresses the activityof the same targets – VEGFR (Vascular Endothelial Growth Factor Receptor 1–3. As before, there is scanty convincing evidence for unique benefits in a particular succession of targeted drugs: a VEGFR inhibitor – a VEGFR inhibitor or a VEGFR inhibitor – an mТOR inhibitor. In a number of cases, the succession of prescribing of targeted drugs may be practically determined by clinical criteria, specifically by the possibility of controlling toxic complications that may be typical for VEFGR inhibitors and may accumulate in case of their successive use. It must be also remembered that VEGFR inhibitors may be successfully reused in patients who have received second- or

  6. Targeting the treatment of drug abuse with molecular imaging

    International Nuclear Information System (INIS)

    Schiffer, Wynne K.; Liebling, Courtney N.B.; Patel, Vinal; Dewey, Stephen L.

    2007-01-01

    Although imaging studies in and of themselves have significant contributions to the study of human behavior, imaging in drug abuse has a much broader agenda. Drugs of abuse bind to molecules in specific parts of the brain in order to produce their effects. Positron emission tomography (PET) provides a unique opportunity to track this process, capturing the kinetics with which an abused compound is transported to its site of action. The specific examples discussed here were chosen to illustrate how PET can be used to map the regional distribution and kinetics of compounds that may or may not have abuse liability. We also discussed some morphological and functional changes associated with drug abuse and different stages of recovery following abstinence. PET measurements of functional changes in the brain have also led to the development of several treatment strategies, one of which is discussed in detail here. Information such as this becomes more than a matter of academic interest. Such knowledge can provide the bases for anticipating which compounds may be abused and which may not. It can also be used to identify biological markers or changes in brain function that are associated with progression from drug use to drug abuse and also to stage the recovery process. This new knowledge can guide legislative initiatives on the optimal duration of mandatory treatment stays, promoting long-lasting abstinence and greatly reducing the societal burden of drug abuse. Imaging can also give some insights into potential pharmacotherapeutic targets to manage the reinforcing effects of addictive compounds, as well as into protective strategies to minimize their toxic consequences

  7. Targeting the treatment of drug abuse with molecular imaging

    Energy Technology Data Exchange (ETDEWEB)

    Schiffer, Wynne K. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States)], E-mail: wynne@bnl.gov; Liebling, Courtney N.B.; Patel, Vinal; Dewey, Stephen L. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States)

    2007-10-15

    Although imaging studies in and of themselves have significant contributions to the study of human behavior, imaging in drug abuse has a much broader agenda. Drugs of abuse bind to molecules in specific parts of the brain in order to produce their effects. Positron emission tomography (PET) provides a unique opportunity to track this process, capturing the kinetics with which an abused compound is transported to its site of action. The specific examples discussed here were chosen to illustrate how PET can be used to map the regional distribution and kinetics of compounds that may or may not have abuse liability. We also discussed some morphological and functional changes associated with drug abuse and different stages of recovery following abstinence. PET measurements of functional changes in the brain have also led to the development of several treatment strategies, one of which is discussed in detail here. Information such as this becomes more than a matter of academic interest. Such knowledge can provide the bases for anticipating which compounds may be abused and which may not. It can also be used to identify biological markers or changes in brain function that are associated with progression from drug use to drug abuse and also to stage the recovery process. This new knowledge can guide legislative initiatives on the optimal duration of mandatory treatment stays, promoting long-lasting abstinence and greatly reducing the societal burden of drug abuse. Imaging can also give some insights into potential pharmacotherapeutic targets to manage the reinforcing effects of addictive compounds, as well as into protective strategies to minimize their toxic consequences.

  8. Electrospun Nanofibers of Guar Galactomannan for Targeted Drug Delivery

    Science.gov (United States)

    Chu, Hsiao Mei Annie

    2011-12-01

    Guar galactomannan is a biodegradable polysaccharide used widely in the food industry but also in the cosmetics, pharmaceutical, oil drilling, textile and paper industries. Guar consists of a mannose backbone and galactose side groups that are both susceptible to enzyme degradation, a unique property that can be explored for targeted drug delivery especially since those enzymes are naturally secreted by the microflora in human colon. The present study can be divided into three parts. In the first part, we discuss ways to modify guar to produce nanofibers by electrospinning, a process that involves the application of an electric field to a polymer solution or melt to facilitate production of fibers in the sub-micron range. Nanofibers are currently being explored as the next generation of drug carriers due to its many advantages, none more important than the fact that nanofibers are on a size scale that is a fraction of a hair's width and have large surface-to-volume ratio. The incorporation and controlled release of nano-sized drugs is one way in which nanofibers are being utilized in drug delivery. In the second part of the study, we explore various methods to crosslink guar nanofibers as a means to promote water-resistance in a potential drug carrier. The scope and utility of water-resistant guar nanofibers can only be fully appreciated when subsequent drug release studies are carried out. To that end, the third part of our study focuses on understanding the kinetics and diffusion mechanisms of a model drug, Rhodamine B, through moderately-swelling (crosslinked) hydrogel nanofibers in comparison to rapidly-swelling (non-crosslinked) nanofibers. Along the way, our investigations led us to a novel electrospinning set-up that has a unique collector designed to capture aligned nanofibers. These aligned nanofiber bundles can then be twisted to hold them together like yarn. From a practical standpoint, these yarns are advantageous because they come freely suspended and

  9. Photosensitizer-mediated mitochondria-targeting nanosized drug carriers: Subcellular targeting, therapeutic, and imaging potentials.

    Science.gov (United States)

    Choi, Yeon Su; Kwon, Kiyoon; Yoon, Kwonhyeok; Huh, Kang Moo; Kang, Han Chang

    2017-03-30

    Mitochondria-targeting drug carriers have considerable potential because of the presence of many molecular drug targets in the mitochondria and their pivotal roles in cellular viability, metabolism, maintenance, and death. To compare the mitochondria-targeting abilities of triphenylphosphonium (TPP) and pheophorbide a (PhA) in nanoparticles (NPs), this study prepared mitochondria-targeting NPs using mixtures of methoxy poly(ethylene glycol)-(SS-PhA) 2 [mPEG-(SS-PhA) 2 or PPA] and TPP-b-poly(ε-caprolactone)-b-TPP [TPP-b-PCL-b-TPP or TPCL], which were designated PPA n -TPCL 4-n (0≤n≤4) NPs. With increasing TPCL content, the formed PPA n -TPCL 4-n NPs decreased in size from 33nm to 18nm and increased in terms of positive zeta-potentials from -12mV to 33mV. Although the increased TPCL content caused some dark toxicity of the PPA n -TPCL 4-n NPs due to the intrinsic positive character of TPCL, the NPs showed strong light-induced killing effects in tumor cells. In addition, the mitochondrial distribution of the PPA n -TPCL 4-n NPs was analyzed and imaged by flow cytometry and confocal microscopy, respectively. Thus, the PhA-containing NPs specifically targeted the mitochondria, and light stimulation caused PhA-mediated therapeutic effects and imaging functions. Expanding the capabilities of these nanocarriers by incorporating other drugs should enable multiple potential applications (e.g., targeting, therapy, and imaging) for combination and synergistic treatments. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Prediction of Effective Drug Combinations by Chemical Interaction, Protein Interaction and Target Enrichment of KEGG Pathways

    Directory of Open Access Journals (Sweden)

    Lei Chen

    2013-01-01

    Full Text Available Drug combinatorial therapy could be more effective in treating some complex diseases than single agents due to better efficacy and reduced side effects. Although some drug combinations are being used, their underlying molecular mechanisms are still poorly understood. Therefore, it is of great interest to deduce a novel drug combination by their molecular mechanisms in a robust and rigorous way. This paper attempts to predict effective drug combinations by a combined consideration of: (1 chemical interaction between drugs, (2 protein interactions between drugs’ targets, and (3 target enrichment of KEGG pathways. A benchmark dataset was constructed, consisting of 121 confirmed effective combinations and 605 random combinations. Each drug combination was represented by 465 features derived from the aforementioned three properties. Some feature selection techniques, including Minimum Redundancy Maximum Relevance and Incremental Feature Selection, were adopted to extract the key features. Random forest model was built with its performance evaluated by 5-fold cross-validation. As a result, 55 key features providing the best prediction result were selected. These important features may help to gain insights into the mechanisms of drug combinations, and the proposed prediction model could become a useful tool for screening possible drug combinations.

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

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2015-08-01

    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.

  12. 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.

  13. Discovering the first microRNA-targeted drug

    DEFF Research Database (Denmark)

    Lindow, Morten; Kauppinen, Sakari

    2012-01-01

    MicroRNAs (miRNAs) are important post-transcriptional regulators of nearly every biological process in the cell and play key roles in the pathogenesis of human disease. As a result, there are many drug discovery programs that focus on developing miRNA-based therapeutics. The most advanced...... of these programs targets the liver-expressed miRNA-122 using the locked nucleic acid (LNA)–modified antisense oligonucleotide miravirsen. Here, we describe the discovery of miravirsen, which is currently in phase 2 clinical trials for treatment of hepatitis C virus (HCV) infection....

  14. Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy

    Directory of Open Access Journals (Sweden)

    Han-Chung Wu

    2010-01-01

    Full Text Available Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy.

  15. PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database.

    Science.gov (United States)

    Wang, Xia; Shen, Yihang; Wang, Shiwei; Li, Shiliang; Zhang, Weilin; Liu, Xiaofeng; Lai, Luhua; Pei, Jianfeng; Li, Honglin

    2017-07-03

    The PharmMapper online tool is a web server for potential drug target identification by reversed pharmacophore matching the query compound against an in-house pharmacophore model database. The original version of PharmMapper includes more than 7000 target pharmacophores derived from complex crystal structures with corresponding protein target annotations. In this article, we present a new version of the PharmMapper web server, of which the backend pharmacophore database is six times larger than the earlier one, with a total of 23 236 proteins covering 16 159 druggable pharmacophore models and 51 431 ligandable pharmacophore models. The expanded target data cover 450 indications and 4800 molecular functions compared to 110 indications and 349 molecular functions in our last update. In addition, the new web server is united with the statistically meaningful ranking of the identified drug targets, which is achieved through the use of standard scores. It also features an improved user interface. The proposed web server is freely available at http://lilab.ecust.edu.cn/pharmmapper/. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  16. Design of a tripartite network for the prediction of drug targets

    Science.gov (United States)

    Kunimoto, Ryo; Bajorath, Jürgen

    2018-02-01

    Drug-target networks have aided in many target prediction studies aiming at drug repurposing or the analysis of side effects. Conventional drug-target networks are bipartite. They contain two different types of nodes representing drugs and targets, respectively, and edges indicating pairwise drug-target interactions. In this work, we introduce a tripartite network consisting of drugs, other bioactive compounds, and targets from different sources. On the basis of analog relationships captured in the network and so-called neighbor targets of drugs, new drug targets can be inferred. The tripartite network was found to have a stable structure and simulated network growth was accompanied by a steady increase in assortativity, reflecting increasing correlation between degrees of connected nodes leading to even network connectivity. Local drug environments in the tripartite network typically contained neighbor targets and revealed interesting drug-compound-target relationships for further analysis. Candidate targets were prioritized. The tripartite network design extends standard drug-target networks and provides additional opportunities for drug target prediction.

  17. Identification of Drug Characteristics for Implementing Multiregional Clinical Trials Including Japan.

    Science.gov (United States)

    Rokuda, Mitsuhiro; Matsumaru, Naoki; Tsukamoto, Katsura

    2018-02-01

    Multiregional clinical trials (MRCT) are a standard strategy used to improve global drug approval efficiency and the feasibility of clinical trials. Japan is the world's third largest drug market with a unique health care system, making it a key inclusion as an operational region for MRCT (MRCT-JP) for global drug development. We aimed to identify the factors required for efficient drug development by comprehensively reviewing the clinical trials of drugs approved in Japan to identify the factors associated with whether or not MRCT-JP is implemented. We surveyed the review reports and summaries of application data published by the Pharmaceuticals and Medical Devices Agency. We identified drugs for which the clinical trial data package included MRCT-JP and selected the same number of drugs for which the clinical trial data package did not include MRCT-JP from the most recent survey period for comparison. We also examined other publication information, in addition to the review reports, as necessary. The influence of each explanatory variable was analyzed by logistic regression analysis, with whether or not MRCT-JP was implemented as the explanatory variable. Statistical significance was set at 5%. In the survey period up to September 2017, 165 drugs developed with MRCT-JP were approved for manufacture and sale in Japan. "Respiratory system," "inhalation," "biological drug," and "under review" evaluation status for the United States, European Union, and other areas, "approved" evaluation status for the United States, "new ingredients," "priority review," "non-Japanese firm," and "Top 1-10" and "Top 11-20" drug sales rankings for pharmaceutical companies were identified as potential factors leading to the implementation of MRCT-JP. In contrast, "general anti-infectives for systemic use," "various," "external," "chemical compound," "unsubmitted" evaluation status for both the United States and European Union, and "Top 51+" drug sales rankings were potential factors for

  18. Relationship of sea level muon charge ratio to primary composition including nuclear target effects

    Science.gov (United States)

    Goned, A.; Shalaby, M.; Salem, A. M.; Roushdy, M.

    1985-01-01

    The discrepancy between the muon charge ratio observed at low energies and that calculated using pp data is removed by including nuclear target effects. Calculations at high energies show that the primary iron spectrum is expected to change slope from 2 to 2.2 to 2.4 to 2.5 for energies approx. 4 x 10 to the 3 GeV/nucleon if scaling features continue to the highest energies.

  19. Sigma-1 receptor: The novel intracellular target of neuropsychotherapeutic drugs

    Directory of Open Access Journals (Sweden)

    Teruo Hayashi

    2015-01-01

    Full Text Available Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent research exploring the molecular function of the sigma-1 receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone activity is activated or inhibited by synthetic sigma-1 receptor ligands in an agonist-antagonist manner. Sigma-1 receptors are localized at the endoplasmic reticulum (ER membranes that are physically associated with the mitochondria (MAM: mitochondria-associated ER membrane. In specific types of neurons (e.g., those at the spinal cord, sigma-1 receptors are also clustered at ER membranes that juxtapose postsynaptic plasma membranes. Recent studies indicate that sigma-1 receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation. The sigma-1 receptor may thus provide an intracellular drug target that enables controlling ER stress and free radical generation under pathological conditions.

  20. Nanomaterials for the Local and Targeted Delivery of Osteoarthritis Drugs

    Directory of Open Access Journals (Sweden)

    Parthiban Chinnagounder Periyasamy

    2012-01-01

    Full Text Available Nanotechnology has found its potential in every possible field of science and engineering. It offers a plethora of options to design tools at the nanometer scale, which can be expected to function more effectively than micro- and macrosystems for specific applications. Although the debate regarding the safety of synthetic nanomaterials for clinical applications endures, it is a promising technology due to its potential to augment current treatments. Various materials such as synthetic polymer, biopolymers, or naturally occurring materials such as proteins and peptides can serve as building blocks for adaptive nanoscale formulations. The choice of materials depends highly on the application. We focus on the use of nanoparticles for the treatment of degenerative cartilage diseases, such as osteoarthritis (OA. Current therapies for OA focus on treating the symptoms rather than modifying the disease. The usefulness of OA disease modifying drugs is hampered by side effects and lack of suitable drug delivery systems that target, deliver, and retain drugs locally. This challenge can be overcome by using nanotechnological formulations. We describe the different nanodrug delivery systems and their potential for cartilage repair. This paper provides the reader basal understanding of nanomaterials and aims at drawing new perspectives on the use of existing nanotechnological formulations for the treatment of osteoarthritis.

  1. Vaccines targeting drugs of abuse: is the glass half-empty or half-full?

    Science.gov (United States)

    Janda, Kim D; Treweek, Jennifer B

    2011-12-16

    The advent of vaccines targeting drugs of abuse heralded a fundamentally different approach to treating substance-related disorders. In contrast to traditional pharmacotherapies for drug abuse, vaccines act by sequestering circulating drugs and terminating the drug-induced 'high' without inducing unwanted neuromodulatory effects. Drug-targeting vaccines have entered clinical evaluation, and although these vaccines show promise from a biomedical viewpoint, the ethical and socioeconomic implications of vaccinating patients against drugs of abuse merit discussion within the scientific community.

  2. Retention of ferrofluid aggregates at the target site during magnetic drug targeting

    Energy Technology Data Exchange (ETDEWEB)

    Asfer, Mohammed, E-mail: asfer786@gmail.com [School of Engineering and Technology, BML Munjal University, Haryana (India); Saroj, Sunil Kumar [Department of Mechanical Engineering, IIT Kanpur, Kanpur (India); Panigrahi, Pradipta Kumar, E-mail: panig@iitk.ac.in [Department of Mechanical Engineering, IIT Kanpur, Kanpur (India)

    2017-08-15

    Highlights: • The present in vitro work reports the retention dynamics of ferrofluid aggregates at the target site against a bulk flow of DI water inside a micro capillary during magnetic drug targeting. • The recirculation zone at the downstream of the aggregate is found to be a function of aggregate height, Reynolds number and the degree of surface roughness of the outer boundary of the aggregate. • The reported results of the present work can be used as a guideline for the better design of MDT technique for in vivo applications. - Abstract: The present study reports the retention dynamics of a ferrofluid aggregate localized at the target site inside a glass capillary (500 × 500 µm{sup 2} square cross section) against a bulk flow of DI water (Re = 0.16 and 0.016) during the process of magnetic drug targeting (MDT). The dispersion dynamics of iron oxide nanoparticles (IONPs) into bulk flow for different initial size of aggregate at the target site is reported using the brightfield visualization technique. The flow field around the aggregate during the retention is evaluated using the µPIV technique. IONPs at the outer boundary experience a higher shear force as compared to the magnetic force, resulting in dispersion of IONPs into the bulk flow downstream to the aggregate. The blockage effect and the roughness of the outer boundary of the aggregate resulting from chain like clustering of IONPs contribute to the flow recirculation at the downstream region of the aggregate. The entrapment of seeding particles inside the chain like clusters of IONPs at the outer boundary of the aggregate reduces the degree of roughness resulting in a streamlined aggregate at the target site at later time. The effect of blockage, structure of the aggregate, and disturbed flow such as recirculation around the aggregate are the primary factors, which must be investigated for the effectiveness of the MDT process for in vivo applications.

  3. REV-ERB and ROR nuclear receptors as drug targets

    Science.gov (United States)

    Kojetin, Douglas J.; Burris, Thomas P.

    2016-01-01

    The nuclear receptors REV-ERB (consisting of REV-ERBα and REV-ERBβ) and retinoic acid receptor-related orphan receptors (RORs; consisting of RORα, RORβ and RORγ) are involved in many physiological processes, including regulation of metabolism, development and immunity as well as the circadian rhythm. The recent characterization of endogenous ligands for these former orphan nuclear receptors has stimulated the development of synthetic ligands and opened up the possibility of targeting these receptors to treat several diseases, including diabetes, atherosclerosis, autoimmunity and cancer. This Review focuses on the latest developments in ROR and REV-ERB pharmacology indicating that these nuclear receptors are druggable targets and that ligands targeting these receptors may be useful in the treatment of several disorders. PMID:24577401

  4. Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets.

    Directory of Open Access Journals (Sweden)

    Reagan M Mogire

    Full Text Available Malaria causes about half a million deaths annually, with Plasmodium falciparum being responsible for 90% of all the cases. Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for the treatment of malaria. However, most bioactive compounds fail to progress to treatments due to safety concerns. Drug repositioning offers an alternative strategy where drugs that have already been approved as safe for other diseases could be used to treat malaria. This study screened approved drugs for antimalarial activity using an in silico chemogenomics approach prior to in vitro verification. All the P. falciparum proteins sequences available in NCBI RefSeq were mined and used to perform a similarity search against DrugBank, TTD and STITCH databases to identify similar putative drug targets. Druggability indices of the potential P. falciparum drug targets were obtained from TDR targets database. Functional amino acid residues of the drug targets were determined using ConSurf server which was used to fine tune the similarity search. This study predicted 133 approved drugs that could target 34 P. falciparum proteins. A literature search done at PubMed and Google Scholar showed 105 out of the 133 drugs to have been previously tested against malaria, with most showing activity. For further validation, drug susceptibility assays using SYBR Green I method were done on a representative group of 10 predicted drugs, eight of which did show activity against P. falciparum 3D7 clone. Seven had IC50 values ranging from 1 μM to 50 μM. This study also suggests drug-target association and hence possible mechanisms of action of drugs that did show antiplasmodial activity. The study results validate the use of proteome-wide target similarity approach in identifying approved drugs with activity against P. falciparum and could be adapted for other pathogens.

  5. Muscarinic Acetylcholine Receptor Subtypes as Potential Drug Targets for the Treatment of Schizophrenia, Drug Abuse and Parkinson's Disease

    DEFF Research Database (Denmark)

    Dencker, Ditte; Thomsen, Morgane; Wörtwein, Gitta

    2011-01-01

    's disease and drug abuse. Dopaminergic systems are regulated by cholinergic, especially muscarinic, input. Not surprisingly, increasing evidence implicates muscarinic acetylcholine receptor-mediated pathways as potential targets for the treatment of these disorders classically viewed as "dopamine based...... site. Such agents may lead to the development of novel classes of drugs useful for the treatment of psychosis, drug abuse and Parkinson's disease. The present review highlights recent studies carried out using muscarinic receptor knock-out mice and new subtype-selective allosteric ligands to assess......The neurotransmitter dopamine plays important roles in modulating cognitive, affective, and motor functions. Dysregulation of dopaminergic neurotransmission is thought to be involved in the pathophysiology of several psychiatric and neurological disorders, including schizophrenia, Parkinson...

  6. Prediction of drug-target interaction networks from the integration of chemical and genomic spaces.

    Science.gov (United States)

    Yamanishi, Yoshihiro; Araki, Michihiro; Gutteridge, Alex; Honda, Wataru; Kanehisa, Minoru

    2008-07-01

    The identification of interactions between drugs and target proteins is a key area in genomic drug discovery. Therefore, there is a strong incentive to develop new methods capable of detecting these potential drug-target interactions efficiently. In this article, we characterize four classes of drug-target interaction networks in humans involving enzymes, ion channels, G-protein-coupled receptors (GPCRs) and nuclear receptors, and reveal significant correlations between drug structure similarity, target sequence similarity and the drug-target interaction network topology. We then develop new statistical methods to predict unknown drug-target interaction networks from chemical structure and genomic sequence information simultaneously on a large scale. The originality of the proposed method lies in the formalization of the drug-target interaction inference as a supervised learning problem for a bipartite graph, the lack of need for 3D structure information of the target proteins, and in the integration of chemical and genomic spaces into a unified space that we call 'pharmacological space'. In the results, we demonstrate the usefulness of our proposed method for the prediction of the four classes of drug-target interaction networks. Our comprehensively predicted drug-target interaction networks enable us to suggest many potential drug-target interactions and to increase research productivity toward genomic drug discovery. Softwares are available upon request. Datasets and all prediction results are available at http://web.kuicr.kyoto-u.ac.jp/supp/yoshi/drugtarget/.

  7. Detecting drug-target binding in cells using fluorescence-activated cell sorting coupled with mass spectrometry analysis

    Science.gov (United States)

    Wilson, Kris; Webster, Scott P.; Iredale, John P.; Zheng, Xiaozhong; Homer, Natalie Z.; Pham, Nhan T.; Auer, Manfred; Mole, Damian J.

    2018-01-01

    The assessment of drug-target engagement for determining the efficacy of a compound inside cells remains challenging, particularly for difficult target proteins. Existing techniques are more suited to soluble protein targets. Difficult target proteins include those with challenging in vitro solubility, stability or purification properties that preclude target isolation. Here, we report a novel technique that measures intracellular compound-target complex formation, as well as cellular permeability, specificity and cytotoxicity-the toxicity-affinity-permeability-selectivity (TAPS) technique. The TAPS assay is exemplified here using human kynurenine 3-monooxygenase (KMO), a challenging intracellular membrane protein target of significant current interest. TAPS confirmed target binding of known KMO inhibitors inside cells. We conclude that the TAPS assay can be used to facilitate intracellular hit validation on most, if not all intracellular drug targets.

  8. Predicting targeted drug combinations based on Pareto optimal patterns of coexpression network connectivity.

    Science.gov (United States)

    Penrod, Nadia M; Greene, Casey S; Moore, Jason H

    2014-01-01

    Molecularly targeted drugs promise a safer and more effective treatment modality than conventional chemotherapy for cancer patients. However, tumors are dynamic systems that readily adapt to these agents activating alternative survival pathways as they evolve resistant phenotypes. Combination therapies can overcome resistance but finding the optimal combinations efficiently presents a formidable challenge. Here we introduce a new paradigm for the design of combination therapy treatment strategies that exploits the tumor adaptive process to identify context-dependent essential genes as druggable targets. We have developed a framework to mine high-throughput transcriptomic data, based on differential coexpression and Pareto optimization, to investigate drug-induced tumor adaptation. We use this approach to identify tumor-essential genes as druggable candidates. We apply our method to a set of ER(+) breast tumor samples, collected before (n = 58) and after (n = 60) neoadjuvant treatment with the aromatase inhibitor letrozole, to prioritize genes as targets for combination therapy with letrozole treatment. We validate letrozole-induced tumor adaptation through coexpression and pathway analyses in an independent data set (n = 18). We find pervasive differential coexpression between the untreated and letrozole-treated tumor samples as evidence of letrozole-induced tumor adaptation. Based on patterns of coexpression, we identify ten genes as potential candidates for combination therapy with letrozole including EPCAM, a letrozole-induced essential gene and a target to which drugs have already been developed as cancer therapeutics. Through replication, we validate six letrozole-induced coexpression relationships and confirm the epithelial-to-mesenchymal transition as a process that is upregulated in the residual tumor samples following letrozole treatment. To derive the greatest benefit from molecularly targeted drugs it is critical to design combination

  9. Identification of the Schistosoma mansoni Molecular Target for the Antimalarial Drug Artemether

    KAUST Repository

    Lepore, Rosalba

    2011-11-28

    Plasmodium falciparum and Schistosoma mansonii are the parasites responsible for most of the malaria and schistosomiasis cases in the world. Notwithstanding their many differences, the two agents have striking similarities in that they both are blood feeders and are targets of an overlapping set of drugs, including the well-known artemether molecule. Here we explore the possibility of using the known information about the mode of action of artemether in Plasmodium to identify the molecular target of the drug in Schistosoma and provide evidence that artemether binds to SmSERCA, a putative Ca2+-ATPase of Schistosoma. We also predict the putative binding mode of the molecule for both its Plasmodium and Schistosoma targets. Our analysis of the mode of binding of artemether to Ca2+-ATPases also provides an explanation for the apparent paradox that, although the molecule has no side effect in humans, it has been shown to possess antitumoral activity. © 2011 American Chemical Society.

  10. Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis.

    Directory of Open Access Journals (Sweden)

    Bálint Mészáros

    2011-07-01

    Full Text Available Lengthy co-evolution of Homo sapiens and Mycobacterium tuberculosis, the main causative agent of tuberculosis, resulted in a dramatically successful pathogen species that presents considerable challenge for modern medicine. The continuous and ever increasing appearance of multi-drug resistant mycobacteria necessitates the identification of novel drug targets and drugs with new mechanisms of action. However, further insights are needed to establish automated protocols for target selection based on the available complete genome sequences. In the present study, we perform complete proteome level comparisons between M. tuberculosis, mycobacteria, other prokaryotes and available eukaryotes based on protein domains, local sequence similarities and protein disorder. We show that the enrichment of certain domains in the genome can indicate an important function specific to M. tuberculosis. We identified two families, termed pkn and PE/PPE that stand out in this respect. The common property of these two protein families is a complex domain organization that combines species-specific regions, commonly occurring domains and disordered segments. Besides highlighting promising novel drug target candidates in M. tuberculosis, the presented analysis can also be viewed as a general protocol to identify proteins involved in species-specific functions in a given organism. We conclude that target selection protocols should be extended to include proteins with complex domain architectures instead of focusing on sequentially unique and essential proteins only.

  11. Medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and invention of boron tracedrugs as innovative future-architectural drugs.

    Science.gov (United States)

    Hori, Hitoshi; Uto, Yoshihiro; Nakata, Eiji

    2010-09-01

    We describe herein for the first time our medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and boron tracedrugs as newly emerging drug classes. A new area of antineoplastic drugs and treatments has recently focused on neoplastic cells of the tumor environment/microenvironment involving accessory cells. This tumor hypoxic environment is now considered as a major factor that influences not only the response to antineoplastic therapies but also the potential for malignant progression and metastasis. We review our medicinal electronomics bricolage design of hypoxia-targeting drugs, antiangiogenic hypoxic cell radiosensitizers, sugar-hybrid hypoxic cell radiosensitizers, and hypoxia-targeting 10B delivery agents, in which we design drug candidates based on their electronic structures obtained by molecular orbital calculations, not based solely on pharmacophore development. These drugs include an antiangiogenic hypoxic cell radiosensitizer TX-2036, a sugar-hybrid hypoxic cell radiosensitizer TX-2244, new hypoxia-targeting indoleamine 2,3-dioxygenase (IDO) inhibitors, and a hypoxia-targeting BNCT agent, BSH (sodium borocaptate-10B)-hypoxic cytotoxin tirapazamine (TPZ) hybrid drug TX-2100. We then discuss the concept of boron tracedrugs as a new drug class having broad potential in many areas.

  12. Biologic Drugs: A New Target Therapy in COPD?

    Science.gov (United States)

    Yousuf, Ahmed; Brightling, Christopher E

    2018-04-23

    Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease associated with significant morbidity and mortality. Current diagnostic criteria based on the presence of fixed airflow obstruction and symptoms do not integrate the complex pathological changes occurring within the lung and they do not define different airway inflammatory patterns. The current management of COPD is based on 'one size fits all' approach and does not take the importance of heterogeneity in COPD population into account. The available treatments aim to alleviate symptoms and reduce exacerbation frequency but do not alter the course of the disease. Recent advances in molecular biology have furthered our understanding of inflammatory pathways in pathogenesis of COPD and have led to development of targeted therapies (biologics and small molecules) based on predefined biomarkers. Herein we shall review the trials of biologics in COPD and potential future drug developments in the field.

  13. Identification of attractive drug targets in neglected-disease pathogens using an in silico approach.

    Directory of Open Access Journals (Sweden)

    Gregory J Crowther

    Full Text Available BACKGROUND: The increased sequencing of pathogen genomes and the subsequent availability of genome-scale functional datasets are expected to guide the experimental work necessary for target-based drug discovery. However, a major bottleneck in this has been the difficulty of capturing and integrating relevant information in an easily accessible format for identifying and prioritizing potential targets. The open-access resource TDRtargets.org facilitates drug target prioritization for major tropical disease pathogens such as the mycobacteria Mycobacterium leprae and Mycobacterium tuberculosis; the kinetoplastid protozoans Leishmania major, Trypanosoma brucei, and Trypanosoma cruzi; the apicomplexan protozoans Plasmodium falciparum, Plasmodium vivax, and Toxoplasma gondii; and the helminths Brugia malayi and Schistosoma mansoni. METHODOLOGY/PRINCIPAL FINDINGS: Here we present strategies to prioritize pathogen proteins based on whether their properties meet criteria considered desirable in a drug target. These criteria are based upon both sequence-derived information (e.g., molecular mass and functional data on expression, essentiality, phenotypes, metabolic pathways, assayability, and druggability. This approach also highlights the fact that data for many relevant criteria are lacking in less-studied pathogens (e.g., helminths, and we demonstrate how this can be partially overcome by mapping data from homologous genes in well-studied organisms. We also show how individual users can easily upload external datasets and integrate them with existing data in TDRtargets.org to generate highly customized ranked lists of potential targets. CONCLUSIONS/SIGNIFICANCE: Using the datasets and the tools available in TDRtargets.org, we have generated illustrative lists of potential drug targets in seven tropical disease pathogens. While these lists are broadly consistent with the research community's current interest in certain specific proteins, and suggest

  14. Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate

    Directory of Open Access Journals (Sweden)

    Miguel Angel Moreno

    2014-12-01

    Full Text Available Leishmania infantum is the etiological agent of zoonotic visceral leishmaniasis in the Mediterranean basin. The disease is fatal without treatment, which has been based on antimonial pentavalents for more than 60 years. Due to resistances, relapses and toxicity to current treatment, the development of new drugs is required. The structure of the L. infantum tyrosine aminotransferase (LiTAT has been recently solved showing important differences with the mammalian orthologue. The characterization of LiTAT is reported herein. This enzyme is cytoplasmic and is over-expressed in the more infective stages and nitric oxide resistant parasites. Unlike the mammalian TAT, LiTAT is able to use ketomethiobutyrate as co-substrate. The pharmacophore model of LiTAT with this specific co-substrate is described herein. This may allow the identification of new inhibitors present in the databases. All the data obtained support that LiTAT is a good target candidate for the development of new anti-leishmanial drugs.

  15. NGR-peptide-drug conjugates with dual targeting properties.

    Directory of Open Access Journals (Sweden)

    Kata Nóra Enyedi

    Full Text Available Peptides containing the asparagine-glycine-arginine (NGR motif are recognized by CD13/aminopeptidase N (APN receptor isoforms that are selectively overexpressed in tumor neovasculature. Spontaneous decomposition of NGR peptides can result in isoAsp derivatives, which are recognized by RGD-binding integrins that are essential for tumor metastasis. Peptides binding to CD13 and RGD-binding integrins provide tumor-homing, which can be exploited for dual targeted delivery of anticancer drugs. We synthesized small cyclic NGR peptide-daunomycin conjugates using NGR peptides of varying stability (c[KNGRE]-NH2, Ac-c[CNGRC]-NH2 and the thioether bond containing c[CH2-CO-NGRC]-NH2, c[CH2-CO-KNGRC]-NH2. The cytotoxic effect of the novel cyclic NGR peptide-Dau conjugates were examined in vitro on CD13 positive HT-1080 (human fibrosarcoma and CD13 negative HT-29 (human colon adenocarcinoma cell lines. Our results confirm the influence of structure on the antitumor activity and dual acting properties of the conjugates. Attachment of the drug through an enzyme-labile spacer to the C-terminus of cyclic NGR peptide resulted in higher antitumor activity on both CD13 positive and negative cells as compared to the branching versions.

  16. Modern Prodrug Design for Targeted Oral Drug Delivery

    Directory of Open Access Journals (Sweden)

    Arik Dahan

    2014-10-01

    Full Text Available The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.

  17. In Vitro Drug Sensitivity Tests to Predict Molecular Target Drug Responses in Surgically Resected Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Ryohei Miyazaki

    Full Text Available Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs and anaplastic lymphoma kinase (ALK inhibitors have dramatically changed the strategy of medical treatment of lung cancer. Patients should be screened for the presence of the EGFR mutation or echinoderm microtubule-associated protein-like 4 (EML4-ALK fusion gene prior to chemotherapy to predict their clinical response. The succinate dehydrogenase inhibition (SDI test and collagen gel droplet embedded culture drug sensitivity test (CD-DST are established in vitro drug sensitivity tests, which may predict the sensitivity of patients to cytotoxic anticancer drugs. We applied in vitro drug sensitivity tests for cyclopedic prediction of clinical responses to different molecular targeting drugs.The growth inhibitory effects of erlotinib and crizotinib were confirmed for lung cancer cell lines using SDI and CD-DST. The sensitivity of 35 cases of surgically resected lung cancer to erlotinib was examined using SDI or CD-DST, and compared with EGFR mutation status.HCC827 (Exon19: E746-A750 del and H3122 (EML4-ALK cells were inhibited by lower concentrations of erlotinib and crizotinib, respectively than A549, H460, and H1975 (L858R+T790M cells were. The viability of the surgically resected lung cancer was 60.0 ± 9.8 and 86.8 ± 13.9% in EGFR-mutants vs. wild types in the SDI (p = 0.0003. The cell viability was 33.5 ± 21.2 and 79.0 ± 18.6% in EGFR mutants vs. wild-type cases (p = 0.026 in CD-DST.In vitro drug sensitivity evaluated by either SDI or CD-DST correlated with EGFR gene status. Therefore, SDI and CD-DST may be useful predictors of potential clinical responses to the molecular anticancer drugs, cyclopedically.

  18. Minireview: Targeting GPCR Activated ERK Pathways for Drug Discovery.

    Science.gov (United States)

    Eishingdrelo, Haifeng; Kongsamut, Sathapana

    2013-01-01

    It has become clear in recent years that multiple signal transduction pathways are employed upon GPCR activation. One of the major cellular effectors activated by GPCRs is extracellular signal-regulated kinase (ERK). Both G-protein and β-arrestin mediated signaling pathways can lead to ERK activation. However, depending on activation pathway, the subcellular destination of activated ERK1/2 may be different. G-protein -dependent ERK activation results in the translocation of active ERK to the nucleus, whereas ERK activated via an arrestin-dependent mechanism remains largely in the cytoplasm. The subcellular location of activated ERK1/2 determines the downstream signaling cascade. Many substrates of ERK1/2 are found in the nucleus: nuclear transcription factors that participate in gene transcription, cell proliferation and differentiation. ERK1/2 substrates are also found in cytosol and other cellular organelles: they may play roles in translation, mitosis, apoptosis and cross-talk with other signaling pathways. Therefore, determining specific subcellular locations of activated ERK1/2 mediated by GPCR ligands would be important in correlating signaling pathways with cellular physiological functions. While GPCR-stimulated selective ERK pathway activation has been studied in several receptor systems, exploitation of these different signaling cascades for therapeutics has not yet been seriously pursued. Many old drug candidates were identified from screens based on G-protein signaling assays, and their activity on β-arrestin signaling pathways being mostly unknown, especially regarding their subcellular ERK pathways. With today's knowledge of complicated GPCR signaling pathways, drug discovery can no longer rely on single-pathway approaches. Since ERK activation is an important signaling pathway and associated with many physiological functions, targeting the ERK pathway, especially specific subcellular activation pathways should provide new avenues for GPCR drug

  19. Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

    Directory of Open Access Journals (Sweden)

    Grant Sugiura

    2014-02-01

    Full Text Available Owing to their large size proteinaceous drugs offer higher operative information content compared to the small molecules that correspond to the traditional understanding of druglikeness. As a consequence these drugs allow developing patient-specific therapies that provide the means to go beyond the possibilities of current drug therapy. However, the efficacy of these strategies, in particular “personalized medicine”, depends on precise information about individual target expression rates. Molecular imaging combines non-invasive imaging methods with tools of molecular and cellular biology and thus bridges current knowledge to the clinical use. Moreover, nuclear medicine techniques provide therapeutic applications with tracers that behave like the diagnostic tracer. The advantages of radioiodination, still the most versatile radiolabeling strategy, and other labeled compounds comprising covalently attached radioisotopes are compared to the use of chelator-protein conjugates that are complexed with metallic radioisotopes. With the techniques using radioactive isotopes as a reporting unit or even the therapeutic principle, care has to be taken to avoid cleavage of the radionuclide from the protein it is linked to. The tracers used in molecular imaging require labeling techniques that provide site specific conjugation and metabolic stability. Appropriate choice of the radionuclide allows tailoring the properties of the labeled protein to the application required. Until the event of positron emission tomography the spectrum of nuclides used to visualize cellular and biochemical processes was largely restricted to iodine isotopes and 99m-technetium. Today, several nuclides such as 18-fluorine, 68-gallium and 86-yttrium have fundamentally extended the possibilities of tracer design and in turn caused the need for the development of chemical methods for their conjugation.

  20. PCSK9: Regulation and Target for Drug Development for Dyslipidemia.

    Science.gov (United States)

    Burke, Amy C; Dron, Jacqueline S; Hegele, Robert A; Huff, Murray W

    2017-01-06

    Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.

  1. Cdc7 kinase - a new target for drug development.

    Science.gov (United States)

    Swords, Ronan; Mahalingam, Devalingam; O'Dwyer, Michael; Santocanale, Corrado; Kelly, Kevin; Carew, Jennifer; Giles, Francis

    2010-01-01

    The cell division cycle 7 (Cdc7) is a serine threonine kinase that is of critical importance in the regulation of normal cell cycle progression. Cdc7 kinase is highly conserved during evolution and much has been learned about its biological roles in humans through the study of lower eukaryotes, particularly yeasts. Two important regulator proteins, Dbf4 and Drf1, bind to and modulate the kinase activity of human Cdc7 which phosphorylates several sites on Mcm2 (minichromosome maintenance protein 2), one of the six subunits of the replicative DNA helicase needed for duplication of the genome. Through regulation of both DNA synthesis and DNA damage response, both key functions in the survival of tumour cells, Cdc7 becomes an attractive target for pharmacological inhibition. There are much data available on the pre-clinical anti-cancer effects of Cdc7 depletion and although there are no available Cdc7 inhibitors in clinical trials as yet, several lead compounds are being optimised for this purpose. In this review, we will address the current status of Cdc7 as an important target for new drug development.

  2. Recent Trends in Nanotechnology-Based Drugs and Formulations for Targeted Therapeutic Delivery.

    Science.gov (United States)

    Iqbal, Hafiz M N; Rodriguez, Angel M V; Khandia, Rekha; Munjal, Ashok; Dhama, Kuldeep

    2017-01-01

    In the recent past, a wider spectrum of nanotechnologybased drugs or drug-loaded devices and systems has been engineered and investigated with high interests. The key objective is to help for an enhanced/better quality of patient life in a secure way by avoiding/limiting drug abuse, or severe adverse effects of some in practice traditional therapies. Various methodological approaches including in vitro, in vivo, and ex vivo techniques have been exploited, so far. Among them, nanoparticles-based therapeutic agents are of supreme interests for an enhanced and efficient delivery in the current biomedical sector of the modern world. The development of new types of novel, effective and highly reliable therapeutic drug delivery system (DDS) for multipurpose applications is essential and a core demand to tackle many human health related diseases. In this context, nanotechnology-based several advanced DDS have been engineered with novel characteristics for biomedical, pharmaceutical and cosmeceutical applications that include but not limited to the enhanced/improved bioactivity, bioavailability, drug efficacy, targeted delivery, and therapeutically safer with an extra advantage of overcoming demerits of traditional drug formulations/designs. This review work is focused on recent trends/advances in nanotechnology-based drugs and formulations designed for targeted therapeutic delivery. Moreover, information is also reviewed and given from recent patents and summarized or illustrated diagrammatically to depict a better understanding. Recent patents covering various nanotechnology-based approaches for several applications have also been reviewed. The drug-loaded nanoparticles are among versatile candidates with multifunctional characteristics for potential applications in biomedical, and tissue engineering sector. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases.

    Science.gov (United States)

    Sarafianos, Stefan G; Das, Kalyan; Hughes, Stephen H; Arnold, Eddy

    2004-12-01

    HIV undergoes rapid genetic variation; this variation is caused primarily by the enormous number of viruses produced daily in an infected individual. Because of this variation, HIV presents a moving target for drug and vaccine development. The variation within individuals has led to the generation of diverse HIV-1 subtypes, which further complicates the development of effective drugs and vaccines. In general, it is more difficult to hit a moving target than a stationary target. Two broad strategies for hitting a moving target (in this case, HIV replication) are to understand the movement and to aim at the portions that move the least. In the case of anti-HIV drug development, the first option can be addressed by understanding the mechanism(s) of drug resistance and developing drugs that effectively inhibit mutant viruses. The second can be addressed by designing drugs that interact with portions of the viral machinery that are evolutionarily conserved, such as enzyme active sites.

  4. The endocannabinoid system as a target for novel anxiolytic drugs.

    Science.gov (United States)

    Patel, Sachin; Hill, Mathew N; Cheer, Joseph F; Wotjak, Carsten T; Holmes, Andrew

    2017-05-01

    The endocannabinoid (eCB) system has attracted attention for its role in various behavioral and brain functions, and as a therapeutic target in neuropsychiatric disease states, including anxiety disorders and other conditions resulting from dysfunctional responses to stress. In this mini-review, we highlight components of the eCB system that offer potential 'druggable' targets for new anxiolytic medications, emphasizing some of the less well-discussed options. We discuss how selectively amplifying eCBs recruitment by interfering with eCB-degradation, via fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been linked to reductions in anxiety-like behaviors in rodents and variation in human anxiety symptoms. We also discuss a non-canonical route to regulate eCB degradation that involves interfering with cyclooxygenase-2 (COX-2). Next, we discuss approaches to targeting eCB receptor-signaling in ways that do not involve the cannabinoid receptor subtype 1 (CB1R); by targeting the CB2R subtype and the transient receptor potential vanilloid type 1 (TRPV1). Finally, we review evidence that cannabidiol (CBD), while representing a less specific pharmacological approach, may be another way to modulate eCBs and interacting neurotransmitter systems to alleviate anxiety. Taken together, these various approaches provide a range of plausible paths to developing novel compounds that could prove useful for treating trauma-related and anxiety disorders. Published by Elsevier Ltd.

  5. Cannabinoid CB1 receptor-interacting proteins: novel targets for central nervous system drug discovery?

    OpenAIRE

    Smith, Tricia H; Sim-Selley, Laura J; Selley, Dana E

    2010-01-01

    The main pharmacological effects of marijuana, as well as synthetic and endogenous cannabinoids, are mediated through G-protein-coupled receptors (GPCRs), including CB1 and CB2 receptors. The CB1 receptor is the major cannabinoid receptor in the central nervous system and has gained increasing interest as a target for drug discovery for treatment of nausea, cachexia, obesity, pain, spasticity, neurodegenerative diseases and mood and substance abuse disorders. Evidence has accumulated to sugge...

  6. Neighborhood Regularized Logistic Matrix Factorization for Drug-Target Interaction Prediction.

    Directory of Open Access Journals (Sweden)

    Yong Liu

    2016-02-01

    Full Text Available In pharmaceutical sciences, a crucial step of the drug discovery process is the identification of drug-target interactions. However, only a small portion of the drug-target interactions have been experimentally validated, as the experimental validation is laborious and costly. To improve the drug discovery efficiency, there is a great need for the development of accurate computational approaches that can predict potential drug-target interactions to direct the experimental verification. In this paper, we propose a novel drug-target interaction prediction algorithm, namely neighborhood regularized logistic matrix factorization (NRLMF. Specifically, the proposed NRLMF method focuses on modeling the probability that a drug would interact with a target by logistic matrix factorization, where the properties of drugs and targets are represented by drug-specific and target-specific latent vectors, respectively. Moreover, NRLMF assigns higher importance levels to positive observations (i.e., the observed interacting drug-target pairs than negative observations (i.e., the unknown pairs. Because the positive observations are already experimentally verified, they are usually more trustworthy. Furthermore, the local structure of the drug-target interaction data has also been exploited via neighborhood regularization to achieve better prediction accuracy. We conducted extensive experiments over four benchmark datasets, and NRLMF demonstrated its effectiveness compared with five state-of-the-art approaches.

  7. Neighborhood Regularized Logistic Matrix Factorization for Drug-Target Interaction Prediction.

    Science.gov (United States)

    Liu, Yong; Wu, Min; Miao, Chunyan; Zhao, Peilin; Li, Xiao-Li

    2016-02-01

    In pharmaceutical sciences, a crucial step of the drug discovery process is the identification of drug-target interactions. However, only a small portion of the drug-target interactions have been experimentally validated, as the experimental validation is laborious and costly. To improve the drug discovery efficiency, there is a great need for the development of accurate computational approaches that can predict potential drug-target interactions to direct the experimental verification. In this paper, we propose a novel drug-target interaction prediction algorithm, namely neighborhood regularized logistic matrix factorization (NRLMF). Specifically, the proposed NRLMF method focuses on modeling the probability that a drug would interact with a target by logistic matrix factorization, where the properties of drugs and targets are represented by drug-specific and target-specific latent vectors, respectively. Moreover, NRLMF assigns higher importance levels to positive observations (i.e., the observed interacting drug-target pairs) than negative observations (i.e., the unknown pairs). Because the positive observations are already experimentally verified, they are usually more trustworthy. Furthermore, the local structure of the drug-target interaction data has also been exploited via neighborhood regularization to achieve better prediction accuracy. We conducted extensive experiments over four benchmark datasets, and NRLMF demonstrated its effectiveness compared with five state-of-the-art approaches.

  8. A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia

    DEFF Research Database (Denmark)

    Marstrand, T T; Borup, R; Willer, A

    2010-01-01

    Chromosomal translocations of transcription factors generating fusion proteins with aberrant transcriptional activity are common in acute leukemia. In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARA) fusion protein, which emerges as a conseque......Chromosomal translocations of transcription factors generating fusion proteins with aberrant transcriptional activity are common in acute leukemia. In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARA) fusion protein, which emerges...... regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost....... In a broader perspective, our study provides strong evidence that genomic strategies might be used in a clinical setting to prospectively identify candidate drugs that subsequently are validated in vitro to define the most effective drug combination for individual cancer patients on a rational basis....

  9. G protein-coupled receptors as anabolic drug targets in osteoporosis.

    Science.gov (United States)

    Diepenhorst, Natalie; Rueda, Patricia; Cook, Anna E; Pastoureau, Philippe; Sabatini, Massimo; Langmead, Christopher J

    2018-04-01

    Osteoporosis is a progressive bone disorder characterised by imbalance between bone building (anabolism) and resorption (catabolism). Most therapeutics target inhibition of osteoclast-mediated bone resorption, but more recent attention in early drug discovery has focussed on anabolic targets in osteoblasts or their precursors. Two marketed agents that display anabolic properties, strontium ranelate and teriparatide, mediate their actions via the G protein-coupled calcium-sensing and parathyroid hormone-1 receptors, respectively. This review explores their activity, the potential for improved therapeutics targeting these receptors and other putative anabolic GPCR targets, including Smoothened, Wnt/Frizzled, relaxin family peptide, adenosine, cannabinoid, prostaglandin and sphingosine-1-phosphate receptors. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Magnetic Nanoparticle Facilitated Drug Delivery for Cancer Therapy with Targeted and Image-Guided Approaches.

    Science.gov (United States)

    Huang, Jing; Li, Yuancheng; Orza, Anamaria; Lu, Qiong; Guo, Peng; Wang, Liya; Yang, Lily; Mao, Hui

    2016-06-14

    With rapid advances in nanomedicine, magnetic nanoparticles (MNPs) have emerged as a promising theranostic tool in biomedical applications, including diagnostic imaging, drug delivery and novel therapeutics. Significant preclinical and clinical research has explored their functionalization, targeted delivery, controllable drug release and image-guided capabilities. To further develop MNPs for theranostic applications and clinical translation in the future, we attempt to provide an overview of the recent advances in the development and application of MNPs for drug delivery, specifically focusing on the topics concerning the importance of biomarker targeting for personalized therapy and the unique magnetic and contrast-enhancing properties of theranostic MNPs that enable image-guided delivery. The common strategies and considerations to produce theranostic MNPs and incorporate payload drugs into MNP carriers are described. The notable examples are presented to demonstrate the advantages of MNPs in specific targeting and delivering under image guidance. Furthermore, current understanding of delivery mechanisms and challenges to achieve efficient therapeutic efficacy or diagnostic capability using MNP-based nanomedicine are discussed.

  11. The therapeutic potential of targeting ABC transporters to combat multi-drug resistance.

    Science.gov (United States)

    Bugde, Piyush; Biswas, Riya; Merien, Fabrice; Lu, Jun; Liu, Dong-Xu; Chen, Mingwei; Zhou, Shufeng; Li, Yan

    2017-05-01

    Most disseminated cancers remain fatal despite the availability of a variety of conventional and novel treatments including surgery, chemotherapy, radiotherapy, immunotherapy, and biologically targeted therapy. A major factor responsible for the failure of chemotherapy in the treatment of cancer is the development of multidrug resistance (MDR). The overexpression of various ABC transporters in cancer cells can efficiently remove the anticancer drug from the cell, thus causing the drug to lose its effect. Areas covered: In this review, we summarised the ongoing research related to the mechanism, function, and regulation of ABC transporters. We integrated our current knowledge at different levels from molecular biology to clinical trials. We also discussed potential therapeutic strategies of targeting ABC transporters to reverse MDR in cancer cells. Expert opinion: Involvement of various ABC transporters to cancer MDR lays the foundation for developing tailored therapies that can overcome MDR. An ideal MDR reversal agent should have broad-spectrum ABC-transporter inhibitory activity, be potent, have good pharmacokinetics, have no trans-stimulation effects, and have low or no toxicity. Alternatively, nanotechnology-based drug delivery systems containing both the cytotoxic drug and reversing agent may represent a useful approach to reversing MDR with minimal off-target toxicity.

  12. Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4.

    Science.gov (United States)

    Bachtell, Ryan; Hutchinson, Mark R; Wang, Xiaohui; Rice, Kenner C; Maier, Steven F; Watkins, Linda R

    2015-01-01

    There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, methamphetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics; that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drugprimed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse.

  13. Drug targets for cell cycle dysregulators in leukemogenesis: in silico docking studies.

    Directory of Open Access Journals (Sweden)

    Archana Jayaraman

    Full Text Available Alterations in cell cycle regulating proteins are a key characteristic in neoplastic proliferation of lymphoblast cells in patients with Acute Lymphoblastic Leukemia (ALL. The aim of our study was to investigate whether the routinely administered ALL chemotherapeutic agents would be able to bind and inhibit the key deregulated cell cycle proteins such as--Cyclins E1, D1, D3, A1 and Cyclin Dependent Kinases (CDK 2 and 6. We used Schrödinger Glide docking protocol to dock the chemotherapeutic drugs such as Doxorubicin and Daunorubicin and others which are not very common including Clofarabine, Nelarabine and Flavopiridol, to the crystal structures of these proteins. We observed that the drugs were able to bind and interact with cyclins E1 and A1 and CDKs 2 and 6 while their docking to cyclins D1 and D3 were not successful. This binding proved favorable to interact with the G1/S cell cycle phase proteins that were examined in this study and may lead to the interruption of the growth of leukemic cells. Our observations therefore suggest that these drugs could be explored for use as inhibitors for these cell cycle proteins. Further, we have also highlighted residues which could be important in the designing of pharmacophores against these cell cycle proteins. This is the first report in understanding the mechanism of action of the drugs targeting these cell cycle proteins in leukemia through the visualization of drug-target binding and molecular docking using computational methods.

  14. 14 CFR 1267.215 - What must I include in my drug-free awareness program?

    Science.gov (United States)

    2010-01-01

    ... abuse violations occurring in the workplace. ... ADMINISTRATION GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for... establish an ongoing drug-free awareness program to inform employees about— (a) The dangers of drug abuse in...

  15. 13 CFR 147.215 - What must I include in my drug-free awareness program?

    Science.gov (United States)

    2010-01-01

    ... abuse violations occurring in the workplace. ... ADMINISTRATION GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (NONPROCUREMENT) Requirements for Recipients... establish an ongoing drug-free awareness program to inform employees about— (a) The dangers of drug abuse in...

  16. Drug Targets in Infections With Ebola and Marburg Viruses

    Science.gov (United States)

    2009-01-01

    recombinant nematode anticoagulant protein c2 (rNAPc2), which inhibits the FVUalTF complex activation of factor X, were protected - 33% of the time when...human diseaees including anti-TNF-a and anti-IL-6 for the treatment of rheumatoid arthritis select cancers . Targeting of the Host Immune Response...Tyburski, 1. G.; Warsow, K. M.; Kubinec, S. M. J. Trauma, 1996 40(3), 384-7. [58J Sato, N.; Fukuda, K.; Nariuchi, H.; Sagara, N. J. Natl. Cancer Inst

  17. Identification of novel drugs to target dormant micrometastases

    International Nuclear Information System (INIS)

    Hurst, Robert E.; Hauser, Paul J.; You, Youngjae; Bailey-Downs, Lora C.; Bastian, Anja; Matthews, Stephen M.; Thorpe, Jessica; Earle, Christine; Bourguignon, Lilly Y. W.; Ihnat, Michael A.

    2015-01-01

    Cancer-specific survival has changed remarkably little over the past half century, mainly because metastases that are occult at diagnosis and generally resistant to chemotherapy subsequently develop months, years or even decades following definitive therapy. Targeting the dormant micrometastases responsible for these delayed or occult metastases would represent a major new tool in cancer patient management. Our hypothesis is that these metastases develop from micrometastatic cells that are suppressed by normal extracellular matrix (ECM). A new screening method was developed that compared the effect of drugs on the proliferation of cells grown on a normal ECM gel (small intestine submucosa, SISgel) to cells grown on plastic cell culture plates. The desired endpoint was that cells on SISgel were more sensitive than the same cells grown as monolayers. Known cancer chemotherapeutic agents show the opposite pattern. Screening 13,000 compounds identified two leads with low toxicity in mice and EC 50 values in the range of 3–30 μM, depending on the cell line, and another two leads that were too toxic to mice to be useful. In a novel flank xenograft method of suppressed/dormant cells co-injected with SISgel into the flank, the lead compounds significantly eliminated the suppressed cells, whereas conventional chemotherapeutics were ineffective. Using a 4T1 triple negative breast cancer model, modified for physiological metastatic progression, as predicted, both lead compounds reduced the number of large micrometastases/macrometastases in the lung. One of the compounds also targeted cancer stem cells (CSC) isolated from the parental line. The CSC also retained their stemness on SISgel. Mechanistic studies showed a mild, late apoptotic response and depending on the compound, a mild arrest either at S or G 2 /M in the cell cycle. In summary we describe a novel, first in class set of compounds that target micrometastatic cells and prevent their reactivation to form recurrent

  18. Proline Rich Motifs as Drug Targets in Immune Mediated Disorders

    Directory of Open Access Journals (Sweden)

    Mythily Srinivasan

    2012-01-01

    Full Text Available The current version of the human immunome network consists of nearly 1400 interactions involving approximately 600 proteins. Intermolecular interactions mediated by proline-rich motifs (PRMs are observed in many facets of the immune response. The proline-rich regions are known to preferentially adopt a polyproline type II helical conformation, an extended structure that facilitates transient intermolecular interactions such as signal transduction, antigen recognition, cell-cell communication and cytoskeletal organization. The propensity of both the side chain and the backbone carbonyls of the polyproline type II helix to participate in the interface interaction makes it an excellent recognition motif. An advantage of such distinct chemical features is that the interactions can be discriminatory even in the absence of high affinities. Indeed, the immune response is mediated by well-orchestrated low-affinity short-duration intermolecular interactions. The proline-rich regions are predominantly localized in the solvent-exposed regions such as the loops, intrinsically disordered regions, or between domains that constitute the intermolecular interface. Peptide mimics of the PRM have been suggested as potential antagonists of intermolecular interactions. In this paper, we discuss novel PRM-mediated interactions in the human immunome that potentially serve as attractive targets for immunomodulation and drug development for inflammatory and autoimmune pathologies.

  19. Structure determination of drug target proteins by neutron crystallography

    International Nuclear Information System (INIS)

    Tamada, Taro; Adachi, Motoyasu

    2010-01-01

    High resolution X-ray crystallography provides information for most of the atoms comprising the proteins, with the exception of hydrogen atoms. Whereas, neutron crystallography, which is a powerful technique for locating hydrogen atoms, enables us to obtain accurate atomic positions within proteins. Neutron diffraction data can provide information of the location of hydrogen atoms to the structural information determined by X-ray crystallography. Here, we show the recent results of the structural determination of drug-target proteins, porcine pancreatic elastase and human immuno-deficiency virus type-1 protease by both X-ray and neutron diffraction. The structure of porcine pancreatic elastase with its potent inhibitor was determined to 0.094 nm resolution by X-ray diffraction and 0.165 nm resolution by neutron diffraction. The structure of HIV-PR with its potent inhibitor was also determined to 0.093 nm resolution by X-ray diffraction and 0.19 nm resolution by neutron diffraction. The ionization state and the location of hydrogen atoms of the catalytic residue in these enzymes were determined by neutron diffraction. Furthermore, collaborative use of both X-ray and neutron crystallography to identify the location of ambiguous hydrogen atoms will be shown. (author)

  20. RGD-modified lipid disks as drug carriers for tumor targeted drug delivery

    Science.gov (United States)

    Gao, Jie; Xie, Cao; Zhang, Mingfei; Wei, Xiaoli; Yan, Zhiqiang; Ren, Yachao; Ying, Man; Lu, Weiyue

    2016-03-01

    Melittin, the major component of the European bee venom, is a potential anticancer candidate due to its lytic properties. However, in vivo applications of melittin are limited due to its main side effect, hemolysis, especially when applied through intravenous administration. The polyethylene glycol-stabilized lipid disk is a novel type of nanocarrier, and the rim of lipid disks has a high affinity to amphiphilic peptides. In our study, a c(RGDyK) modified lipid disk was developed as a tumor targeted drug delivery system for melittin. Cryo-TEM was used to confirm the shape and size of lipid disks with or without c(RGDyK) modification. In vitro and in vivo hemolysis analyses revealed that the hemolysis effect significantly decreased after melittin associated with lipid disks. Importantly, the results of our in vivo biodistribution and tumor growth inhibitory experiments showed that c(RGDyK) modification increased the distribution of lipid disks in the tumor and the anticancer efficacy of melittin loaded lipid disks. Thus, we successfully achieved a targeted drug delivery system for melittin and other amphiphilic peptides with a good therapeutic effect and low side effects.

  1. Emissions and targets of greenhouse gases not included in the Emission Trading System 2013-2020

    Energy Technology Data Exchange (ETDEWEB)

    Verdonk, M.

    2011-06-15

    This report evaluates the European Commission's (EC) proposal to calculate Member States' targets for emissions not included in the Emission Trading System (ETS) (as announced in the so-called Effort Sharing Decision). The calculation procedures and data sources proposed by the EC have been used for calculating non-ETS emission targets for the Netherlands, for the years from 2013 to 2020. In order to compare results, an alternative approach also was introduced and evaluated. In this approach more transparent data sources were used. Furthermore, the report updates the emission forecast of non-ETS emission levels in the Netherlands, for 2020, and evaluates the consequences of excluding uncertainties related to monitoring from the (updated) emission forecast. It is concluded that, for the Netherlands, the non-ETS emission caps as proposed by the EC would result in an emission cap of 105 Mt CO2 equivalent by 2020. This is higher than in the alternative approach, which would result in a cap of 103 Mt CO2 equivalents. The difference is explained by the different data sources that were used. A drawback of the data sources used in the EC proposal is the lack of transparency of part of the data, which resulted in an additional uncertainty as not all issues could be verified. However, other Member States may not have similar data sources available, in case the EC decides to adopt the alternative approach. The calculated emission caps are to be considered as estimates based on the most recent (but sometimes uncertain) statistics. The EC will determine the definite caps by the end of 2012. Based on a 2010 forecast, and including both an updated division of emissions into ETS and non-ETS emissions and a revised methodology for calculating nitrous oxide emissions, we estimate that non-ETS emissions in the Netherlands would be 104 Mt CO2 equivalents by 2020, with an uncertainty range of between 96 and 112 Mt CO2 equivalents. It is our conclusion that non-ETS emission

  2. Functional alterations of astrocytes in mental disorders: pharmacological significance as a drug target

    Directory of Open Access Journals (Sweden)

    Yutaka eKoyama

    2015-07-01

    Full Text Available Astrocytes play an essential role in supporting brain functions in physiological and pathological states. Modulation of their pathophysiological responses have beneficial actions on nerve tissue injured by brain insults and neurodegenerative diseases, therefore astrocytes are recognized as promising targets for neuroprotective drugs. Recent investigations have identified several astrocytic mechanisms for modulating synaptic transmission and neural plasticity. These include altered expression of transporters for neurotransmitters, release of gliotransmitters and neurotrophic factors, and intercellular communication through gap junctions. Investigation of patients with mental disorders shows morphological and functional alterations in astrocytes. According to these observations, manipulation of astrocytic function by gene mutation and pharmacological tools reproduce mental disorder-like behavior in experimental animals. Some drugs clinically used for mental disorders affect astrocyte function. As experimental evidence shows their role in the pathogenesis of mental disorders, astrocytes have gained much attention as drug targets for mental disorders. In this article, I review functional alterations of astrocytes in several mental disorders including schizophrenia, mood disorder, drug dependence, and neurodevelopmental disorders. The pharmacological significance of astrocytes in mental disorders is also discussed.

  3. Platelets as Contractile Nanomachines for Targeting Drug Delivery in Hemostasis and Thrombosis

    Science.gov (United States)

    2015-12-01

    AWARD NUMBER: W81XWH-13-1-0495 TITLE: Platelets as Contractile Nanomachines for Targeting Drug Delivery in Hemostasis and Thrombosis PRINCIPAL...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Platelets as Contractile Nanomachines for Targeting Drug Delivery in Hemostasis and Thrombosis 5b. GRANT...controlled nanocarriers as a novel and potentially paradigm-shifting strategy for targeted drug delivery to achieve hemostasis during bleeding. We have

  4. Targeted lipid based drug conjugates: a novel strategy for drug delivery.

    Science.gov (United States)

    Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Kwatra, Deep; Earla, Ravinder; Samanta, Swapan K; Pal, Dhananjay; Mitra, Ashim K

    2012-09-15

    A majority of studies involving prodrugs are directed to overcome low bioavailability of the parent drug. The aim of this study is to increase the bioavailability of acyclovir (ACV) by designing a novel prodrug delivery system which is more lipophilic, and at the same time site specific. In this study, a lipid raft has been conjugated to the parent drug molecule to impart lipophilicity. Simultaneously a targeting moiety that can be recognized by a specific transporter/receptor in the cell membrane has also been tethered to the other terminal of lipid raft. Targeted lipid prodrugs i.e., biotin-ricinoleicacid-acyclovir (B-R-ACV) and biotin-12hydroxystearicacid-acyclovir (B-12HS-ACV) were synthesized with ricinoleicacid and 12hydroxystearicacid as the lipophilic rafts and biotin as the targeting moiety. Biotin-ACV (B-ACV), ricinoleicacid-ACV (R-ACV) and 12hydroxystearicacid-ACV (12HS-ACV) were also synthesized to delineate the individual effects of the targeting and the lipid moieties. Cellular accumulation studies were performed in confluent MDCK-MDR1 and Caco-2 cells. The targeted lipid prodrugs B-R-ACV and B-12HS-ACV exhibited much higher cellular accumulation than B-ACV, R-ACV and 12HS-ACV in both cell lines. This result indicates that both the targeting and the lipid moiety act synergistically toward cellular uptake. The biotin conjugated prodrugs caused a decrease in the uptake of [(3)H] biotin suggesting the role of sodium dependent multivitamin transporter (SMVT) in uptake. The affinity of these targeted lipid prodrugs toward SMVT was studied in MDCK-MDR1 cells. Both the targeted lipid prodrugs B-R-ACV (20.25 ± 1.74 μM) and B-12HS-ACV (23.99 ± 3.20 μM) demonstrated higher affinity towards SMVT than B-ACV (30.90 ± 4.19 μM). Further, dose dependent studies revealed a concentration dependent inhibitory effect on [(3)H] biotin uptake in the presence of biotinylated prodrugs. Transepithelial transport studies showed lowering of [(3)H] biotin permeability in

  5. Combating Drug Abuse by Targeting Toll-Like Receptor 4 (TLR)

    Science.gov (United States)

    2015-12-01

    AWARD NUMBER: W81XWH-12-1-0345 PROJECT TITLE: Combating drug abuse by targeting toll-like receptor 4 (TLR) PRINCIPAL INVESTIGATOR: Dr. Linda...5a. CONTRACT NUMBER not applicable Combating drug abuse by targeting toll-like receptor 4 (TLR) 5b. GRANT NUMBER W81XWH-12-1-0345 5c. PROGRAM...naltrexone; drug abuse ; glial activation; therapeutic approach to treating drug abuse ; opioids; cocaine 16. SECURITY CLASSIFICATION OF: 17. LIMITATION

  6. Target-mediated drug disposition model and its approximations for antibody-drug conjugates.

    Science.gov (United States)

    Gibiansky, Leonid; Gibiansky, Ekaterina

    2014-02-01

    Antibody-drug conjugate (ADC) is a complex structure composed of an antibody linked to several molecules of a biologically active cytotoxic drug. The number of ADC compounds in clinical development now exceeds 30, with two of them already on the market. However, there is no rigorous mechanistic model that describes pharmacokinetic (PK) properties of these compounds. PK modeling of ADCs is even more complicated than that of other biologics as the model should describe distribution, binding, and elimination of antibodies with different toxin load, and also the deconjugation process and PK of the released toxin. This work extends the target-mediated drug disposition (TMDD) model to describe ADCs, derives the rapid binding (quasi-equilibrium), quasi-steady-state, and Michaelis-Menten approximations of the TMDD model as applied to ADCs, derives the TMDD model and its approximations for ADCs with load-independent properties, and discusses further simplifications of the system under various assumptions. The developed models are shown to describe data simulated from the available clinical population PK models of trastuzumab emtansine (T-DM1), one of the two currently approved ADCs. Identifiability of model parameters is also discussed and illustrated on the simulated T-DM1 examples.

  7. Cancer therapy with drug loaded magnetic nanoparticles-magnetic drug targeting

    International Nuclear Information System (INIS)

    Alexiou, Christoph; Tietze, Rainer; Schreiber, Eveline; Jurgons, Roland; Richter, Heike; Trahms, Lutz; Rahn, Helene; Odenbach, Stefan; Lyer, Stefan

    2011-01-01

    The aim of magnetic drug targeting (MDT) in cancer therapy is to concentrate chemotherapeutics to a tumor region while simultaneously the overall dose is reduced. This can be achieved with coated superparamagnetic nanoparticles bound to a chemotherapeutic agent. These particles are applied intra arterially close to the tumor region and focused to the tumor by a strong external magnetic field. The interaction of the particles with the field gradient leads to an accumulation in the region of interest (i.e. tumor). The particle enrichment and thereby the drug-load in the tumor during MDT has been proven by several analytical and imaging methods. Moreover, in pilot studies we investigated in an experimental in vivo tumor model the effectiveness of this approach. Complete tumor regressions without any negative side effects could be observed. - Research Highlights: →Iron oxide nanoparticles can be enriched in tumors by external magnetic fields. → Histology evidences the intravasation of particles enter the intracellular space. → Non-invasive imaging techniques can display the spatial arrangement of particles. → HPLC-analysis show outstanding drug enrichment in tumors after MDT.

  8. Micro RNA, A Review: Pharmacogenomic drug targets for complex diseases

    Directory of Open Access Journals (Sweden)

    Sandhya Bawa

    2010-01-01

    Full Text Available

    Micro RNAs (miRNAs are non-coding RNAs that can regulate gene expression to target several mRNAs in a gene regulatory network. MiRNA related Single Nucleotide Polymorphisms (S.N.P.s represent a newly identified type of genetic variability that can be of influence to the risk of certain human diseases and also affect how drugs can be activated and metabolized by patients. This will help in personalized medicines which are used for administrating the correct dosage of drug and drug efficacy. miRNA deregulated expression has been extensively described in a variety of diseases such as Cancer, Obesity , Diabetes, Schizophrenia and control and self renewal of stem cells. MiRNA can function as oncogenes and/or tumor suppressors. MiRNAs may act as key regulators of processes as diverse as early development, cell proliferation and cell death, apoptosis and fat metabolism and cell differentiation .miRNA expression have shown their role in brain development chronic lymphocytic leukemia, colonic adeno carcinoma, Burkiff’s lymphoma and viral infection. These show their links with viral disease, neurodevelopment and cancer. It has been shown that they play a key role in melanoma metastasis. These may be

  9. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood-Brain Barrier.

    Science.gov (United States)

    Georgieva, Julia V; Hoekstra, Dick; Zuhorn, Inge S

    2014-11-17

    The blood-brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics into the brain. This concept relies on the application of natural or genetically engineered proteins or small peptides, capable of specifically ferrying a drug-payload that is either directly coupled or encapsulated in an appropriate nanocarrier, across the blood-brain barrier via receptor-mediated transcytosis. Specifically, in this process the nanocarrier-drug system ("Trojan horse complex") is transported transcellularly across the brain endothelium, from the blood to the brain interface, essentially trailed by a native receptor. Naturally, only certain properties would favor a receptor to serve as a transporter for nanocarriers, coated with appropriate ligands. Here we briefly discuss brain microvascular endothelial receptors that have been explored until now, highlighting molecular features that govern the efficiency of nanocarrier-mediated drug delivery into the brain.

  10. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood–Brain Barrier

    Directory of Open Access Journals (Sweden)

    Julia V. Georgieva

    2014-11-01

    Full Text Available The blood–brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics into the brain. This concept relies on the application of natural or genetically engineered proteins or small peptides, capable of specifically ferrying a drug-payload that is either directly coupled or encapsulated in an appropriate nanocarrier, across the blood–brain barrier via receptor-mediated transcytosis. Specifically, in this process the nanocarrier–drug system (“Trojan horse complex” is transported transcellularly across the brain endothelium, from the blood to the brain interface, essentially trailed by a native receptor. Naturally, only certain properties would favor a receptor to serve as a transporter for nanocarriers, coated with appropriate ligands. Here we briefly discuss brain microvascular endothelial receptors that have been explored until now, highlighting molecular features that govern the efficiency of nanocarrier-mediated drug delivery into the brain.

  11. Sirtuins: Novel targets for metabolic disease in drug development

    International Nuclear Information System (INIS)

    Jiang Weijian

    2008-01-01

    Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases such as type 2 diabetes. SIRT1, an NAD + -dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produces beneficial effects on glucose homeostasis and insulin sensitivity. Activation of SIRT1 leads to enhanced activity of multiple proteins, including peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) and FOXO which helps to mediate some of the in vitro and in vivo effects of sirtuins. Resveratrol, a polyphenolic SIRT1 activator, mimics the effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance. In this review, we summarize recent research advances in unveiling the molecular mechanisms that underpin sirtuin as therapeutic candidates and discuss the possibility of using resveratrol as potential drug for treatment of diabetes

  12. Multifunctional polymer-capped mesoporous silica nanoparticles for pH-responsive targeted drug delivery

    Science.gov (United States)

    Niedermayer, Stefan; Weiss, Veronika; Herrmann, Annika; Schmidt, Alexandra; Datz, Stefan; Müller, Katharina; Wagner, Ernst; Bein, Thomas; Bräuchle, Christoph

    2015-04-01

    A highly stable modular platform, based on the sequential covalent attachment of different functionalities to the surface of core-shell mesoporous silica nanoparticles (MSNs) for targeted drug delivery is presented. A reversible pH-responsive cap system based on covalently attached poly(2-vinylpyridine) (PVP) was developed as drug release mechanism. Our platform offers (i) tuneable interactions and release kinetics with the cargo drug in the mesopores based on chemically orthogonal core-shell design, (ii) an extremely robust and reversible closure and release mechanism based on endosomal acidification of the covalently attached PVP polymer block, (iii) high colloidal stability due to a covalently coupled PEG shell, and (iv) the ability to covalently attach a wide variety of dyes, targeting ligands and other functionalities at the outer periphery of the PEG shell. The functionality of the system was demonstrated in several cell studies, showing pH-triggered release in the endosome, light-triggered endosomal escape with an on-board photosensitizer, and efficient folic acid-based cell targeting.A highly stable modular platform, based on the sequential covalent attachment of different functionalities to the surface of core-shell mesoporous silica nanoparticles (MSNs) for targeted drug delivery is presented. A reversible pH-responsive cap system based on covalently attached poly(2-vinylpyridine) (PVP) was developed as drug release mechanism. Our platform offers (i) tuneable interactions and release kinetics with the cargo drug in the mesopores based on chemically orthogonal core-shell design, (ii) an extremely robust and reversible closure and release mechanism based on endosomal acidification of the covalently attached PVP polymer block, (iii) high colloidal stability due to a covalently coupled PEG shell, and (iv) the ability to covalently attach a wide variety of dyes, targeting ligands and other functionalities at the outer periphery of the PEG shell. The

  13. 45 CFR 1155.215 - What must I include in my drug-free awareness program?

    Science.gov (United States)

    2010-10-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals...

  14. 24 CFR 21.215 - What must I include in my drug-free awareness program?

    Science.gov (United States)

    2010-04-01

    ... dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any... may impose upon them for drug abuse violations occurring in the workplace. ... of Housing and Urban Development GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (GRANTS...

  15. 22 CFR 1509.215 - What must I include in my drug-free awareness program?

    Science.gov (United States)

    2010-04-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals...

  16. 38 CFR 48.215 - What must I include in my drug-free awareness program?

    Science.gov (United States)

    2010-07-01

    ...) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c... that you may impose upon them for drug abuse violations occurring in the workplace. ... OF VETERANS AFFAIRS (CONTINUED) GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL...

  17. 20 CFR 439.215 - What must I include in my drug-free awareness program?

    Science.gov (United States)

    2010-04-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals...

  18. 29 CFR 1472.215 - What must I include in my drug-free awareness program?

    Science.gov (United States)

    2010-07-01

    ... of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any... may impose upon them for drug abuse violations occurring in the workplace. ... CONCILIATION SERVICE GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements...

  19. 49 CFR 32.215 - What must I include in my drug-free awareness program?

    Science.gov (United States)

    2010-10-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals...

  20. 21 CFR 1405.215 - What must I include in my drug-free awareness program?

    Science.gov (United States)

    2010-04-01

    ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals...

    1. 40 CFR 36.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-07-01

      ... dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any... may impose upon them for drug abuse violations occurring in the workplace. ... AND OTHER FEDERAL ASSISTANCE GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...

    2. 10 CFR 607.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-01-01

      ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals...

    3. 32 CFR 26.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-07-01

      ...) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c... that you may impose upon them for drug abuse violations occurring in the workplace. ... DoD GRANT AND AGREEMENT REGULATIONS GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL...

    4. 22 CFR 1008.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-04-01

      ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee... FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals...

    5. 22 CFR 210.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-04-01

      ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals...

    6. 45 CFR 630.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-10-01

      ... dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any... may impose upon them for drug abuse violations occurring in the workplace. ...) NATIONAL SCIENCE FOUNDATION GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE...

    7. 31 CFR 20.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-07-01

      ...-free awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation... GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than...

    8. 34 CFR 84.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-07-01

      ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals...

    9. 43 CFR 43.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-10-01

      ...-free awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation... GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than...

    10. 45 CFR 1173.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-10-01

      ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals...

    11. 22 CFR 133.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-04-01

      ... awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee... REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals...

    12. 28 CFR 83.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-07-01

      ...-free awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation...) GOVERNMENT-WIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (GRANTS) Requirements for Recipients Other Than...

    13. 2 CFR 182.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-01-01

      ... employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free... penalties that you may impose upon them for drug abuse violations occurring in the workplace. ... GOVERNMENTWIDE GUIDANCE FOR GRANTS AND AGREEMENTS Reserved GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE...

    14. 15 CFR 29.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-01-01

      ...-free awareness program to inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation... GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than...

    15. 36 CFR 1212.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-07-01

      ... employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free... penalties that you may impose upon them for drug abuse violations occurring in the workplace. ... ARCHIVES AND RECORDS ADMINISTRATION GENERAL RULES GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE...

    16. Comparative genomics allowed the identification of drug targets against human fungal pathogens

      Directory of Open Access Journals (Sweden)

      Martins Natalia F

      2011-01-01

      Full Text Available Abstract Background The prevalence of invasive fungal infections (IFIs has increased steadily worldwide in the last few decades. Particularly, there has been a global rise in the number of infections among immunosuppressed people. These patients present severe clinical forms of the infections, which are commonly fatal, and they are more susceptible to opportunistic fungal infections than non-immunocompromised people. IFIs have historically been associated with high morbidity and mortality, partly because of the limitations of available antifungal therapies, including side effects, toxicities, drug interactions and antifungal resistance. Thus, the search for alternative therapies and/or the development of more specific drugs is a challenge that needs to be met. Genomics has created new ways of examining genes, which open new strategies for drug development and control of human diseases. Results In silico analyses and manual mining selected initially 57 potential drug targets, based on 55 genes experimentally confirmed as essential for Candida albicans or Aspergillus fumigatus and other 2 genes (kre2 and erg6 relevant for fungal survival within the host. Orthologs for those 57 potential targets were also identified in eight human fungal pathogens (C. albicans, A. fumigatus, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Paracoccidioides lutzii, Coccidioides immitis, Cryptococcus neoformans and Histoplasma capsulatum. Of those, 10 genes were present in all pathogenic fungi analyzed and absent in the human genome. We focused on four candidates: trr1 that encodes for thioredoxin reductase, rim8 that encodes for a protein involved in the proteolytic activation of a transcriptional factor in response to alkaline pH, kre2 that encodes for α-1,2-mannosyltransferase and erg6 that encodes for Δ(24-sterol C-methyltransferase. Conclusions Our data show that the comparative genomics analysis of eight fungal pathogens enabled the identification of

    17. Identifying the Right Disease Targets to Develop Better Drugs, Faster | NIH MedlinePlus the Magazine

      Science.gov (United States)

      ... this page please turn JavaScript on. Identifying the Right Disease Targets to Develop Better Drugs, Faster Past ... reason is that we're not selecting the right biological changes to target from the start. How ...

    18. Targeting Membrane-Bound Viral RNA Synthesis Reveals Potent Inhibition of Diverse Coronaviruses Including the Middle East Respiratory Syndrome Virus

      NARCIS (Netherlands)

      Lundin, A.; Dijkman, R.; Bergstrom, T.; Kann, N.; Adamiak, B.; Hannoun, C.; Kindler, E.; Jonsdottir, H.R.; Muth, D.; Kint, J.; Forlenza, M.

      2014-01-01

      Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound

    19. CPP-ZFN: A potential DNA-targeting anti-malarial drug

      Directory of Open Access Journals (Sweden)

      Nain Vikrant

      2010-09-01

      . Implications of the hypothesis Targeting of the Plasmodium genome using ZFN has great potential for the development of anti-malarial drugs. It allows the development of a single drug against all malarial infections, including multidrug-resistant strains. Availability of multiple ZFN target sites in a single gene will provide alternative drug target sites to combat the development of resistance in the future.

    20. Thiamin (Vitamin B1) Biosynthesis and Regulation: A Rich Source of Antimicrobial Drug Targets?

      Science.gov (United States)

      Du, Qinglin; Wang, Honghai; Xie, Jianping

      2011-01-01

      Drug resistance of pathogens has necessitated the identification of novel targets for antibiotics. Thiamin (vitamin B1) is an essential cofactor for all organisms in its active form thiamin diphosphate (ThDP). Therefore, its metabolic pathways might be one largely untapped source of antibiotics targets. This review describes bacterial thiamin biosynthetic, salvage, and transport pathways. Essential thiamin synthetic enzymes such as Dxs and ThiE are proposed as promising drug targets. The regulation mechanism of thiamin biosynthesis by ThDP riboswitch is also discussed. As drug targets of existing antimicrobial compound pyrithiamin, the ThDP riboswitch might serves as alternative targets for more antibiotics. PMID:21234302

    1. Hedgehog pathway as a drug target: Smoothened inhibitors in development

      Directory of Open Access Journals (Sweden)

      Lin TL

      2012-03-01

      Full Text Available Tara L Lin1, William Matsui21Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas, Kansas City, MO, USA; 2Division of Hematologic Malignancies, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian, the transmembrane receptor Patched, the signal transducer Smoothened (Smo, and transcription factors Gli1–3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain

    2. Hedgehog pathway as a drug target: Smoothened inhibitors in development.

      Science.gov (United States)

      Lin, Tara L; Matsui, William

      2012-01-01

      Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh) represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian), the transmembrane receptor Patched, the signal transducer Smoothened (Smo), and transcription factors Gli1-3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells) have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain for appropriate patient selection and the optimal combination and sequence of these targeted therapies into current treatment paradigms.

    3. A network integration approach for drug-target interaction prediction and computational drug repositioning from heterogeneous information.

      Science.gov (United States)

      Luo, Yunan; Zhao, Xinbin; Zhou, Jingtian; Yang, Jinglin; Zhang, Yanqing; Kuang, Wenhua; Peng, Jian; Chen, Ligong; Zeng, Jianyang

      2017-09-18

      The emergence of large-scale genomic, chemical and pharmacological data provides new opportunities for drug discovery and repositioning. In this work, we develop a computational pipeline, called DTINet, to predict novel drug-target interactions from a constructed heterogeneous network, which integrates diverse drug-related information. DTINet focuses on learning a low-dimensional vector representation of features, which accurately explains the topological properties of individual nodes in the heterogeneous network, and then makes prediction based on these representations via a vector space projection scheme. DTINet achieves substantial performance improvement over other state-of-the-art methods for drug-target interaction prediction. Moreover, we experimentally validate the novel interactions between three drugs and the cyclooxygenase proteins predicted by DTINet, and demonstrate the new potential applications of these identified cyclooxygenase inhibitors in preventing inflammatory diseases. These results indicate that DTINet can provide a practically useful tool for integrating heterogeneous information to predict new drug-target interactions and repurpose existing drugs.Network-based data integration for drug-target prediction is a promising avenue for drug repositioning, but performance is wanting. Here, the authors introduce DTINet, whose performance is enhanced in the face of noisy, incomplete and high-dimensional biological data by learning low-dimensional vector representations.

    4. Targeted drug delivery into reversibly injured myocardium with silica nanoparticles: surface functionalization,  natural biodistribution, and acute toxicity

      Directory of Open Access Journals (Sweden)

      Michael M Galagudza

      2010-03-01

      Full Text Available Michael M Galagudza1, Dmitry V Korolev1, Dmitry L Sonin1, Viktor N Postnov2, Garry V Papayan3, Ivan S Uskov1, Anastasia V Belozertseva1, Eugene V Shlyakhto11Institute of Experimental Medicine, VA. Almazov Federal Heart, Blood and Endocrinology Center, St-Petersburg, Russian Federation; 2Chemical Faculty, St-Petersburg State University, St-Petersburg, Russian Federation;  3Department of Pathophysiology, IP. Pavlov State Medical University, St-Petersburg, Russian FederationAbstract: The clinical outcome of patients with ischemic heart disease can be significantly improved with the implementation of targeted drug delivery into the ischemic myocardium. In this paper, we present our original findings relevant to the problem of therapeutic heart targeting with use of nanoparticles. Experimental approaches included fabrication of carbon and silica nanoparticles, their characterization and surface modification. The acute hemodynamic effects of nanoparticle formulation as well as nanoparticle biodistribution were studied in male Wistar rats. Carbon and silica nanoparticles are non-toxic materials that can be used as carriers for heart-targeted drug delivery. Concepts of passive and active targeting can be applied to the development of targeted drug delivery to the ischemic myocardial cells. Provided that ischemic heart-targeted drug delivery can be proved to be safe and efficient, the results of this research may contribute to the development of new technologies in the pharmaceutical industry.Keywords: nanocarriers, targeted drug delivery, myocardial ischemia

    5. IAP proteins as targets for drug development in oncology

      Directory of Open Access Journals (Sweden)

      Dubrez L

      2013-09-01

      Full Text Available Laurence Dubrez,1,2 Jean Berthelet,1,2 Valérie Glorian,1,21Institut National de la Santé et de la Recherche Médicale (Inserm, Dijon, France; 2Université de Bourgogne, Dijon, FranceAbstract: The inhibitors of apoptosis (IAPs constitute a family of proteins involved in the regulation of various cellular processes, including cell death, immune and inflammatory responses, cell proliferation, cell differentiation, and cell motility. There is accumulating evidence supporting IAP-targeting in tumors: IAPs regulate various cellular processes that contribute to tumor development, such as cell death, cell proliferation, and cell migration; their expression is increased in a number of human tumor samples, and IAP overexpression has been correlated with tumor growth, and poor prognosis or low response to treatment; and IAP expression can be rapidly induced in response to chemotherapy or radiotherapy because of the presence of an internal ribosome entry site (IRES-dependent mechanism of translation initiation, which could contribute to resistance to antitumor therapy. The development of IAP antagonists is an important challenge and was subject to intense research over the past decade. Six molecules are currently in clinical trials. This review focuses on the role of IAPs in tumors and the development of IAP-targeting molecules for anticancer therapy.Keywords: Smac mimetics, apoptosis, antitumor therapy

    6. Novel drugs and vaccines based on the structure and function of HIV pathogenic proteins including Nef.

      Science.gov (United States)

      Azad, Ahmed A

      2005-11-01

      Evidence is presented to suggest that HIV-1 accessory protein Nef could be involved in AIDS pathogenesis. When present in extracellular medium, Nef causes the death of a wide variety of cells in vitro and may therefore be responsible for the depletion of bystander cells in lymphoid tissues during HIV infection. When present inside the cell, Nef could prevent the death of infected cells and thereby contribute to increased viral load. Intracellular Nef does this by preventing apoptosis of infected cells by either inhibiting proteins involved in apoptosis or preventing the infected cells from being recognized by CTLs. Neutralization of extracellular Nef could prevent the death of uninfected immune cells and thereby the destruction of the immune system. Neutralization of intracellular Nef could hasten the death of infected cells and help reduce the viral load. Nef is therefore a very important molecular target for developing therapeutics that slow progression to AIDS. The N-terminal region of Nef and the naturally occurring bee venom mellitin have very similar primary and tertiary structures, and they both act by destroying membranes. Chemical analogs of a mellitin inhibitor prevent Nef-mediated cell death and inhibit the interaction of Nef with cellular proteins involved in apoptosis. Naturally occurring bee propolis also contains substances that prevent Nef-mediated cell lysis and increases proliferation of CD4 cells in HIV-infected cultures. These chemical compounds and natural products are water soluble and nontoxic and are therefore potentially very useful candidate drugs.

    7. Drug-target residence time--a case for G protein-coupled receptors.

      Science.gov (United States)

      Guo, Dong; Hillger, Julia M; IJzerman, Adriaan P; Heitman, Laura H

      2014-07-01

      A vast number of marketed drugs act on G protein-coupled receptors (GPCRs), the most successful category of drug targets to date. These drugs usually possess high target affinity and selectivity, and such combined features have been the driving force in the early phases of drug discovery. However, attrition has also been high. Many investigational new drugs eventually fail in clinical trials due to a demonstrated lack of efficacy. A retrospective assessment of successfully launched drugs revealed that their beneficial effects in patients may be attributed to their long drug-target residence times (RTs). Likewise, for some other GPCR drugs short RT could be beneficial to reduce the potential for on-target side effects. Hence, the compounds' kinetics behavior might in fact be the guiding principle to obtain a desired and durable effect in vivo. We therefore propose that drug-target RT should be taken into account as an additional parameter in the lead selection and optimization process. This should ultimately lead to an increased number of candidate drugs moving to the preclinical development phase and on to the market. This review contains examples of the kinetics behavior of GPCR ligands with improved in vivo efficacy and summarizes methods for assessing drug-target RT. © 2014 Wiley Periodicals, Inc.

    8. The RNA-dependent-RNA polymerase, an emerging antiviral drug target for the Hendra virus.

      Science.gov (United States)

      Velkov, Tony; Carbone, Vincenzo; Akter, Jesmin; Sivanesan, Sivashangarie; Li, Jian; Beddoe, Travis; Marsh, Glenn A

      2014-01-01

      Australia is facing a major national medical challenge with the emergence of the Hendra virus (HeV) as a medically and economically important pathogen of humans and animals. Clinical symptoms of human HeV infection can include fever, hypotension, dizziness, encephalitis, respiratory haemorrhage and edema. The window of opportunity for successful patient treatment remains unknown, but is likely to be very narrow. Currently, very few effective therapeutic options are available for the case management of severe HeV infections or the rapid silencing of local outbreaks. This underscores the need for more activity in the drug discovery arena to develop much needed therapeutics that specifically targets this deadly disease. The structural analysis of HeV is very much in its infancy, which leaves many gaps in our understanding of the biology of HeV and makes structure-guided drug design difficult. Structural studies of the viral RNAdependent- RNA polymerase (RdRp), which is the heart of the viral replication machinery, will set the stage for rational drug design and fill a major gap in our understanding of the HeV replication machinery. This review examines the current knowledge based on the multi-domain architecture of the Hendra RdRp and highlights which essential domain functions represent tangible targets for drug development against this deadly disease.

    9. Metabolic network analysis-based identification of antimicrobial drug targets in category A bioterrorism agents.

      Directory of Open Access Journals (Sweden)

      Yong-Yeol Ahn

      Full Text Available The 2001 anthrax mail attacks in the United States demonstrated the potential threat of bioterrorism, hence driving the need to develop sophisticated treatment and diagnostic protocols to counter biological warfare. Here, by performing flux balance analyses on the fully-annotated metabolic networks of multiple, whole genome-sequenced bacterial strains, we have identified a large number of metabolic enzymes as potential drug targets for each of the three Category A-designated bioterrorism agents including Bacillus anthracis, Francisella tularensis and Yersinia pestis. Nine metabolic enzymes- belonging to the coenzyme A, folate, phosphatidyl-ethanolamine and nucleic acid pathways common to all strains across the three distinct genera were identified as targets. Antimicrobial agents against some of these enzymes are available. Thus, a combination of cross species-specific antibiotics and common antimicrobials against shared targets may represent a useful combinatorial therapeutic approach against all Category A bioterrorism agents.

    10. Cos-Seq for high-throughput identification of drug target and resistance mechanisms in the protozoan parasite Leishmania.

      Science.gov (United States)

      Gazanion, Élodie; Fernández-Prada, Christopher; Papadopoulou, Barbara; Leprohon, Philippe; Ouellette, Marc

      2016-05-24

      Innovative strategies are needed to accelerate the identification of antimicrobial drug targets and resistance mechanisms. Here we develop a sensitive method, which we term Cosmid Sequencing (or "Cos-Seq"), based on functional cloning coupled to next-generation sequencing. Cos-Seq identified >60 loci in the Leishmania genome that were enriched via drug selection with methotrexate and five major antileishmanials (antimony, miltefosine, paromomycin, amphotericin B, and pentamidine). Functional validation highlighted both known and previously unidentified drug targets and resistance genes, including novel roles for phosphatases in resistance to methotrexate and antimony, for ergosterol and phospholipid metabolism genes in resistance to miltefosine, and for hypothetical proteins in resistance to paromomycin, amphothericin B, and pentamidine. Several genes/loci were also found to confer resistance to two or more antileishmanials. This screening method will expedite the discovery of drug targets and resistance mechanisms and is easily adaptable to other microorganisms.

    11. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

      Science.gov (United States)

      Aryal, Muna; Arvanitis, Costas D.; Alexander, Phillip M.; McDannold, Nathan

      2014-01-01

      The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. This review provides insight on the current status of this unique drug delivery technique, experience in preclinical models, and potential for clinical translation. If translated to humans, this method would offer a flexible means to target therapeutics to desired points or volumes in the brain, and enable the whole arsenal of drugs in the CNS that are currently prevented by the BBB. PMID:24462453

    12. Target Essentiality and Centrality Characterize Drug Side Effects

      OpenAIRE

      Wang, Xiujuan; Thijssen, Bram; Yu, Haiyuan

      2013-01-01

      Author Summary The ultimate goal of medical research is to develop effective treatments for disease with minimal side effects. Currently, about 20% of drug candidates failed at clinical trial phases II and III due to safety issues. Therefore, understanding the determining factors of drug side effects is of paramount importance to human health and the pharmaceutical industry. Here, we present the first systematic study to uncover key factors leading to drug side effects within the framework of...

    13. Cognitive enhancers (Nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. Disease-modifying drugs. Update 2014.

      Science.gov (United States)

      Froestl, Wolfgang; Pfeifer, Andrea; Muhs, Andreas

      2014-01-01

      Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review "Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs" was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

    14. Dominant drug targets suppress the emergence of antiviral resistance

      OpenAIRE

      Tanner, Elizabeth J; Liu, Hong-mei; Oberste, M Steven; Pallansch, Mark; Collett, Marc S; Kirkegaard, Karla

      2014-01-01

      eLife digest Treating a viral infection with a drug sometimes has an unwanted side effect?the virus quickly becomes resistant to the drug. Viruses whose genetic information is encoded in molecules of RNA mutate faster than DNA viruses and are particularly good at developing resistance to drugs. This is because the process of copying the RNA is prone to errors, and by chance some of these errors, or mutations, may allow the virus to resist the drug's effects. Treating viral infections with mos...

    15. Centredale Manor Superfund Site in Rhode Island included on EPA List of Targeted for Immediate Attention

      Science.gov (United States)

      Today, the U.S. Environmental Protection Agency released the list of Superfund sites that Administrator Pruitt has targeted for immediate and intense attention. The Centredale Manor Restoration Project superfund site is one of the 21 sites on the list.

    16. Rational polypharmacology: systematically identifying and engaging multiple drug targets to promote axon growth

      Science.gov (United States)

      Al-Ali, Hassan; Lee, Do-Hun; Danzi, Matt C.; Nassif, Houssam; Gautam, Prson; Wennerberg, Krister; Zuercher, Bill; Drewry, David H.; Lee, Jae K.; Lemmon, Vance P.; Bixby, John L.

      2016-01-01

      Mammalian Central Nervous System (CNS) neurons regrow their axons poorly following injury, resulting in irreversible functional losses. Identifying therapeutics that encourage CNS axon repair has been difficult, in part because multiple etiologies underlie this regenerative failure. This suggests a particular need for drugs that engage multiple molecular targets. Although multi-target drugs are generally more effective than highly selective alternatives, we lack systematic methods for discovering such drugs. Target-based screening is an efficient technique for identifying potent modulators of individual targets. In contrast, phenotypic screening can identify drugs with multiple targets; however, these targets remain unknown. To address this gap, we combined the two drug discovery approaches using machine learning and information theory. We screened compounds in a phenotypic assay with primary CNS neurons and also in a panel of kinase enzyme assays. We used learning algorithms to relate the compounds’ kinase inhibition profiles to their influence on neurite outgrowth. This allowed us to identify kinases that may serve as targets for promoting neurite outgrowth, as well as others whose targeting should be avoided. We found that compounds that inhibit multiple targets (polypharmacology) promote robust neurite outgrowth in vitro. One compound with exemplary polypharmacology, was found to promote axon growth in a rodent spinal cord injury model. A more general applicability of our approach is suggested by its ability to deconvolve known targets for a breast cancer cell line, as well as targets recently shown to mediate drug resistance. PMID:26056718

    17. Anticancer drug development from traditional cytotoxic to targeted therapies: evidence of shorter drug research and development time, and shorter drug lag in Japan.

      Science.gov (United States)

      Kawabata-Shoda, E; Masuda, S; Kimura, H

      2012-10-01

      Concern about the drug lag, the delay in marketing approval between one country and another, for anticancer drugs has increased in Japan. Although a number of studies have investigated the drug lag, none has investigated it in relation to the transition of anticancer therapy from traditional cytotoxic drugs to molecularly targeted agents. Our aim was to investigate current trend in oncology drug lag between the US and Japan and identify oncology drugs approved in only one of the two countries. Publicly and commercially available data sources were used to identify drugs approved in the US and Japan as of 31 December 2010 and the data used to calculate the drug lag for individual drugs. Fifty-one drugs were approved in both the US and Japan, whereas 34 and 19 drugs were approved only in the US or Japan, respectively. Of the 19 drugs approved only in Japan, 12 had not been subject to development for a cancer indication in the US, and all were approved before 1996 in Japan. Of the 34 drugs approved only in the US, 20 had not been subject to development in Japan, and none was in the top 25 by annual US anticancer drug-class sales. For drugs approved in both countries, the mean approval lag of the molecularly targeted drugs (MTDs) was significantly shorter than that of the non-molecularly targeted drugs (non-MTDs) (3·3 vs. 5·4 years). Further, mean R&D time of the MTDs was significantly shorter than that of non-MTDs (10·0 vs. 13·7 years). The price of MTDs had increased on average by 6·6% annually in the US, whereas it had decreased on average by 4·3% biyearly in Japan. The emergence of new molecularly targeted agents has contributed to reducing the approval lag, most likely due to improvements in R&D strategy. © 2012 Blackwell Publishing Ltd.

    18. Identification of putative drug targets in Vancomycin-resistant Staphylococcus aureus (VRSA) using computer aided protein data analysis.

      Science.gov (United States)

      Hasan, Md Anayet; Khan, Md Arif; Sharmin, Tahmina; Hasan Mazumder, Md Habibul; Chowdhury, Afrin Sultana

      2016-01-01

      Vancomycin-resistant Staphylococcus aureus (VRSA) is a Gram-positive, facultative aerobic bacterium which is evolved from the extensive exposure of Vancomycin to Methicillin resistant S. aureus (MRSA) that had become the most common cause of hospital and community-acquired infections. Due to the emergence of different antibiotic resistance strains, there is an exigency to develop novel drug targets to address the provocation of multidrug-resistant bacteria. In this study, in-silico genome subtraction methodology was used to design potential and pathogen specific drug targets against VRSA. Our study divulged 1987 proteins from the proteome of 34,549 proteins, which have no homologues in human genome after sequential analysis through CD-HIT and BLASTp. The high stringency analysis of the remaining proteins against database of essential genes (DEG) resulted in 169 proteins which are essential for S. aureus. Metabolic pathway analysis of human host and pathogen by KAAS at the KEGG server sorted out 19 proteins involved in unique metabolic pathways. 26 human non-homologous membrane-bound essential proteins including 4 which were also involved in unique metabolic pathway were deduced through PSORTb, CELLO v.2.5, ngLOC. Functional classification of uncharacterized proteins through SVMprot derived 7 human non-homologous membrane-bound hypothetical essential proteins. Study of potential drug target against Drug Bank revealed pbpA-penicillin-binding protein 1 and hypothetical protein MQW_01796 as the best drug target candidate. 2D structure was predicted by PRED-TMBB, 3D structure and functional analysis was also performed. Protein-protein interaction network of potential drug target proteins was analyzed by using STRING. The identified drug targets are expected to have great potential for designing novel drugs against VRSA infections and further screening of the compounds against these new targets may result in the discovery of novel therapeutic compounds that can be

    19. 7 CFR 3021.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-01-01

      ... inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee assistance... WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 3021.215 What must I...

    20. 29 CFR 94.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-07-01

      ... inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee assistance... WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 94.215 What must I...

    1. 22 CFR 312.215 - What must I include in my drug-free awareness program?

      Science.gov (United States)

      2010-04-01

      ... inform employees about— (a) The dangers of drug abuse in the workplace; (b) Your policy of maintaining a drug-free workplace; (c) Any available drug counseling, rehabilitation, and employee assistance... WORKPLACE (FINANCIAL ASSISTANCE) Requirements for Recipients Other Than Individuals § 312.215 What must I...

    2. Associating Drugs, Targets and Clinical Outcomes into an Integrated Network Affords a New Platform for Computer-Aided Drug Repurposing

      DEFF Research Database (Denmark)

      Oprea, Tudor; Nielsen, Sonny Kim; Ursu, Oleg

      2011-01-01

      benefit from an integrated, semantic-web compliant computer-aided drug repurposing (CADR) effort, one that would enable deep data mining of associations between approved drugs (D), targets (T), clinical outcomes (CO) and SE. We report preliminary results from text mining and multivariate statistics, based...

    3. Hallucinogens and Dissociative Drugs, Including LSD, PCP, Ketamine, Dextromethorphan. National Institute on Drug Abuse Research Report Series.

      Science.gov (United States)

      National Inst. on Drug Abuse (DHHS/PHS), Rockville, MD.

      Research is developing a clearer picture of the dangers of mind-altering drugs. The goal of this report is to present the latest information to providers to help them strengthen their prevention and treatment efforts. A description is presented of dissociative drugs, and consideration is given as to why people take hallucinogens. The physical…

    4. Advancing cancer drug discovery towards more agile development of targeted combination therapies.

      Science.gov (United States)

      Carragher, Neil O; Unciti-Broceta, Asier; Cameron, David A

      2012-01-01

      Current drug-discovery strategies are typically 'target-centric' and are based upon high-throughput screening of large chemical libraries against nominated targets and a selection of lead compounds with optimized 'on-target' potency and selectivity profiles. However, high attrition of targeted agents in clinical development suggest that combinations of targeted agents will be most effective in treating solid tumors if the biological networks that permit cancer cells to subvert monotherapies are identified and retargeted. Conventional drug-discovery and development strategies are suboptimal for the rational design and development of novel drug combinations. In this article, we highlight a series of emerging technologies supporting a less reductionist, more agile, drug-discovery and development approach for the rational design, validation, prioritization and clinical development of novel drug combinations.

    5. Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration.

      Science.gov (United States)

      Gu, Wenyi; Wu, Chengtie; Chen, Jiezhong; Xiao, Yin

      2013-01-01

      Nanotechnology is a vigorous research area and one of its important applications is in biomedical sciences. Among biomedical applications, targeted drug delivery is one of the most extensively studied subjects. Nanostructured particles and scaffolds have been widely studied for increasing treatment efficacy and specificity of present treatment approaches. Similarly, this technique has been used for treating bone diseases including bone regeneration. In this review, we have summarized and highlighted the recent advancement of nanostructured particles and scaffolds for the treatment of cancer bone metastasis, osteosarcoma, bone infections and inflammatory diseases, osteoarthritis, as well as for bone regeneration. Nanoparticles used to deliver deoxyribonucleic acid and ribonucleic acid molecules to specific bone sites for gene therapies are also included. The investigation of the implications of nanoparticles in bone diseases have just begun, and has already shown some promising potential. Further studies have to be conducted, aimed specifically at assessing targeted delivery and bioactive scaffolds to further improve their efficacy before they can be used clinically.

    6. Alzheimer’s Disease, Brain Injury, and C.N.S. Nanotherapy in Humans: Sonoporation Augmenting Drug Targeting

      Directory of Open Access Journals (Sweden)

      Joseph S. D’Arrigo

      2017-11-01

      Full Text Available Owing to the complexity of neurodegenerative diseases, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted nanoemulsion are available. Versatile small-molecule drug(s targeting multiple pathways of Alzheimer’s disease pathogenesis are known. By incorporating such drug(s into the targeted lipid-coated microbubble/nanoparticle-derived (LCM/ND lipid nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly scavenger receptor class B type I (SR-BI, making it possible for various Alzheimer’s-related cell types to be simultaneously sought for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s include a characteristic lipid-coated microbubble (LCM subpopulation (i.e., a stable LCM suspension; such LCM substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer’s patient.

    7. Alzheimer’s Disease, Brain Injury, and C.N.S. Nanotherapy in Humans: Sonoporation Augmenting Drug Targeting

      Science.gov (United States)

      D’Arrigo, Joseph S.

      2017-01-01

      Owing to the complexity of neurodegenerative diseases, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted nanoemulsion) are available. Versatile small-molecule drug(s) targeting multiple pathways of Alzheimer’s disease pathogenesis are known. By incorporating such drug(s) into the targeted lipid-coated microbubble/nanoparticle-derived (LCM/ND) lipid nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly scavenger receptor class B type I (SR-BI)), making it possible for various Alzheimer’s-related cell types to be simultaneously sought for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble (LCM) subpopulation (i.e., a stable LCM suspension); such LCM substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer’s patient.

    8. Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration

      Directory of Open Access Journals (Sweden)

      Gu W

      2013-06-01

      Full Text Available Wenyi Gu,1,2 Chengtie Wu,3 Jiezhong Chen,1 Yin Xiao1 1Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia; 2Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia; 3State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, People's Republic of China Abstract: Nanotechnology is a vigorous research area and one of its important applications is in biomedical sciences. Among biomedical applications, targeted drug delivery is one of the most extensively studied subjects. Nanostructured particles and scaffolds have been widely studied for increasing treatment efficacy and specificity of present treatment approaches. Similarly, this technique has been used for treating bone diseases including bone regeneration. In this review, we have summarized and highlighted the recent advancement of nanostructured particles and scaffolds for the treatment of cancer bone metastasis, osteosarcoma, bone infections and inflammatory diseases, osteoarthritis, as well as for bone regeneration. Nanoparticles used to deliver deoxyribonucleic acid and ribonucleic acid molecules to specific bone sites for gene therapies are also included. The investigation of the implications of nanoparticles in bone diseases have just begun, and has already shown some promising potential. Further studies have to be conducted, aimed specifically at assessing targeted delivery and bioactive scaffolds to further improve their efficacy before they can be used clinically. Keywords: nanoparticles, nanostructured scaffold, cancer bone metastasis, bone diseases, target drug delivery, bone regeneration

    9. Drug targeting systems for inflammatory disease: one for all, all for one.

      Science.gov (United States)

      Crielaard, Bart J; Lammers, Twan; Schiffelers, Raymond M; Storm, Gert

      2012-07-20

      In various systemic disorders, structural changes in the microenvironment of diseased tissues enable both passive and active targeting of therapeutic agents to these tissues. This has led to a number of targeting approaches that enhance the accumulation of drugs in the target tissues, making drug targeting an attractive strategy for the treatment of various diseases. Remarkably, the strategic principles that form the basis of drug targeting are often employed for tumor targeting, while chronic inflammatory diseases appear to draw much less attention. To provide the reader with a general overview of the current status of drug targeting to inflammatory diseases, the passive and active targeting strategies that have been used for the treatment of rheumatoid arthritis (RA) and multiple sclerosis (MS) are discussed. The last part of this review addresses the dualism of platform technology-oriented ("one for all") and disease-oriented drug targeting research ("all for one"), both of which are key elements of effective drug targeting research. Copyright © 2012 Elsevier B.V. All rights reserved.

    10. Target Nanoparticles for Therapy - SANS and DLS of Drug Carrier Liposomes and Polymer Nanoparticles

      Science.gov (United States)

      Nawroth, T.; Johnson, R.; Krebs, L.; Khoshakhlagh, P.; Langguth, P.; Hellmann, N.; Goerigk, G.; Boesecke, P.; Bravin, A.; Le Duc, G.; Szekely, N.; Schweins, R.

      2016-09-01

      T arget Nano-Pharmaceutics shall improve therapy and diagnosis of severe diseases, e.g. cancer, by individual targeting of drug-loaded nano-pharmaceuticals towards cancer cells, and drug uptake receptors in other diseases. Specific ligands, proteins or cofactors, which are recognized by the diseased cells or cells of food and drug uptake, are bound to the nanoparticle surface, and thus capable of directing the drug carriers. The strategy has two branches: a) for parenteral cancer medicine a ligand set (2-5 different, surface-linked) are selected according to the biopsy analysis of the patient tissue e.g. from tumor.; b) in the oral drug delivery part the drug transport is enforced by excipients/ detergents in combination with targeting materials for cellular receptors resulting in an induced drug uptake. Both targeting nanomaterials are characterized by a combination of SANS + DLS and SAXS or ASAXS in a feedback process during development by synthesis, nanoparticle assembly and formulation.

    11. Target Nanoparticles for Therapy - SANS and DLS of Drug Carrier Liposomes and Polymer Nanoparticles

      International Nuclear Information System (INIS)

      Nawroth, T; Johnson, R; Krebs, L; Khoshakhlagh, P; Langguth, P; Hellmann, N; Goerigk, G; Boesecke, P; Bravin, A; Duc, G Le; Szekely, N; Schweins, R

      2016-01-01

      T arget Nano-Pharmaceutics shall improve therapy and diagnosis of severe diseases, e.g. cancer, by individual targeting of drug-loaded nano-pharmaceuticals towards cancer cells, and drug uptake receptors in other diseases. Specific ligands, proteins or cofactors, which are recognized by the diseased cells or cells of food and drug uptake, are bound to the nanoparticle surface, and thus capable of directing the drug carriers. The strategy has two branches: a) for parenteral cancer medicine a ligand set (2-5 different, surface-linked) are selected according to the biopsy analysis of the patient tissue e.g. from tumor.; b) in the oral drug delivery part the drug transport is enforced by excipients/ detergents in combination with targeting materials for cellular receptors resulting in an induced drug uptake. Both targeting nanomaterials are characterized by a combination of SANS + DLS and SAXS or ASAXS in a feedback process during development by synthesis, nanoparticle assembly and formulation. (paper)

    12. Drug-target interaction prediction via class imbalance-aware ensemble learning

      OpenAIRE

      Ezzat, Ali; Wu, Min; Li, Xiao-Li; Kwoh, Chee-Keong

      2016-01-01

      Background Multiple computational methods for predicting drug-target interactions have been developed to facilitate the drug discovery process. These methods use available data on known drug-target interactions to train classifiers with the purpose of predicting new undiscovered interactions. However, a key challenge regarding this data that has not yet been addressed by these methods, namely class imbalance, is potentially degrading the prediction performance. Class imbalance can be divided ...

    13. Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

      OpenAIRE

      Burkhart, Keith K.; Abernethy, Darrell; Jackson, David

      2015-01-01

      Drug features that are associated with Stevens-Johnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was al...

    14. RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance

      Directory of Open Access Journals (Sweden)

      Richard J. Bingham

      2017-11-01

      Full Text Available The rapid occurrence of therapy-resistant mutant strains provides a challenge for anti-viral therapy. An ideal drug target would be a highly conserved molecular feature in the viral life cycle, such as the packaging signals in the genomes of RNA viruses that encode an instruction manual for their efficient assembly. The ubiquity of this assembly code in RNA viruses, including major human pathogens, suggests that it confers selective advantages. However, their impact on viral evolution cannot be assessed in current models of viral infection that lack molecular details of virus assembly. We introduce here a quasispecies-based model of a viral infection that incorporates structural and mechanistic knowledge of packaging signal function in assembly to construct a phenotype-fitness map, capturing the impact of this RNA code on assembly yield and efficiency. Details of viral replication and assembly inside an infected host cell are coupled with a population model of a viral infection, allowing the occurrence of therapy resistance to be assessed in response to drugs inhibiting packaging signal recognition. Stochastic simulations of viral quasispecies evolution in chronic HCV infection under drug action and/or immune clearance reveal that drugs targeting all RNA signals in the assembly code collectively have a high barrier to drug resistance, even though each packaging signal in isolation has a lower barrier than conventional drugs. This suggests that drugs targeting the RNA signals in the assembly code could be promising routes for exploitation in anti-viral drug design.

    15. RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance.

      Science.gov (United States)

      Bingham, Richard J; Dykeman, Eric C; Twarock, Reidun

      2017-11-17

      The rapid occurrence of therapy-resistant mutant strains provides a challenge for anti-viral therapy. An ideal drug target would be a highly conserved molecular feature in the viral life cycle, such as the packaging signals in the genomes of RNA viruses that encode an instruction manual for their efficient assembly. The ubiquity of this assembly code in RNA viruses, including major human pathogens, suggests that it confers selective advantages. However, their impact on viral evolution cannot be assessed in current models of viral infection that lack molecular details of virus assembly. We introduce here a quasispecies-based model of a viral infection that incorporates structural and mechanistic knowledge of packaging signal function in assembly to construct a phenotype-fitness map, capturing the impact of this RNA code on assembly yield and efficiency. Details of viral replication and assembly inside an infected host cell are coupled with a population model of a viral infection, allowing the occurrence of therapy resistance to be assessed in response to drugs inhibiting packaging signal recognition. Stochastic simulations of viral quasispecies evolution in chronic HCV infection under drug action and/or immune clearance reveal that drugs targeting all RNA signals in the assembly code collectively have a high barrier to drug resistance, even though each packaging signal in isolation has a lower barrier than conventional drugs. This suggests that drugs targeting the RNA signals in the assembly code could be promising routes for exploitation in anti-viral drug design.

    16. New drugs in psychiatry: focus on new pharmacological targets [version 1; referees: 3 approved

      Directory of Open Access Journals (Sweden)

      Filippo Caraci

      2017-03-01

      Full Text Available The approval of psychotropic drugs with novel mechanisms of action has been rare in recent years. To address this issue, further analysis of the pathophysiology of neuropsychiatric disorders is essential for identifying new pharmacological targets for psychotropic medications. In this report, we detail drug candidates being examined as treatments for psychiatric disorders. Particular emphasis is placed on agents with novel mechanisms of action that are being tested as therapies for depression, schizophrenia, or Alzheimer’s disease. All of the compounds considered were recently approved for human use or are in advanced clinical trials. Drugs included here are new antipsychotic medications endowed with a preferential affinity at dopamine D3 receptor (cariprazine or at glutamatergic or cannabinoid receptors, as well as vortioxetine, a drug approved for managing the cognitive deficits associated with major depression. New mechanistic approaches for the treatment of depression include intravenous ketamine or esketamine or intranasal esketamine. As for Alzheimer’s disease, the possible value of passive immunotherapy with agents such as aducanumab is considered to be a potential disease-modifying approach that could slow or halt the progressive decline associated with this devastating disorder.

    17. Recent developments in the nanostructured materials functionalized with ruthenium complexes for targeted drug delivery to tumors

      Directory of Open Access Journals (Sweden)

      Thangavel P

      2017-04-01

      Full Text Available Prakash Thangavel,1 Buddolla Viswanath,1 Sanghyo Kim1,2 1Department of Bionanotechnology, Gachon University, Bokjeong-Dong, Sujeong-Gu, Seongnam-Si, Gyeonggi-Do, 2Graduate Gachon Medical Research Institute, Gil Medical Center, Incheon, Republic of Korea Abstract: In recent years, the field of metal-based drugs has been dominated by other existing precious metal drugs, and many researchers have focused their attention on the synthesis of various ruthenium (Ru complexes due to their potential medical and pharmaceutical applications. The beneficial properties of Ru, which make it a highly promising therapeutic agent, include its variable oxidation states, low toxicity, high selectivity for diseased cells, ligand exchange properties, and the ability to mimic iron binding to biomolecules. In addition, Ru complexes have favorable adsorption properties, along with excellent photochemical and photophysical properties, which make them promising tools for photodynamic therapy. At present, nanostructured materials functionalized with Ru complexes have become an efficient way to administer Ru-based anticancer drugs for cancer treatment. In this review, the recent developments in the nanostructured materials functionalized with Ru complexes for targeted drug delivery to tumors are discussed. In addition, information on “traditional” (ie, non-nanostructured Ru-based cancer therapies is included in a precise manner. Keywords: metallodrugs, nanotechnology, cancer treatment, cell apoptosis, DNA damage, toxicity

    18. Recent developments in the nanostructured materials functionalized with ruthenium complexes for targeted drug delivery to tumors.

      Science.gov (United States)

      Thangavel, Prakash; Viswanath, Buddolla; Kim, Sanghyo

      2017-01-01

      In recent years, the field of metal-based drugs has been dominated by other existing precious metal drugs, and many researchers have focused their attention on the synthesis of various ruthenium (Ru) complexes due to their potential medical and pharmaceutical applications. The beneficial properties of Ru, which make it a highly promising therapeutic agent, include its variable oxidation states, low toxicity, high selectivity for diseased cells, ligand exchange properties, and the ability to mimic iron binding to biomolecules. In addition, Ru complexes have favorable adsorption properties, along with excellent photochemical and photophysical properties, which make them promising tools for photodynamic therapy. At present, nanostructured materials functionalized with Ru complexes have become an efficient way to administer Ru-based anticancer drugs for cancer treatment. In this review, the recent developments in the nanostructured materials functionalized with Ru complexes for targeted drug delivery to tumors are discussed. In addition, information on "traditional" (ie, non-nanostructured) Ru-based cancer therapies is included in a precise manner.

    19. Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders.

      Science.gov (United States)

      Koeberle, Andreas; Werz, Oliver

      2015-11-01

      Prostaglandin (PG)E2 encompasses crucial roles in pain, fever, inflammation and diseases with inflammatory component, such as cancer, but is also essential for gastric, renal, cardiovascular and immune homeostasis. Cyclooxygenases (COX) convert arachidonic acid to the intermediate PGH2 which is isomerized to PGE2 by at least three different PGE2 synthases. Inhibitors of COX - non-steroidal anti-inflammatory drugs (NSAIDs) - are currently the only available therapeutics that target PGE2 biosynthesis. Due to adverse effects of COX inhibitors on the cardiovascular system (COX-2-selective), stomach and kidney (COX-1/2-unselective), novel pharmacological strategies are in demand. The inducible microsomal PGE2 synthase (mPGES)-1 is considered mainly responsible for the excessive PGE2 synthesis during inflammation and was suggested as promising drug target for suppressing PGE2 biosynthesis. However, 15 years after intensive research on the biology and pharmacology of mPGES-1, the therapeutic value of mPGES-1 as drug target is still vague and mPGES-1 inhibitors did not enter the market so far. This commentary will first shed light on the structure, mechanism and regulation of mPGES-1 and will then discuss its biological function and the consequence of its inhibition for the dynamic network of eicosanoids. Moreover, we (i) present current strategies for interfering with mPGES-1-mediated PGE2 synthesis, (ii) summarize bioanalytical approaches for mPGES-1 drug discovery and (iii) describe preclinical test systems for the characterization of mPGES-1 inhibitors. The pharmacological potential of selective mPGES-1 inhibitor classes as well as dual mPGES-1/5-lipoxygenase inhibitors is reviewed and pitfalls in their development, including species discrepancies and loss of in vivo activity, are discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

    20. The use of microbubbles to target drug delivery

      Directory of Open Access Journals (Sweden)

      Porter Richard

      2004-11-01

      Full Text Available Abstract Ultrasound-mediated microbubbles destruction has been proposed as an innovative method for noninvasive delivering of drugs and genes to different tissues. Microbubbles are used to carry a drug or gene until a specific area of interest is reached, and then ultrasound is used to burst the microbubbles, causing site-specific delivery of the bioactive materials. Furthermore, the ability of albumin-coated microbubbles to adhere to vascular regions with glycocalix damage or endothelial dysfunction is another possible mechanism to deliver drugs even in the absence of ultrasound. This review focuses on the characteristics of microbubbles that give them therapeutic properties and some important aspects of ultrasound parameters that are known to influence microbubble-mediated drug delivery. In addition, current studies involving this novel therapeutical application of microbubbles will be discussed.

    1. Pharmacological approaches for Alzheimer's disease: neurotransmitter as drug targets.

      Science.gov (United States)

      Prakash, Atish; Kalra, Jaspreet; Mani, Vasudevan; Ramasamy, Kalavathy; Majeed, Abu Bakar Abdul

      2015-01-01

      Alzheimer's disease (AD) is the most common CNS disorder occurring worldwide. There is neither proven effective prevention for AD nor a cure for patients with this disorder. Hence, there is an urgent need to develop safer and more efficacious drugs to help combat the tremendous increase in disease progression. The present review is an attempt at discussing the treatment strategies and drugs under clinical trials governing the modulation of neurotransmitter. Therefore, looking at neurotransmitter abnormalities, there is an urge for developing the pharmacological approaches aimed at correcting those abnormalities and dysfunctioning. In addition, this review also discusses the drugs that are in Phase III trials for the treatment of AD. Despite advances in treatment strategies aimed at correcting neurotransmitter abnormalities, there exists a need for the development of drug therapies focusing on the attempts to remove the pathogenomic protein deposits, thus combating the disease progression.

    2. A Target Repurposing Approach Identifies N-myristoyltransferase as a New Candidate Drug Target in Filarial Nematodes

      Science.gov (United States)

      Villemaine, Estelle; Poole, Catherine B.; Chapman, Melissa S.; Pollastri, Michael P.; Wyatt, Paul G.; Carlow, Clotilde K. S.

      2014-01-01

      Myristoylation is a lipid modification involving the addition of a 14-carbon unsaturated fatty acid, myristic acid, to the N-terminal glycine of a subset of proteins, a modification that promotes their binding to cell membranes for varied biological functions. The process is catalyzed by myristoyl-CoA:protein N-myristoyltransferase (NMT), an enzyme which has been validated as a drug target in human cancers, and for infectious diseases caused by fungi, viruses and protozoan parasites. We purified Caenorhabditis elegans and Brugia malayi NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and peptide substrates. Biochemical and structural analyses both revealed that the nematode enzymes are canonical NMTs, sharing a high degree of conservation with protozoan NMT enzymes. Inhibitory compounds that target NMT in protozoan species inhibited the nematode NMTs with IC50 values of 2.5–10 nM, and were active against B. malayi microfilariae and adult worms at 12.5 µM and 50 µM respectively, and C. elegans (25 µM) in culture. RNA interference and gene deletion in C. elegans further showed that NMT is essential for nematode viability. The effects observed are likely due to disruption of the function of several downstream target proteins. Potential substrates of NMT in B. malayi are predicted using bioinformatic analysis. Our genetic and chemical studies highlight the importance of myristoylation in the synthesis of functional proteins in nematodes and have shown for the first time that NMT is required for viability in parasitic nematodes. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against nematode diseases including filariasis. PMID:25188325

    3. GRP78 Protein Expression in Ovarian Cancer Patients and Perspectives for a Drug-Targeting Approach

      Directory of Open Access Journals (Sweden)

      Florence Delie

      2012-01-01

      Full Text Available Glucose-regulated protein of 78 kD (GRP78 is a chaperone protein mainly located in the endoplasmic reticulum (ER. This protein is normally present at low levels in adult cells but its expression is triggered by ER stress including glucose deprivation and hypoxia. In tumor cells, it is overexpressed with fraction of protein found at the cell surface. This paper presents the physiology of GRP78 in the context of ovarian cancer and its potential use as drug delivery systems targeting ovarian cancer cell.

    4. Targeted liposomes for cytosolic drug delivery to tumor cells

      NARCIS (Netherlands)

      Mastrobattista, E.

      2001-01-01

      In this thesis, a Trojan horse strategy with antibody-targeted liposomes has been followed to obtain cytosolic delivery of biotherapeutics to tumor cells in vitro. This strategy involves targeting of immunoliposomes to specific receptors on tumor cells that result in receptor-mediated uptake of the

    5. HIV LIFE CYCLE AND POTENTIAl TARGETS FOR DRUG ACTIVITY

      African Journals Online (AJOL)

      TABLE Ill. STAGES IN THE HIV UFE CYCLE THAT ARE TARGETS FOR CURRENTLY AVAIlABLE ANTIRETROVIRAlS. Fig. 7. Life cycle ofHIVand targets for ontiretrovirol theropy. (Reproduced with permission from: 5Miller, The Clinician's Guide to. Antiretroviral Resistance, 2007.) JULY 2002. Budding: immature virus.

    6. Theoretical modelling of physiologically stretched vessel in magnetisable stent assisted magnetic drug targeting application

      International Nuclear Information System (INIS)

      Mardinoglu, Adil; Cregg, P.J.; Murphy, Kieran; Curtin, Maurice; Prina-Mello, Adriele

      2011-01-01

      The magnetisable stent assisted magnetic targeted drug delivery system in a physiologically stretched vessel is considered theoretically. The changes in the mechanical behaviour of the vessel are analysed under the influence of mechanical forces generated by blood pressure. In this 2D mathematical model a ferromagnetic, coiled wire stent is implanted to aid collection of magnetic drug carrier particles in an elastic tube, which has similar mechanical properties to the blood vessel. A cyclic mechanical force is applied to the elastic tube to mimic the mechanical stress and strain of both the stent and vessel while in the body due to pulsatile blood circulation. The magnetic dipole-dipole and hydrodynamic interactions for multiple particles are included and agglomeration of particles is also modelled. The resulting collection efficiency of the mathematical model shows that the system performance can decrease by as much as 10% due to the effects of the pulsatile blood circulation. - Research highlights: →Theoretical modelling of magnetic drug targeting on a physiologically stretched stent-vessel system. →Cyclic mechanical force applied to mimic the mechanical stress and strain of both stent and vessel. →The magnetic dipole-dipole and hydrodynamic interactions for multiple particles is modelled. →Collection efficiency of the mathematical model is calculated for different physiological blood flow and magnetic field strength.

    7. The challenges of modulating the 'rest and digest' system: acetylcholine receptors as drug targets.

      Science.gov (United States)

      VanPatten, Sonya; Al-Abed, Yousef

      2017-01-01

      Acetylcholine, a major neurotransmitter of the parasympathetic and sympathetic nervous systems, was discovered in the early 1900s. Over the years, researchers have revealed much about its regulation, properties of its receptors and features of the downstream signaling that influence its terminal effects. The acetylcholine system, traditionally associated with neuromuscular communication, is now known to play a crucial part in modulation of the immune system and other 'rest and digest' effects. Recent research seeks to elucidate the system's role in brain functions including cognition, sleep, arousal, motivation, reward and pain. We highlight clinically approved and experimental drugs that modulate the acetylcholine receptors. The complexities in targeting the acetylcholine receptors are vast and finding future indications for drug development associated with specific acetylcholine receptors remains a challenge. Copyright © 2016 Elsevier Ltd. All rights reserved.

    8. Targeted drugs for pulmonary arterial hypertension: a network meta-analysis of 32 randomized clinical trials

      Directory of Open Access Journals (Sweden)

      Gao XF

      2017-05-01

      Full Text Available Xiao-Fei Gao,1 Jun-Jie Zhang,1,2 Xiao-Min Jiang,1 Zhen Ge,1,2 Zhi-Mei Wang,1 Bing Li,1 Wen-Xing Mao,1 Shao-Liang Chen1,2 1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 2Department of Cardiology, Nanjing Heart Center, Nanjing, People’s Republic of China Background: Pulmonary arterial hypertension (PAH is a devastating disease and ultimately leads to right heart failure and premature death. A total of four classical targeted drugs, prostanoids, endothelin receptor antagonists (ERAs, phosphodiesterase 5 inhibitors (PDE-5Is, and soluble guanylate cyclase stimulator (sGCS, have been proved to improve exercise capacity and hemodynamics compared to placebo; however, direct head-to-head comparisons of these drugs are lacking. This network meta-analysis was conducted to comprehensively compare the efficacy of these targeted drugs for PAH.Methods: Medline, the Cochrane Library, and other Internet sources were searched for randomized clinical trials exploring the efficacy of targeted drugs for patients with PAH. The primary effective end point of this network meta-analysis was a 6-minute walk distance (6MWD.Results: Thirty-two eligible trials including 6,758 patients were identified. There was a statistically significant improvement in 6MWD, mean pulmonary arterial pressure, pulmonary vascular resistance, and clinical worsening events associated with each of the four targeted drugs compared with placebo. Combination therapy improved 6MWD by 20.94 m (95% confidence interval [CI]: 6.94, 34.94; P=0.003 vs prostanoids, and 16.94 m (95% CI: 4.41, 29.47; P=0.008 vs ERAs. PDE-5Is improved 6MWD by 17.28 m (95% CI: 1.91, 32.65; P=0.028 vs prostanoids, with a similar result with combination therapy. In addition, combination therapy reduced mean pulmonary artery pressure by 3.97 mmHg (95% CI: -6.06, -1.88; P<0.001 vs prostanoids, 8.24 mmHg (95% CI: -10.71, -5.76; P<0.001 vs ERAs, 3.38 mmHg (95% CI: -6.30, -0.47; P=0.023 vs

    9. Drug targeting systems for inflammatory disease: one for all, all for one

      NARCIS (Netherlands)

      Crielaard, B.J.; Lammers, Twan Gerardus Gertudis Maria; Schiffelers, R.M.; Storm, Gerrit

      2012-01-01

      Abstract In various systemic disorders, structural changes in the microenvironment of diseased tissues enable both passive and active targeting of therapeutic agents to these tissues. This has led to a number of targeting approaches that enhance the accumulation of drugs in the target tissues,

    10. Mathematical description of drug-target interactions: application to biologics that bind to targets with two binding sites.

      Science.gov (United States)

      Gibiansky, Leonid; Gibiansky, Ekaterina

      2018-02-01

      The emerging discipline of mathematical pharmacology occupies the space between advanced pharmacometrics and systems biology. A characteristic feature of the approach is application of advance mathematical methods to study the behavior of biological systems as described by mathematical (most often differential) equations. One of the early application of mathematical pharmacology (that was not called this name at the time) was formulation and investigation of the target-mediated drug disposition (TMDD) model and its approximations. The model was shown to be remarkably successful, not only in describing the observed data for drug-target interactions, but also in advancing the qualitative and quantitative understanding of those interactions and their role in pharmacokinetic and pharmacodynamic properties of biologics. The TMDD model in its original formulation describes the interaction of the drug that has one binding site with the target that also has only one binding site. Following the framework developed earlier for drugs with one-to-one binding, this work aims to describe a rigorous approach for working with similar systems and to apply it to drugs that bind to targets with two binding sites. The quasi-steady-state, quasi-equilibrium, irreversible binding, and Michaelis-Menten approximations of the model are also derived. These equations can be used, in particular, to predict concentrations of the partially bound target (RC). This could be clinically important if RC remains active and has slow internalization rate. In this case, introduction of the drug aimed to suppress target activity may lead to the opposite effect due to RC accumulation.

    11. Data driven polypharmacological drug design for lung cancer: analyses for targeting ALK, MET, and EGFR

      DEFF Research Database (Denmark)

      Narayanan, Dilip; Gani, Osman ABSM; Gruber, Franz XE

      2017-01-01

      Drug design of protein kinase inhibitors is now greatly enabled by thousands of publicly available X-ray structures, extensive ligand binding data, and optimized scaffolds coming off patent. The extensive data begin to enable design against a spectrum of targets (polypharmacology); however...... consider polypharmacological targeting of protein kinases ALK, MET, and EGFR (and its drug resistant mutant T790M) in non small cell lung cancer as an example. Both EGFR and ALK represent sources of primary oncogenic lesions, while drug resistance arises from MET amplification and EGFR mutation. A drug...... which inhibits these targets will expand relevant patient populations and forestall drug resistance. Crizotinib co-targets ALK and MET. Analysis of the crystal structures reveals few shared interaction types, highlighting proton-arene and key CH–O hydrogen bonding interactions. These are not typically...

    12. Identification of drug targets by chemogenomic and metabolomic profiling in yeast

      KAUST Repository

      Wu, Manhong

      2012-12-01

      OBJECTIVE: To advance our understanding of disease biology, the characterization of the molecular target for clinically proven or new drugs is very important. Because of its simplicity and the availability of strains with individual deletions in all of its genes, chemogenomic profiling in yeast has been used to identify drug targets. As measurement of drug-induced changes in cellular metabolites can yield considerable information about the effects of a drug, we investigated whether combining chemogenomic and metabolomic profiling in yeast could improve the characterization of drug targets. BASIC METHODS: We used chemogenomic and metabolomic profiling in yeast to characterize the target for five drugs acting on two biologically important pathways. A novel computational method that uses a curated metabolic network was also developed, and it was used to identify the genes that are likely to be responsible for the metabolomic differences found. RESULTS AND CONCLUSION: The combination of metabolomic and chemogenomic profiling, along with data analyses carried out using a novel computational method, could robustly identify the enzymes targeted by five drugs. Moreover, this novel computational method has the potential to identify genes that are causative of metabolomic differences or drug targets. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

    13. Some Remarks on Prediction of Drug-Target Interaction with Network Models.

      Science.gov (United States)

      Zhang, Shao-Wu; Yan, Xiao-Ying

      2017-01-01

      System-level understanding of the relationships between drugs and targets is very important for enhancing drug research, especially for drug function repositioning. The experimental methods used to determine drug-target interactions are usually time-consuming, tedious and expensive, and sometimes lack reproducibility. Thus, it is highly desired to develop computational methods for efficiently and effectively analyzing and detecting new drug-target interaction pairs. With the explosive growth of different types of omics data, such as genome, pharmacology, phenotypic, and other kinds of molecular networks, numerous computational approaches have been developed to predict Drug-Target Interactions (DTI). In this review, we make a survey on the recent advances in predicting drug-target interaction with network-based models from the following aspects: i) Available public data sources and benchmark datasets; ii) Drug/target similarity metrics; iii) Network construction; iv) Common network algorithms; v) Performance comparison of existing network-based DTI predictors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

    14. Systems biology-embedded target validation: improving efficacy in drug discovery.

      Science.gov (United States)

      Vandamme, Drieke; Minke, Benedikt A; Fitzmaurice, William; Kholodenko, Boris N; Kolch, Walter

      2014-01-01

      The pharmaceutical industry is faced with a range of challenges with the ever-escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in -omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment. © 2013 Wiley Periodicals, Inc.

    15. Off-target effects of psychoactive drugs revealed by genome-wide assays in yeast.

      Directory of Open Access Journals (Sweden)

      Elke Ericson

      2008-08-01

      Full Text Available To better understand off-target effects of widely prescribed psychoactive drugs, we performed a comprehensive series of chemogenomic screens using the budding yeast Saccharomyces cerevisiae as a model system. Because the known human targets of these drugs do not exist in yeast, we could employ the yeast gene deletion collections and parallel fitness profiling to explore potential off-target effects in a genome-wide manner. Among 214 tested, documented psychoactive drugs, we identified 81 compounds that inhibited wild-type yeast growth and were thus selected for genome-wide fitness profiling. Many of these drugs had a propensity to affect multiple cellular functions. The sensitivity profiles of half of the analyzed drugs were enriched for core cellular processes such as secretion, protein folding, RNA processing, and chromatin structure. Interestingly, fluoxetine (Prozac interfered with establishment of cell polarity, cyproheptadine (Periactin targeted essential genes with chromatin-remodeling roles, while paroxetine (Paxil interfered with essential RNA metabolism genes, suggesting potential secondary drug targets. We also found that the more recently developed atypical antipsychotic clozapine (Clozaril had no fewer off-target effects in yeast than the typical antipsychotics haloperidol (Haldol and pimozide (Orap. Our results suggest that model organism pharmacogenetic studies provide a rational foundation for understanding the off-target effects of clinically important psychoactive agents and suggest a rational means both for devising compound derivatives with fewer side effects and for tailoring drug treatment to individual patient genotypes.

    16. Peptide deformylase as an antibacterial drug target: target validation and resistance development.

      Science.gov (United States)

      Apfel, C M; Locher, H; Evers, S; Takács, B; Hubschwerlen, C; Pirson, W; Page, M G; Keck, W

      2001-04-01

      New inhibitors of peptide deformylase (PDF) which are very potent against the isolated enzyme and show a certain degree of antibacterial activity have recently been synthesized by our group. Several lines of experimental evidence indicate that these inhibitors indeed interfere with the target enzyme in the bacterial cell. (i) The inhibition of Escherichia coli growth could be counteracted by overexpression of PDF from different organisms, including E. coli, Streptococcus pneumoniae, and Haemophilus influenzae. Conversely, reduced expression of PDF in S. pneumoniae resulted in an increased susceptibility to the inhibitors. (ii) Proteome analysis on two-dimensional gels revealed a shift for many proteins towards lower pI in the presence of PDF inhibitors, as would be expected if the proteins still carry their N-formyl-Met terminus. (iii) PDF inhibitors show no antimicrobial activity against E. coli under conditions that make growth independent of formylation and deformylation. The antibacterial activity in E. coli was characterized as bacteriostatic. Furthermore, the development of resistance in E. coli was observed to occur with high frequency (10(-7)). Resistant mutants show a reduced growth rate, and DNA sequence analysis revealed mutations in their formyl transferase gene. Taking all these aspects into account, we conclude that PDF may not be an optimal target for broad-spectrum antibacterial agents.

    17. Magnetic nanoparticle drug delivery systems for targeting tumor

      Science.gov (United States)

      Mody, Vicky V.; Cox, Arthur; Shah, Samit; Singh, Ajay; Bevins, Wesley; Parihar, Harish

      2014-04-01

      Tumor hypoxia, or low oxygen concentration, is a result of disordered vasculature that lead to distinctive hypoxic microenvironments not found in normal tissues. Many traditional anti-cancer agents are not able to penetrate into these hypoxic zones, whereas, conventional cancer therapies that work by blocking cell division are not effective to treat tumors within hypoxic zones. Under these circumstances the use of magnetic nanoparticles as a drug delivering agent system under the influence of external magnetic field has received much attention, based on their simplicity, ease of preparation, and ability to tailor their properties for specific biological applications. Hence in this review article we have reviewed current magnetic drug delivery systems, along with their application and clinical status in the field of magnetic drug delivery.

    18. Charge-reversal nanoparticles: novel targeted drug delivery carriers.

      Science.gov (United States)

      Chen, Xinli; Liu, Lisha; Jiang, Chen

      2016-07-01

      Spurred by significant progress in materials chemistry and drug delivery, charge-reversal nanocarriers are being developed to deliver anticancer formulations in spatial-, temporal- and dosage-controlled approaches. Charge-reversal nanoparticles can release their drug payload in response to specific stimuli that alter the charge on their surface. They can elude clearance from the circulation and be activated by protonation, enzymatic cleavage, or a molecular conformational change. In this review, we discuss the physiological basis for, and recent advances in the design of charge-reversal nanoparticles that are able to control drug biodistribution in response to specific stimuli, endogenous factors (changes in pH, redox gradients, or enzyme concentration) or exogenous factors (light or thermos-stimulation).

    19. Cell wall: A versatile fountain of drug targets in Mycobacterium tuberculosis.

      Science.gov (United States)

      Bhat, Zubair Shanib; Rather, Muzafar Ahmad; Maqbool, Mubashir; Lah, Hafiz Ul; Yousuf, Syed Khalid; Ahmad, Zahoor

      2017-11-01

      Tuberculosis is the leading infectious disease responsible for an estimated one and a half million human deaths each year around the globe. HIV-TB coinfection and rapid increase in the emergence of drug resistant forms of TB is a dangerous scenario. This underlines the urgent need for new drugs with novel mechanism of action. A plethora of literature exist that highlight the importance of enzymes involved in the biosynthesis of mycobacterial cell wall responsible for its survival, growth, permeability, virulence and resistance to antibiotics. Therefore, assembly of cell wall components is an attractive target for the development of chemotherapeutics against Mycobacterium tuberculosis. The aim of this review is to highlight novel sets of enzyme inhibitors that disrupt its cell wall biosynthetic pathway. These include the currently approved first and second line drugs, candidates in clinical trials and current structure activity guided endeavors of scientific community to identify new potent inhibitors with least cytotoxicity and better efficacy against emergence of drug resistance till date. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

    20. Leveraging 3D chemical similarity, target and phenotypic data in the identification of drug-protein and drug-adverse effect associations.

      Science.gov (United States)

      Vilar, Santiago; Hripcsak, George

      2016-01-01

      Drug-target identification is crucial to discover novel applications for existing drugs and provide more insights about mechanisms of biological actions, such as adverse drug effects (ADEs). Computational methods along with the integration of current big data sources provide a useful framework for drug-target and drug-adverse effect discovery. In this article, we propose a method based on the integration of 3D chemical similarity, target and adverse effect data to generate a drug-target-adverse effect predictor along with a simple leveraging system to improve identification of drug-targets and drug-adverse effects. In the first step, we generated a system for multiple drug-target identification based on the application of 3D drug similarity into a large target dataset extracted from the ChEMBL. Next, we developed a target-adverse effect predictor combining targets from ChEMBL with phenotypic information provided by SIDER data source. Both modules were linked to generate a final predictor that establishes hypothesis about new drug-target-adverse effect candidates. Additionally, we showed that leveraging drug-target candidates with phenotypic data is very useful to improve the identification of drug-targets. The integration of phenotypic data into drug-target candidates yielded up to twofold precision improvement. In the opposite direction, leveraging drug-phenotype candidates with target data also yielded a significant enhancement in the performance. The modeling described in the current study is simple and efficient and has applications at large scale in drug repurposing and drug safety through the identification of mechanism of action of biological effects.

    1. Emergence of the silicon human and network targeting drugs.

      NARCIS (Netherlands)

      Kolodkin, A.N.; Boogerd, F.C.; Plant, N.; Bruggeman, F.J.; Goncharuk, V.; Lunshof, J.E.; Moreno-Sanchez, R.; Yilmaz, N.; Bakker, B.M.; Snoep, J.L.; Balling, R.; Westerhoff, H.V.

      2012-01-01

      The development of disease may be characterized as a pathological shift of homeostasis; the main goal of contemporary drug treatment is, therefore, to return the pathological homeostasis back to the normal physiological range. From the view point of systems biology, homeostasis emerges from the

    2. Therapeutic Targets for Influenza - Perspectives in Drug Development

      Czech Academy of Sciences Publication Activity Database

      Majerová, Taťána; Hoffman, H.; Majer, F.

      2010-01-01

      Roč. 75, č. 1 (2010), s. 81-103 ISSN 0010-0765 R&D Projects: GA MŠk 1M0508 Institutional research plan: CEZ:AV0Z40550506 Keywords : influenza * drug research * protein structure * oligonucleotides Subject RIV: CE - Biochemistry Impact factor: 0.853, year: 2010

    3. Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting

      Directory of Open Access Journals (Sweden)

      Brian C. Palmer

      2016-12-01

      Full Text Available Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.

    4. Advances in research of targeting delivery and controlled release of drug-loaded nanoparticles

      International Nuclear Information System (INIS)

      Tan Zhonghua

      2003-01-01

      Biochemistry drug, at present, is still the main tool that human struggle to defeat the diseases. So, developing safe and efficacious technique of drug targeting delivery and controlled release is key to enhance curative effect, decrease drug dosage, and lessen its side effect. Drug-loaded nanoparticles, which is formed by conjugate between nanotechnology and modern pharmaceutics, is a new fashioned pharmic delivery carrier. Because of advantages in pharmic targeting transport and controlled or slow release and improving bioavailability, it has been one of developing trend of modern pharmaceutical dosage forms

    5. DNA sequence analyses of blended herbal products including synthetic cannabinoids as designer drugs.

      Science.gov (United States)

      Ogata, Jun; Uchiyama, Nahoko; Kikura-Hanajiri, Ruri; Goda, Yukihiro

      2013-04-10

      In recent years, various herbal products adulterated with synthetic cannabinoids have been distributed worldwide via the Internet. These herbal products are mostly sold as incense, and advertised as not for human consumption. Although their labels indicate that they contain mixtures of several potentially psychoactive plants, and numerous studies have reported that they contain a variety of synthetic cannabinoids, their exact botanical contents are not always clear. In this study, we investigated the origins of botanical materials in 62 Spice-like herbal products distributed on the illegal drug market in Japan, by DNA sequence analyses and BLAST searches. The nucleotide sequences of four regions were analyzed to identify the origins of each plant species in the herbal mixtures. The sequences of "Damiana" (Turnera diffusa) and Lamiaceae herbs (Mellissa, Mentha and Thymus) were frequently detected in a number of products. However, the sequences of other plant species indicated on the packaging labels were not detected. In a few products, DNA fragments of potent psychotropic plants were found, including marijuana (Cannabis sativa), "Diviner's Sage" (Salvia divinorum) and "Kratom" (Mitragyna speciosa). Their active constituents were also confirmed using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS), although these plant names were never indicated on the labels. Most plant species identified in the products were different from the plants indicated on the labels. The plant materials would be used mainly as diluents for the psychoactive synthetic compounds, because no reliable psychoactive effects have been reported for most of the identified plants, with the exception of the psychotropic plants named above. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

    6. Anticancer Drugs Induced Severe Adverse Cutaneous Drug Reactions: An Updated Review on the Risks Associated with Anticancer Targeted Therapy or Immunotherapies

      Directory of Open Access Journals (Sweden)

      Chau Yee Ng

      2018-01-01

      Full Text Available Cutaneous adverse drug reactions are commonly seen in patients with anticancer drug treatment. Anticancer drugs, including chemotherapy, target therapy, and recent immunotherapy causing skin reactions ranging from mild skin rash to life-threatening severe cutaneous adverse reactions (SCARs, such as Stevens-Johnson syndrome (SJS and toxic epidermal necrosis (TEN with increase morbidity and mortality while they are receiving cancer treatments, have been proposed to be a result of direct skin toxicity or drug hypersensitivity reactions (these are proposed mechanism, not definite. Differentiating SCARs from other more commonly seen reactions with a better outcome help prevent discontinuation of therapy and inappropriate use of systemic immunosuppressants for presumable allergic reactions, of which will affect the clinical outcome. In this article, we have reviewed published articles from 1950 to August 2017 for SJS/TEN associated with anticancer drugs, including chemotherapy, targeted therapy, and immunotherapy. We aimed to provide an overview of SJS/TEN associated with anticancer drugs to increase clinician recognition and accelerate future studies on the pathomechanism and managements.

    7. Targets and Patented Drugs for Chemotherapy of Chagas Disease in the Last 15 Years-Period.

      Science.gov (United States)

      Duschak, Vilma G

      2016-01-01

      The American trypanosomiasis, Chagas disease, is a parasitic infection typically spread by triatomine vectors affecting millions of people all over Latin America. Existing chemotherapy is centered on the nitroaromatic compounds benznidazole and nifurtimox that provide unsatisfactory results and substantial side effects. So, the finding and exploration of novel ways to challenge this neglected disease is a main priority. The biologic and biochemical progress in the scientific knowledge of Trypanosoma cruzi in the period comprising last 15-years has increased the identification of multiple targets for Chagas´ disease chemotherapy. In the middle of the best encouraging targets for trypanocidal drugs, ergosterol biosynthesis pathway and cruzipain, a key cysteine protease (CP) of T. cruzi, have been pointed out. Unfortunately, recent clinical trials investigating the administration of pozoconazole and ravuconazole to chronic indeterminate Chagas disease patients revealed their inferiority compared to the standard drug Benznidazole. In view of the information gained in the preceding years, a reasonable approach for the fast development of novel anti-T. cruzi chemotherapy would be focused on K777, the cysteine proteinase inhibitor (CPI) near to enter to clinical trials, and founded on the clinical evaluation of combination of known drugs with existing trypanocidal agents to obtain more efficiency and less secondary effects. Top series of xanthine have been recently identified as clinical candidate for Chagas disease. In addition, trypanothione biosynthesis, thiol-dependant redox and polyamine metabolism, the glycolytic, glyconeogenic, pentose phosphate, lipidic and polyisoprenoid biosynthetic pathways, and the enzymes from biosynthetic glycoconjugates pathways have been studied. Several specific enzymes from these particular biosynthetic pathways such as hypoxanthine-guaninephosphoribosyl- transferase and farnesyl-pyrophosphate synthase, among others, have also been

    8. A comparison of machine learning techniques for detection of drug target articles.

      Science.gov (United States)

      Danger, Roxana; Segura-Bedmar, Isabel; Martínez, Paloma; Rosso, Paolo

      2010-12-01

      Important progress in treating diseases has been possible thanks to the identification of drug targets. Drug targets are the molecular structures whose abnormal activity, associated to a disease, can be modified by drugs, improving the health of patients. Pharmaceutical industry needs to give priority to their identification and validation in order to reduce the long and costly drug development times. In the last two decades, our knowledge about drugs, their mechanisms of action and drug targets has rapidly increased. Nevertheless, most of this knowledge is hidden in millions of medical articles and textbooks. Extracting knowledge from this large amount of unstructured information is a laborious job, even for human experts. Drug target articles identification, a crucial first step toward the automatic extraction of information from texts, constitutes the aim of this paper. A comparison of several machine learning techniques has been performed in order to obtain a satisfactory classifier for detecting drug target articles using semantic information from biomedical resources such as the Unified Medical Language System. The best result has been achieved by a Fuzzy Lattice Reasoning classifier, which reaches 98% of ROC area measure. Copyright © 2010 Elsevier Inc. All rights reserved.

    9. In vivo characteristics of targeted drug-carrying filamentous bacteriophage nanomedicines

      Directory of Open Access Journals (Sweden)

      Vaks Lilach

      2011-12-01

      Full Text Available Abstract Background Targeted drug-carrying phage nanomedicines are a new class of nanomedicines that combines biological and chemical components into a modular nanometric drug delivery system. The core of the system is a filamentous phage particle that is produced in the bacterial host Escherichia coli. Target specificity is provided by a targeting moiety, usually an antibody that is displayed on the tip of the phage particle. A large drug payload is chemically conjugated to the protein coat of the phage via a chemically or genetically engineered linker that provides for controlled release of the drug after the particle homed to the target cell. Recently we have shown that targeted drug-carrying phage nanomedicines can be used to eradicate pathogenic bacteria and cultured tumor cells with great potentiation over the activity of the free untargeted drug. We have also shown that poorly water soluble drugs can be efficiently conjugated to the phage coat by applying hydrophilic aminoglycosides as branched solubility-enhancing linkers. Results With an intention to move to animal experimentation of efficacy, we tested anti-bacterial drug-carrying phage nanomedicines for toxicity and immunogenicity and blood pharmacokinetics upon injection into mice. Here we show that anti-bacterial drug-carrying phage nanomedicines that carry the antibiotic chloramphenicol conjugated via an aminoglycoside linker are non-toxic to mice and are greatly reduced in immunogenicity in comparison to native phage particles or particles to which the drug is conjugated directly and are cleared from the blood more slowly in comparison to native phage particles. Conclusion Our results suggest that aminoglycosides may serve as branched solubility enhancing linkers for drug conjugation that also provide for a better safety profile of the targeted nanomedicine.

    10. The 5-HT-7 receptor as a potential target for treating drug and alcohol abuse

      Directory of Open Access Journals (Sweden)

      Sheketha R. Hauser

      2015-01-01

      Full Text Available Alcohol and drug abuse take a large toll on society and affected individuals. However, very few effective treatments are currently available to treat alcohol and drug addiction. Basic and clinical research has begun to provide some insights into the underlying neurobiological systems involved in the addiction process. Several neurotransmitter pathways have been implicated and distinct reward neurocircuitry have been proposed – including the mesocorticolimbic (MCL dopamine system and the extended amygdala. The serotonin (5-HT neurotransmitter system is of particular interest and multiple 5-HT receptors are thought to play significant roles in alcohol and drug self-administration and the development of drug dependence. Among the 5-HT receptors, the 5-HT-7 receptor is currently undergoing characterization as a potential target for the treatment of several psychiatric disorders. Although this receptor has received only limited research regarding addictive behaviors, aspects of its neuroanatomical, biochemical, physiological, pharmacological, and behavioral profiles suggest that it could play a key role in the addiction process. For instance, genomic studies in humans have suggested a link between variants in the gene encoding the 5-HT-7 receptor and alcoholism. Recent behavioral testing using high-affinity antagonists in mice and preliminary tests with alcohol-preferring rats suggest that this receptor could mediate alcohol consumption and/or reinforcement and play a role in seeking/craving behavior. Interest in the development of new and more selective pharmacological agents for this receptor will aid in examining the 5-HT-7 receptor as a novel target for treating addiction.

    11. The 5-HT7 receptor as a potential target for treating drug and alcohol abuse.

      Science.gov (United States)

      Hauser, Sheketha R; Hedlund, Peter B; Roberts, Amanda J; Sari, Youssef; Bell, Richard L; Engleman, Eric A

      2014-01-01

      Alcohol and drug abuse take a large toll on society and affected individuals. However, very few effective treatments are currently available to treat alcohol and drug addiction. Basic and clinical research has begun to provide some insights into the underlying neurobiological systems involved in the addiction process. Several neurotransmitter pathways have been implicated and distinct reward neurocircuitry have been proposed-including the mesocorticolimbic dopamine (MCL-DA) system and the extended amygdala. The serotonin (5-HT) neurotransmitter system is of particular interest and multiple 5-HT receptors are thought to play significant roles in alcohol and drug self-administration and the development of drug dependence. Among the 5-HT receptors, the 5-HT7 receptor is currently undergoing characterization as a potential target for the treatment of several psychiatric disorders. Although this receptor has received only limited research regarding addictive behaviors, aspects of its neuroanatomical, biochemical, physiological, pharmacological, and behavioral profiles suggest that it could play a key role in the addiction process. For instance, genomic studies in humans have suggested a link between variants in the gene encoding the 5-HT7 receptor and alcoholism. Recent behavioral testing using high-affinity antagonists in mice and preliminary tests with alcohol-preferring rats suggest that this receptor could mediate alcohol consumption and/or reinforcement and play a role in seeking/craving behavior. Interest in the development of new and more selective pharmacological agents for this receptor will aid in examining the 5-HT7 receptor as a novel target for treating addiction.

    12. Nitric oxide-related drug targets in headache

      DEFF Research Database (Denmark)

      Olesen, Jes

      2010-01-01

      SUMMARY: Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so-called del......SUMMARY: Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so...... another very likely new treatment. It is more unlikely that antagonism of cGMP or its formation will be feasible, but augmenting its breakdown via phosphodiesterase activation is a possibility, as well as other ways of inhibiting the NO-cGMP pathway....

    13. The Role of Target Binding Kinetics in Drug Discovery.

      Science.gov (United States)

      Guo, Dong; Heitman, Laura H; IJzerman, Adriaan P

      2015-11-01

      Traditionally structure-activity/affinity relationships (SAR) have dominated research in medicinal chemistry. However, structure-kinetics relationships (SKR) can be very informative too. In this viewpoint we explore the molecular determinants of binding kinetics and discuss challenges for future binding kinetics studies. A scheme for future kinetics-directed drug design and discovery is also proposed. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

    14. Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma

      NARCIS (Netherlands)

      Tavanti, E.; Sero, V.; Vella, S.; Fanelli, M.; Michelacci, F.; Landuzzi, L.; Magagnoli, G.; Versteeg, R.; Picci, P.; Hattinger, C. M.; Serra, M.

      2013-01-01

      Aurora kinases are key regulators of cell cycle and represent new promising therapeutic targets in several human tumours. Biological relevance of Aurora kinase-A and -B was assessed on osteosarcoma clinical samples and by silencing these genes with specific siRNA in three human osteosarcoma cell

    15. Y-Trap Cancer Immunotherapy Drug Targets Two Proteins

      Science.gov (United States)

      Two groups of researchers, working independently, have fused a TGF-beta receptor to a monoclonal antibody that targets a checkpoint protein. The result, this Cancer Currents blog describes, is a single hybrid molecule called a Y-trap that blocks two pathways used by tumors to evade the immune system.

    16. Cytotoxicity of Bacterial Metabolic Products, including Listeriolysin O, on Leukocyte Targets

      Directory of Open Access Journals (Sweden)

      R. Stachowiak

      2012-01-01

      Full Text Available Bacterial toxins can exhibit anticancer activities. Here we investigated the anticancer effects of the listeriolysin O toxin produced by Listeria monocytogenes. We found that supernatants of Listeria monocytogenes strains (wild type, 1189, and 1190 were cytotoxic to the Jurkat cell line and human peripheral blood mononuclear cells (PBMC in a concentration-dependent manner. The supernatant of strain 1044, not producing listeriolysin O, was inactive. The supernatants of Listeria strains were also cytotoxic toward B cells of chronic leukemia patients, with no significant differences in activities between strains. We also tested supernatants of Bacillus subtilis strains BR1-90, BR1-S, and BR1-89 producing listeriolysin O. BR1-S and BR1-89 were cytotoxic to PBMC and to Jurkat cells, the latter being more sensitive to the supernatants. BR1-90 was not hemolytic or cytotoxic to PBMC, but was cytotoxic to Jurkat cells in the concentration range of 10–30%, suggesting that listeriolysin O is selectively effective against T cells. Overall, the response of human peripheral blood mononuclear and human leukemia cell lines to bacteria supernatants containing listeriolysin O depended on the bacteria strain, target cell type, and supernatant concentration.

    17. Liposomal Tumor Targeting in Drug Delivery Utilizing MMP-2- and MMP-9-Binding Ligands

      Directory of Open Access Journals (Sweden)

      Oula Penate Medina

      2011-01-01

      Full Text Available Nanotechnology offers an alternative to conventional treatment options by enabling different drug delivery and controlled-release delivery strategies. Liposomes being especially biodegradable and in most cases essentially nontoxic offer a versatile platform for several different delivery approaches that can potentially enhance the delivery and targeting of therapies to tumors. Liposomes penetrate tumors spontaneously as a result of fenestrated blood vessels within tumors, leading to known enhanced permeability and subsequent drug retention effects. In addition, liposomes can be used to carry radioactive moieties, such as radiotracers, which can be bound at multiple locations within liposomes, making them attractive carriers for molecular imaging applications. Phage display is a technique that can deliver various high-affinity and selectivity peptides to different targets. In this study, gelatinase-binding peptides, found by phage display, were attached to liposomes by covalent peptide-PEG-PE anchor creating a targeted drug delivery vehicle. Gelatinases as extracellular targets for tumor targeting offer a viable alternative for tumor targeting. Our findings show that targeted drug delivery is more efficient than non-targeted drug delivery.

    18. An update on anticancer drug development and delivery targeting carbonic anhydrase IX

      Directory of Open Access Journals (Sweden)

      Justina Kazokaitė

      2017-11-01

      Full Text Available The expression of carbonic anhydrase (CA IX is up-regulated in many types of solid tumors in humans under hypoxic and acidic microenvironment. Inhibition of CA IX enzymatic activity with selective inhibitors, antibodies or labeled probes has been shown to reverse the acidic environment of solid tumors and reduce the tumor growth establishing the significant role of CA IX in tumorigenesis. Thus, the development of potent antitumor drugs targeting CA IX with minimal toxic effects is important for the target-specific tumor therapy. Recently, several promising antitumor agents against CA IX have been developed to treat certain types of cancers in combination with radiation and chemotherapy. Here we review the inhibition of CA IX by small molecule compounds and monoclonal antibodies. The methods of enzymatic assays, biophysical methods, animal models including zebrafish and Xenopus oocytes, and techniques of diagnostic imaging to detect hypoxic tumors using CA IX-targeted conjugates are discussed with the aim to overview the recent progress related to novel therapeutic agents that target CA IX in hypoxic tumors.

    19. Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–2

      Directory of Open Access Journals (Sweden)

      Diego Muñoz-Torrero

      2017-12-01

      Full Text Available Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials, which are published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...

    20. Aptamer and nanotechnology- based approaches for active targeted delivery of anti-tuberculosis drugs

      CSIR Research Space (South Africa)

      Ramalapa, B

      2012-10-01

      Full Text Available and Nanotechnology- based Approaches for Active Targeted Delivery of Anti-Tuberculosis Drugs Presented by : Bathabile Ramalapa CSIR Emerging Researcher Symposium 10 0ctober 2012 Outline ? Background: Challenges in the current TB treatment ? Proposed Solution...-expressed by TB infected macrophages Aptamers: RNA/DNA that bind to a specific target molecule ?Enhance drug efficiency at site of infection ?Reduce systemic toxicity Aptamer Synthesis: SELEX Method ? CSIR 2012 www.csir.co.za Partitioning...

    1. Deep mining heterogeneous networks of biomedical linked data to predict novel drug-target associations.

      Science.gov (United States)

      Zong, Nansu; Kim, Hyeoneui; Ngo, Victoria; Harismendy, Olivier

      2017-08-01

      A heterogeneous network topology possessing abundant interactions between biomedical entities has yet to be utilized in similarity-based methods for predicting drug-target associations based on the array of varying features of drugs and their targets. Deep learning reveals features of vertices of a large network that can be adapted in accommodating the similarity-based solutions to provide a flexible method of drug-target prediction. We propose a similarity-based drug-target prediction method that enhances existing association discovery methods by using a topology-based similarity measure. DeepWalk, a deep learning method, is adopted in this study to calculate the similarities within Linked Tripartite Network (LTN), a heterogeneous network generated from biomedical linked datasets. This proposed method shows promising results for drug-target association prediction: 98.96% AUC ROC score with a 10-fold cross-validation and 99.25% AUC ROC score with a Monte Carlo cross-validation with LTN. By utilizing DeepWalk, we demonstrate that: (i) this method outperforms other existing topology-based similarity computation methods, (ii) the performance is better for tripartite than with bipartite networks and (iii) the measure of similarity using network topology outperforms the ones derived from chemical structure (drugs) or genomic sequence (targets). Our proposed methodology proves to be capable of providing a promising solution for drug-target prediction based on topological similarity with a heterogeneous network, and may be readily re-purposed and adapted in the existing of similarity-based methodologies. The proposed method has been developed in JAVA and it is available, along with the data at the following URL: https://github.com/zongnansu1982/drug-target-prediction . nazong@ucsd.edu. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

    2. Enzyme Triggered Drug Delivery for Graft Targeted Immunosupression and Neuroregeneration after VCA

      Science.gov (United States)

      2016-05-11

      FROM: 59 MDW/SGVU SUBJECT: Professional Presentation Approval 6MAY2016 1. Your paper, entitled Enzyme Triggered Drug Delivery for Graft Targeted...6. TITLE OF MATERIAL TO BE PUBLISHED OR PRESENTED: Enzyme Triggered Drug Deli very for Graft Targeted Immunosupprcssion and Ncuroregenerat ion...NO 9. IS THIS MATERIAL CLASSIFIED? 0 YES 181 NO 10. IS THIS MATERIAL SUBJECT TO ANY LEGAL RESTRICTIONS FOR PUBLICATION OR PRESENTATION THROUGH A

    3. Micro-Environmental Signature of The Interactions between Druggable Target Protein, Dipeptidyl Peptidase-IV, and Anti-Diabetic Drugs

      OpenAIRE

      Chakraborty, Chiranjib; Mallick, Bidyut; Sharma, Ashish Ranjan; Sharma, Garima; Jagga, Supriya; Doss, C George Priya; Nam, Ju-Suk; Lee, Sang-Soo

      2016-01-01

      Objective Druggability of a target protein depends on the interacting micro-environment between the target protein and drugs. Therefore, a precise knowledge of the interacting micro-environment between the target protein and drugs is requisite for drug discovery process. To understand such micro-environment, we performed in silico interaction analysis between a human target protein, Dipeptidyl Peptidase-IV (DPP-4), and three anti-diabetic drugs (saxagliptin, linagliptin and vildagliptin). ...

    4. Alzheimer’s Disease, Brain Injury, and C.N.S. Nanotherapy in Humans: Sonoporation Augmenting Drug Targeting

      OpenAIRE

      D’Arrigo, Joseph S.

      2017-01-01

      Owing to the complexity of neurodegenerative diseases, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted nanoemulsion) are available. Versatile small-molecule drug(s) targeting multiple pathways of Alzheimer’s disease pathogenesis are known. By incorporating such drug(s) into the targeted lipid-coated microbubble/nanoparticle-derived (LCM/ND) lipid nanoemulsion...

    5. Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.

      Directory of Open Access Journals (Sweden)

      Adam A Friedman

      Full Text Available A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1 transporter inhibition. We identified drugs sensitizing cell lines that are BRAFV600E mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR and platelet derived growth factor receptor (PDGFR family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs, demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations.

    6. Synthetic Peptide Drugs for Targeting Skin Cancer: Malignant Melanoma and Melanotic Lesions.

      Science.gov (United States)

      Eberle, Alex N; Rout, Bhimsen; Qi, Mei Bigliardi; Bigliardi, Paul L

      2017-01-01

      Peptides play decisive roles in the skin, ranging from host defense responses to various forms of neuroendocrine regulation of cell and organelle function. Synthetic peptides conjugated to radionuclides or photosensitizers may serve to identify and treat skin tumors and their metastatic forms in other organs of the body. In the introductory part of this review, the role and interplay of the different peptides in the skin are briefly summarized, including their potential application for the management of frequently occurring skin cancers. Special emphasis is given to different targeting options for the treatment of melanoma and melanotic lesions. Radionuclide Targeting: α-Melanocyte-stimulating hormone (α-MSH) is the most prominent peptide for targeting of melanoma tumors via the G protein-coupled melanocortin-1 receptor that is (over-)expressed by melanoma cells and melanocytes. More than 100 different linear and cyclic analogs of α-MSH containing chelators for 111In, 67/68Ga, 64Cu, 90Y, 212Pb, 99mTc, 188Re were synthesized and examined with experimental animals and in a few clinical studies. Linear Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys-NH2 (NAP-amide) and Re-cyclized Cys- Cys-Glu-His-D-Phe-Arg-Trp-Cys-Arg-Pro-Val-NH2 (Re[Arg11]CCMSH) containing different chelators at the N- or C-terminus served as lead compounds for peptide drugs with further optimized characteristics. Alternatively, melanoma may be targeted with radiopeptides that bind to melanin granules occurring extracellularly in these tumors. Photosensitizer targeting: A more recent approach is the application of photosensitizers attached to the MSH molecule for targeted photodynamic therapy using LED or coherent laser light that specifically activates the photosensitizer. Experimental studies have demonstrated the feasibility of this approach as a more gentle and convenient alternative compared to radionuclides. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

    7. Hedgehog pathway as a drug target: Smoothened inhibitors in development

      OpenAIRE

      Lin, Tara; Matsui,William

      2012-01-01

      Tara L Lin1, William Matsui21Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas, Kansas City, MO, USA; 2Division of Hematologic Malignancies, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh) represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely reg...

    8. Targeted femtosecond laser driven drug delivery within HIV-1 infected cells: in-vitro studies

      Science.gov (United States)

      Maphanga, Charles; Ombinda-Lemboumba, Saturnin; Manoto, Sello; Maaza, Malik; Mthunzi-Kufa, Patience

      2017-02-01

      Human immunodeficiency virus (HIV-1) infection still remains one amongst the world's most challenging infections since its discovery. Antiretroviral therapy is the recommended treatment of choice for HIV-1 infection taken by patients orally. The highly active antiretroviral therapy (HAART) prevents the replication of HIV-1 and further destruction of the immune system, therefore enabling the body to fight opportunistic life-threatening infections, cancers, and also arrest HIV infection from advancing to AIDS. The major challenge with HAART is the inability to reach the viral reservoirs where the HIV-1 remains latent and persistent, leading to inability to fully eradicate the virus. This study is aimed at initially designing and assembling a fully functional optical translocation setup to optically deliver antiretroviral drugs into HIV-1 infected cells in a targeted manner using Gaussian beam mode femtosecond laser pulses in-vitro. The main objective of our study is to define the in-vitro drug photo-translocation parameters to allow future design of an efficient drug delivery device with potential in-vivo drug delivery applications. In our experiments, HEK 293T cells were used to produce HIV-1 enveloped pseudovirus (ZM53) to infect TZM-bl cells which were later treated with laser pulses emitted by a titanium sapphire laser (800 nm, 1KHz, 113 fs, 6.5 μW) to create sub-microscopic pores on the cell membrane enabling influx of extracellular media. Following laser treatment, changes in cellular responses were analysed using cell morphology studies, cytotoxicity, and luciferase assay studies. Controls included laser untreated cells incubated with the drug for 72 hours. The data in this study was statistically analysed using the SigmaPlot software version 13.

    9. Insights into Integrated Lead Generation and Target Identification in Malaria and Tuberculosis Drug Discovery.

      Science.gov (United States)

      Okombo, John; Chibale, Kelly

      2017-07-18

      New, safe and effective drugs are urgently needed to treat and control malaria and tuberculosis, which affect millions of people annually. However, financial return on investment in the poor settings where these diseases are mostly prevalent is very minimal to support market-driven drug discovery and development. Moreover, the imminent loss of therapeutic lifespan of existing therapies due to evolution and spread of drug resistance further compounds the urgency to identify novel effective drugs. However, the advent of new public-private partnerships focused on tropical diseases and the recent release of large data sets by pharmaceutical companies on antimalarial and antituberculosis compounds derived from phenotypic whole cell high throughput screening have spurred renewed interest and opened new frontiers in malaria and tuberculosis drug discovery. This Account recaps the existing challenges facing antimalarial and antituberculosis drug discovery, including limitations associated with experimental animal models as well as biological complexities intrinsic to the causative pathogens. We enlist various highlights from a body of work within our research group aimed at identifying and characterizing new chemical leads, and navigating these challenges to contribute toward the global drug discovery and development pipeline in malaria and tuberculosis. We describe a catalogue of in-house efforts toward deriving safe and efficacious preclinical drug development candidates via cell-based medicinal chemistry optimization of phenotypic whole-cell medium and high throughput screening hits sourced from various small molecule chemical libraries. We also provide an appraisal of target-based screening, as invoked in our laboratory for mechanistic evaluation of the hits generated, with particular focus on the enzymes within the de novo pyrimidine biosynthetic and hemoglobin degradation pathways, the latter constituting a heme detoxification process and an associated cysteine

    10. COMMENTARY. Pre-emptive Nutrition: Refining the Targets of Drugs Targeted to Colorectal Cancer.

      Science.gov (United States)

      Ferguson, Lynnette R; Denny, William A

      2015-01-01

      It is suggested that our current understanding of the role of nutrients in maintaining genomic stability might be strategically employed alongside current chemotherapy, in order to prevent the emergence of drug resistant tumors and optimize medicinal chemistry approaches.

    11. The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledgebase of drug targets and their ligands

      Science.gov (United States)

      Pawson, Adam J.; Sharman, Joanna L.; Benson, Helen E.; Faccenda, Elena; Alexander, Stephen P.H.; Buneman, O. Peter; Davenport, Anthony P.; McGrath, John C.; Peters, John A.; Southan, Christopher; Spedding, Michael; Yu, Wenyuan; Harmar, Anthony J.

      2014-01-01

      The International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide to PHARMACOLOGY (http://www.guidetopharmacology.org) is a new open access resource providing pharmacological, chemical, genetic, functional and pathophysiological data on the targets of approved and experimental drugs. Created under the auspices of the IUPHAR and the BPS, the portal provides concise, peer-reviewed overviews of the key properties of a wide range of established and potential drug targets, with in-depth information for a subset of important targets. The resource is the result of curation and integration of data from the IUPHAR Database (IUPHAR-DB) and the published BPS ‘Guide to Receptors and Channels’ (GRAC) compendium. The data are derived from a global network of expert contributors, and the information is extensively linked to relevant databases, including ChEMBL, DrugBank, Ensembl, PubChem, UniProt and PubMed. Each of the ∼6000 small molecule and peptide ligands is annotated with manually curated 2D chemical structures or amino acid sequences, nomenclature and database links. Future expansion of the resource will complete the coverage of all the targets of currently approved drugs and future candidate targets, alongside educational resources to guide scientists and students in pharmacological principles and techniques. PMID:24234439

    12. Genome-wide identification of structural variants in genes encoding drug targets

      DEFF Research Database (Denmark)

      Rasmussen, Henrik Berg; Dahmcke, Christina Mackeprang

      2012-01-01

      The objective of the present study was to identify structural variants of drug target-encoding genes on a genome-wide scale. We also aimed at identifying drugs that are potentially amenable for individualization of treatments based on knowledge about structural variation in the genes encoding...

    13. In vivo imaging of passively tumor targeted polymer carrier and the enzymatically cleavable drug model

      Czech Academy of Sciences Publication Activity Database

      Pola, Robert; Heinrich, A. K.; Mueller, T.; Kostka, Libor; Mäder, K.; Pechar, Michal; Etrych, Tomáš

      2017-01-01

      Roč. 6, 4 (Suppl) (2017), s. 90 ISSN 2325-9604. [International Conference and Exhibition on Nanomedicine and Drug Delivery. 29.05.2017-31.05.2017, Osaka] R&D Projects: GA MZd(CZ) NV16-28594A Institutional support: RVO:61389013 Keywords : polymer drug carrier * tumor targeting * enzymatic release Subject RIV: FD - Oncology ; Hematology

    14. Host pharmacokinetics and drug accumulation of anthelmintics within target helminth parasites of ruminants.

      Science.gov (United States)

      Lifschitz, A; Lanusse, C; Alvarez, L

      2017-07-01

      Anthelmintic drugs require effective concentrations to be attained at the site of parasite location for a certain period to assure their efficacy. The processes of absorption, distribution, metabolism and excretion (pharmacokinetic phase) directly influence drug concentrations attained at the site of action and the resultant pharmacological effect. The aim of the current review article was to provide an overview of the relationship between the pharmacokinetic features of different anthelmintic drugs, their availability in host tissues, accumulation within target helminths and resulting therapeutic efficacy. It focuses on the anthelmintics used in cattle and sheep for which published information on the overall topic is available; benzimidazoles, macrocyclic lactones and monepantel. Physicochemical properties, such as water solubility and dissolution rate, determine the ability of anthelmintic compounds to accumulate in the target parasites and consequently final clinical efficacy. The transcuticular absorption process is the main route of penetration for different drugs in nematodes and cestodes. However, oral ingestion is a main route of drug entry into adult liver flukes. Among other factors, the route of administration may substantially affect the pharmacokinetic behaviour of anthelmintic molecules and modify their efficacy. Oral administration improves drug efficacy against nematodes located in the gastroinestinal tract especially if parasites have a reduced susceptibility. Partitioning of the drug between gastrointestinal contents, mucosal tissue and the target parasite is important to enhance the drug exposure of the nematodes located in the lumen of the abomasum and/or small intestine. On the other hand, large inter-animal variability in drug exposure and subsequent high variability in efficacy is observed after topical administration of anthelmintic compounds. As it has been extensively demonstrated under experimental and field conditions, understanding

    15. Nitric oxide-related drug targets in headache

      DEFF Research Database (Denmark)

      Olesen, Jes

      2010-01-01

      SUMMARY: Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so-called del......SUMMARY: Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so......-called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-nitromonomethylarginine effectively treats attacks of migraine without aura. Similar results have been obtained for chronic the tension-type headache and cluster headache....... Inhibition of the breakdown of cyclic guanylate phosphate (cGMP) also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine. Similar evidence suggests an important role of NO in the tension-type headache and cluster headache. These very strong data from human...

    16. Biochemical targets of drugs mitigating oxidative stress via redox-independent mechanisms.

      Science.gov (United States)

      Gesslbauer, Bernd; Bochkov, Valery

      2017-12-15

      Acute or chronic oxidative stress plays an important role in many pathologies. Two opposite approaches are typically used to prevent the damage induced by reactive oxygen and nitrogen species (RONS), namely treatment either with antioxidants or with weak oxidants that up-regulate endogenous antioxidant mechanisms. This review discusses options for the third pharmacological approach, namely amelioration of oxidative stress by 'redox-inert' compounds, which do not inactivate RONS but either inhibit the basic mechanisms leading to their formation (i.e. inflammation) or help cells to cope with their toxic action. The present study describes biochemical targets of many drugs mitigating acute oxidative stress in animal models of ischemia-reperfusion injury or N -acetyl- p -aminophenol overdose. In addition to the pro-inflammatory molecules, the targets of mitigating drugs include protein kinases and transcription factors involved in regulation of energy metabolism and cell life/death balance, proteins regulating mitochondrial permeability transition, proteins involved in the endoplasmic reticulum stress and unfolded protein response, nuclear receptors such as peroxisome proliferator-activated receptors, and isoprenoid synthesis. The data may help in identification of oxidative stress mitigators that will be effective in human disease on top of the current standard of care. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

    17. Many particle magnetic dipole-dipole and hydrodynamic interactions in magnetizable stent assisted magnetic drug targeting

      International Nuclear Information System (INIS)

      Cregg, P.J.; Murphy, Kieran; Mardinoglu, Adil; Prina-Mello, Adriele

      2010-01-01

      The implant assisted magnetic targeted drug delivery system of Aviles, Ebner and Ritter is considered both experimentally (in vitro) and theoretically. The results of a 2D mathematical model are compared with 3D experimental results for a magnetizable wire stent. In this experiment a ferromagnetic, coiled wire stent is implanted to aid collection of particles which consist of single domain magnetic nanoparticles (radius ∼10nm). In order to model the agglomeration of particles known to occur in this system, the magnetic dipole-dipole and hydrodynamic interactions for multiple particles are included. Simulations based on this mathematical model were performed using open source C++ code. Different initial positions are considered and the system performance is assessed in terms of collection efficiency. The results of this model show closer agreement with the measured in vitro experimental results and with the literature. The implications in nanotechnology and nanomedicine are based on the prediction of the particle efficiency, in conjunction with the magnetizable stent, for targeted drug delivery.

    18. Large-scale prediction of drug–target interactions using protein sequences and drug topological structures

      International Nuclear Information System (INIS)

      Cao Dongsheng; Liu Shao; Xu Qingsong; Lu Hongmei; Huang Jianhua; Hu Qiannan; Liang Yizeng

      2012-01-01

      Highlights: ► Drug–target interactions are predicted using an extended SAR methodology. ► A drug–target interaction is regarded as an event triggered by many factors. ► Molecular fingerprint and CTD descriptors are used to represent drugs and proteins. ► Our approach shows compatibility between the new scheme and current SAR methodology. - Abstract: The identification of interactions between drugs and target proteins plays a key role in the process of genomic drug discovery. It is both consuming and costly to determine drug–target interactions by experiments alone. Therefore, there is an urgent need to develop new in silico prediction approaches capable of identifying these potential drug–target interactions in a timely manner. In this article, we aim at extending current structure–activity relationship (SAR) methodology to fulfill such requirements. In some sense, a drug–target interaction can be regarded as an event or property triggered by many influence factors from drugs and target proteins. Thus, each interaction pair can be represented theoretically by using these factors which are based on the structural and physicochemical properties simultaneously from drugs and proteins. To realize this, drug molecules are encoded with MACCS substructure fingerings representing existence of certain functional groups or fragments; and proteins are encoded with some biochemical and physicochemical properties. Four classes of drug–target interaction networks in humans involving enzymes, ion channels, G-protein-coupled receptors (GPCRs) and nuclear receptors, are independently used for establishing predictive models with support vector machines (SVMs). The SVM models gave prediction accuracy of 90.31%, 88.91%, 84.68% and 83.74% for four datasets, respectively. In conclusion, the results demonstrate the ability of our proposed method to predict the drug–target interactions, and show a general compatibility between the new scheme and current SAR

    19. One For All? Hitting multiple Alzheimer’s Disease targets with one drug

      Directory of Open Access Journals (Sweden)

      Rebecca Ellen Hughes

      2016-04-01

      Full Text Available Alzheimer’s disease is a complex and multifactorial disease for which the mechanism is still not fully understood. As new insights into disease progression are discovered, new drugs must be designed to target those aspects of the disease that cause neuronal damage rather than just the symptoms currently addressed by single target drugs. It is becoming possible to target several aspects of the disease pathology at once using multi-target drugs. Intended as a introduction for non-experts, this review describes the key multi-target drug design approaches, namely structure-based, in silico, and data-mining, to evaluate what is preventing compounds progressing through the clinic to the market. Repurposing current drugs using their off-target effects reduces the cost of development, time to launch and also the uncertainty associated with safety and pharmacokinetics. The most promising drugs currently being investigated for repurposing to Alzheimer’s Disease are rasagiline, originally developed for the treatment of Parkinson’s Disease, and liraglutide, an antidiabetic. Rational drug design can combine pharmacophores of multiple drugs, systematically change functional groups, and rank them by virtual screening. Hits confirmed experimentally are rationally modified to generate an effective multi-potent lead compound. Examples from this approach are ASS234 with properties similar to rasagiline, and donecopride, a hybrid of an acetylcholinesterase inhibitor and a 5-HT4 receptor agonist with pro-cognitive effects. Exploiting these interdisciplinary approaches, public-private collaborative lead factories promise faster delivery of new drugs to the clinic.

    20. Interactions of dendrimers with biological drug targets: reality or mystery - a gap in drug delivery and development research.

      Science.gov (United States)

      Ahmed, Shaimaa; Vepuri, Suresh B; Kalhapure, Rahul S; Govender, Thirumala

      2016-07-21

      Dendrimers have emerged as novel and efficient materials that can be used as therapeutic agents/drugs or as drug delivery carriers to enhance therapeutic outcomes. Molecular dendrimer interactions are central to their applications and realising their potential. The molecular interactions of dendrimers with drugs or other materials in drug delivery systems or drug conjugates have been extensively reported in the literature. However, despite the growing application of dendrimers as biologically active materials, research focusing on the mechanistic analysis of dendrimer interactions with therapeutic biological targets is currently lacking in the literature. This comprehensive review on dendrimers over the last 15 years therefore attempts to identify the reasons behind the apparent lack of dendrimer-receptor research and proposes approaches to address this issue. The structure, hierarchy and applications of dendrimers are briefly highlighted, followed by a review of their various applications, specifically as biologically active materials, with a focus on their interactions at the target site. It concludes with a technical guide to assist researchers on how to employ various molecular modelling and computational approaches for research on dendrimer interactions with biological targets at a molecular level. This review highlights the impact of a mechanistic analysis of dendrimer interactions on a molecular level, serves to guide and optimise their discovery as medicinal agents, and hopes to stimulate multidisciplinary research between scientific, experimental and molecular modelling research teams.

    1. Identification of cluster of proteins in the network of MAPK pathways as cancer drug targets

      Directory of Open Access Journals (Sweden)

      V.K. MD Aksam

      2017-01-01

      Full Text Available The quest to develop computational drug target identification methods in complex diseases like cancer is growing in recent years. Feedback, feed-forward loops and cross-talks observed among the MAPK pathways led to the definition of a network of MAPK pathways and considered for single or multiple therapeutic interventions. We developed a computational method to identify clusters of drug targets by analysing the directed network's topological properties and the individual node's functional roles. We aim to identify the primary drug target nodes possessing more cancerous properties and less number of cellular functional roles. For every primary drug targets, we collect the alternate substrate activating nodes for local resistance analysis. Alternate substrate activation free nodes identified as single drug target are SOS, ATF1, BAD, GAB1, LAD, NFAT4, ATF2, MEF2, eEF2K, 4EBP1 and HSP27. Among the remaining identified nodes and their corresponding alternate substrate activating nodes with their cancer retaining and side effects causing properties studied as three different classes-single, multiple and dangerous targets. C-Raf1 and MAPKAP-K observed as a single efficient target due to the absence of resistance mechanism. Due to the resistance mechanism observed among the targeted M3/6, GADD45, and MKK6 multiple target intervention of their corresponding alternate nodes might prove to be the efficient targets. Targeted effect on MLK3, ZAK, DLK and MLTKa/b will impair the network due to intertwined and proximity nature among themselves.

    2. Quantitative modeling of selective lysosomal targeting for drug design

      DEFF Research Database (Denmark)

      Trapp, Stefan; Rosania, G.; Horobin, R.W.

      2008-01-01

      Lysosomes are acidic organelles and are involved in various diseases, the most prominent is malaria. Accumulation of molecules in the cell by diffusion from the external solution into cytosol, lysosome and mitochondrium was calculated with the Fick–Nernst–Planck equation. The cell model considers...... the diffusion of neutral and ionic molecules across biomembranes, protonation to mono- or bivalent ions, adsorption to lipids, and electrical attraction or repulsion. Based on simulation results, high and selective accumulation in lysosomes was found for weak mono- and bivalent bases with intermediate to high...... predicted by the model and three were close. Five of the antimalarial drugs were lipophilic weak dibasic compounds. The predicted optimum properties for a selective accumulation of weak bivalent bases in lysosomes are consistent with experimental values and are more accurate than any prior calculation...

    3. Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

      Science.gov (United States)

      2010-09-01

      Biotransformation of curcumin through reduction and glucuronidation in mice. Drug  Metab. Dispos. 27, 486–494 (1999). 46 Ireson C, Orr S, Jones DJL et...factor receptor (EGFR), and estrogen receptor (ER) [1,10,12]. Curcumin was also found to down-regulate multi- drug resistance proteins (MDR) and P

    4. The Pim kinases: new targets for drug development.

      Science.gov (United States)

      Swords, Ronan; Kelly, Kevin; Carew, Jennifer; Nawrocki, Stefan; Mahalingam, Devalingam; Sarantopoulos, John; Bearss, David; Giles, Francis

      2011-12-01

      The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to cancer development and progression. They were first recognized as pro-viral integration sites for the Moloney Murine Leukemia virus. Unlike other kinases, they possess a hinge region which creates a unique binding pocket for ATP. Absence of a regulatory domain means that these proteins are constitutively active once transcribed. Pim kinases are critical downstream effectors of the ABL (ableson), JAK2 (janus kinase 2), and Flt-3 (FMS related tyrosine kinase 1) oncogenes and are required by them to drive tumorigenesis. Recent investigations have established that the Pim kinases function as effective inhibitors of apoptosis and when overexpressed, produce resistance to the mTOR (mammalian target of rapamycin) inhibitor, rapamycin . Overexpression of the PIM kinases has been reported in several hematological and solid tumors (PIM 1), myeloma, lymphoma, leukemia (PIM 2) and adenocarcinomas (PIM 3). As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Novel small molecule inhibitors of the human Pim kinases have been designed and are currently undergoing preclinical evaluation.

    5. VEGF pathway targeting agents, vessel normalization and tumor drug uptake : from bench to bedside

      NARCIS (Netherlands)

      Arjaans, Marlous; Schroder, Carolien P.; Oosting, Sjoukje F.; Dafni, Urania; Kleibeuker, Josee E.

      2016-01-01

      Vascular endothelial growth factor (VEGF) pathway targeting agents have been combined with other anticancer drugs, leading to improved efficacy in carcinoma of the cervix, stomach, lung, colon and rectum, ovary, and breast. Vessel normalization induced by VEGF pathway targeting agents influences

    6. Structure-based drug design approach to target toll-like receptor ...

      African Journals Online (AJOL)

      Figure 1: Structure-based drug design pipeline modified from Grey and Thompson [3]. Table 1: Examples of potential targets whose three-dimensional structures were determined using NMR, x-ray crystallography or homology modeling. Name of target. Technique. Reference. Human transforming growth factor alpha. NMR.

    7. Surgical Treatment of Complications of Pulmonary Tuberculosis, including Drug-Resistant Tuberculosis

      Directory of Open Access Journals (Sweden)

      Rajhmun Madansein

      2015-03-01

      Full Text Available Surgery for drug-resistant tuberculosis has been shown to be safe and effective, with similar level of mortalities associated with surgical intervention observed with that for lung cancer. While surgery has been an option to treat TB in the pre-antibiotic era, it is now increasingly used to treat complications of pulmonary TB, particularly in patients with drug-resistant TB who do not respond to medical treatment. The two most frequent indications for lung resection in drug- resistant TB, are i failed medical treatment with persistent sputum positivity or ii patients who have had medical treatment and are sputum negative, but with persistent localized cavitary disease or bronchiectasis. Massive hemoptysis is a potentially life-threatening complication of TB. Lung resection is potentially curative in patients with massive hemoptysis and cavitary or bronchiectatic disease. Bronchial artery embolization in these patients has a high success rate but bears also the risk of recurrence. Lung resection can be safely undertaken in selected patients with HIV co-infection and pulmonary complications of TB. Ambulatory drainage is a novel, safe, affordable and effective method of draining a chronic TB associated empyema thoracis. We review here the current surgical treatment of the complications of pulmonary TB and discuss the experience from the Durban Cardiothoracic Surgery Unit for the surgical treatment of patients with complicated pulmonary TB.

    8. In-silico prediction of drug targets, biological activities, signal pathways and regulating networks of dioscin based on bioinformatics.

      Science.gov (United States)

      Yin, Lianhong; Zheng, Lingli; Xu, Lina; Dong, Deshi; Han, Xu; Qi, Yan; Zhao, Yanyan; Xu, Youwei; Peng, Jinyong

      2015-03-05

      Inverse docking technology has been a trend of drug discovery, and bioinformatics approaches have been used to predict target proteins, biological activities, signal pathways and molecular regulating networks affected by drugs for further pharmacodynamic and mechanism studies. In the present paper, inverse docking technology was applied to screen potential targets from potential drug target database (PDTD). Then, the corresponding gene information of the obtained drug-targets was applied to predict the related biological activities, signal pathways and processes networks of the compound by using MetaCore platform. After that, some most relevant regulating networks were considered, which included the nodes and relevant pathways of dioscin. 71 potential targets of dioscin from humans, 7 from rats and 8 from mice were screened, and the prediction results showed that the most likely targets of dioscin were cyclin A2, calmodulin, hemoglobin subunit beta, DNA topoisomerase I, DNA polymerase lambda, nitric oxide synthase and UDP-N-acetylhexosamine pyrophosphorylase, etc. Many diseases including experimental autoimmune encephalomyelitis of human, temporal lobe epilepsy of rat and ankylosing spondylitis of mouse, may be inhibited by dioscin through regulating immune response alternative complement pathway, G-protein signaling RhoB regulation pathway and immune response antiviral actions of interferons, etc. The most relevant networks (5 from human, 3 from rat and 5 from mouse) indicated that dioscin may be a TOP1 inhibitor, which can treat cancer though the cell cycle- transition and termination of DNA replication pathway. Dioscin can down regulate EGFR and EGF to inhibit cancer, and also has anti-inflammation activity by regulating JNK signaling pathway. The predictions of the possible targets, biological activities, signal pathways and relevant regulating networks of dioscin provide valuable information to guide further investigation of dioscin on pharmacodynamics and

    9. Development of novel drug delivery prototypes devices for targeted delivery drug therapy at the molecular level in aqueous media.

      Science.gov (United States)

      George, Roy; Oberhozer, Theunis Gerhardus; Perchyonok, Victoria Tamara

      2011-09-01

      A novel approach in target specific molecular prototype drug delivery system concerns the attempt to employ radical affording substances (RAS) or radical quenching substances (RQS) as prodrugs able to produce irreversible damage on the desired target and therefore to stimulate cellular apoptosis. However, radical species generated can react quickly within the chemical environment prior to reaching its proper site of action. In this short communication, we report our investigations towards developing two alternative novel, simple, flexible and effective drug delivery systems that provide optimal dosage of drugs precisely where and when needed and therefore achieve and sustain a complex delivery profile. We have demonstrated the application of two effective molecular prototype delivery systems able to harness free radical reactivity within the laboratory where biological processes can be studied and controlled, leading to the prevention of disease and the development of new treatments for disease states mediated by free radicals.

    10. EphB1 as a Novel Drug Target to Combat Pain and Addiction

      Science.gov (United States)

      2016-09-01

      Award Number: W81XWH-14-1-0220 Project Title: EphB1 as a Novel Drug Target to Combat Pain and Addiction Principal Investigator Name: Mark...Pain and Addiction 5a. CONTRACT NUMBER EphB1 as a Novel Drug Target to Combat Pain and Addiction 5b. GRANT NUMBER W81XWH-14-1-0220 5c. PROGRAM...SUBJECT TERMS Chronic neuropathic pain, opioid addiction , synaptic plasticity, EphB1 receptor, ephrin-B2, NMDA receptor, drug discovery 16. SECURITY

    11. Structure-guided, target-based drug discovery - exploiting genome information from HIV to mycobacterial infections.

      Science.gov (United States)

      Malhotra, Sony; Thomas, Sherine E; Ochoa Montano, Bernardo; Blundell, Tom L

      The use of protein crystallography in structure-guided drug discovery allows identification of potential inhibitor-binding sites and optimisation of interactions of hits and lead compounds with a target protein. An early example of this approach was the use of the structure of HIV protease in designing AIDS antivirals. More recently, use of structure-guided design with fragment-based drug discovery, which reduces the size of screening libraries by decreasing complexity, has improved ligand efficiency in drug design. Here, we discuss the use of structure-guided target identification and lead optimisation using fragment-based approaches in the development of new antimicrobials for mycobacterial infections.

    12. Visualization of network target crosstalk optimizes drug synergism in myocardial ischemia.

      Directory of Open Access Journals (Sweden)

      Xiaojing Wan

      Full Text Available Numerous drugs and compounds have been validated as protecting against myocardial ischemia (MI, a leading cause of heart failure; however, synergistic possibilities among them have not been systematically explored. Thus, there appears to be significant room for optimization in the field of drug combination therapy for MI. Here, we propose an easy approach for the identification and optimization of MI-related synergistic drug combinations via visualization of the crosstalk between networks of drug targets corresponding to different drugs (each drug has a unique network of targets. As an example, in the present study, 28 target crosstalk networks (TCNs of random pairwise combinations of 8 MI-related drugs (curcumin, capsaicin, celecoxib, raloxifene, silibinin, sulforaphane, tacrolimus, and tamoxifen were established to illustrate the proposed method. The TCNs revealed a high likelihood of synergy between curcumin and the other drugs, which was confirmed by in vitro experiments. Further drug combination optimization showed a synergistic protective effect of curcumin, celecoxib, and sililinin in combination against H₂O₂-induced ischemic injury of cardiomyocytes at a relatively low concentration of 500 nM. This result is in agreement with the earlier finding of a denser and modular functional crosstalk between their networks of targets in the regulation of cell apoptosis. Our study offers a simple approach to rapidly search for and optimize potent synergistic drug combinations, which can be used for identifying better MI therapeutic strategies. Some new light was also shed on the characteristic features of drug synergy, suggesting that it is possible to apply this method to other complex human diseases.

    13. Visualization of network target crosstalk optimizes drug synergism in myocardial ischemia.

      Science.gov (United States)

      Wan, Xiaojing; Meng, Jia; Dai, Yingnan; Zhang, Yina; Yan, Shuang

      2014-01-01

      Numerous drugs and compounds have been validated as protecting against myocardial ischemia (MI), a leading cause of heart failure; however, synergistic possibilities among them have not been systematically explored. Thus, there appears to be significant room for optimization in the field of drug combination therapy for MI. Here, we propose an easy approach for the identification and optimization of MI-related synergistic drug combinations via visualization of the crosstalk between networks of drug targets corresponding to different drugs (each drug has a unique network of targets). As an example, in the present study, 28 target crosstalk networks (TCNs) of random pairwise combinations of 8 MI-related drugs (curcumin, capsaicin, celecoxib, raloxifene, silibinin, sulforaphane, tacrolimus, and tamoxifen) were established to illustrate the proposed method. The TCNs revealed a high likelihood of synergy between curcumin and the other drugs, which was confirmed by in vitro experiments. Further drug combination optimization showed a synergistic protective effect of curcumin, celecoxib, and sililinin in combination against H₂O₂-induced ischemic injury of cardiomyocytes at a relatively low concentration of 500 nM. This result is in agreement with the earlier finding of a denser and modular functional crosstalk between their networks of targets in the regulation of cell apoptosis. Our study offers a simple approach to rapidly search for and optimize potent synergistic drug combinations, which can be used for identifying better MI therapeutic strategies. Some new light was also shed on the characteristic features of drug synergy, suggesting that it is possible to apply this method to other complex human diseases.

    14. Novel Methods for Drug-Target Interaction Prediction using Graph Mining

      KAUST Repository

      Ba Alawi, Wail

      2016-08-31

      The problem of developing drugs that can be used to cure diseases is important and requires a careful approach. Since pursuing the wrong candidate drug for a particular disease could be very costly in terms of time and money, there is a strong interest in minimizing such risks. Drug repositioning has become a hot topic of research, as it helps reduce these risks significantly at the early stages of drug development by reusing an approved drug for the treatment of a different disease. Still, finding new usage for a drug is non-trivial, as it is necessary to find out strong supporting evidence that the proposed new uses of drugs are plausible. Many computational approaches were developed to narrow the list of possible candidate drug-target interactions (DTIs) before any experiments are done. However, many of these approaches suffer from unacceptable levels of false positives. We developed two novel methods based on graph mining networks of drugs and targets. The first method (DASPfind) finds all non-cyclic paths that connect a drug and a target, and using a function that we define, calculates a score from all the paths. This score describes our confidence that DTI is correct. We show that DASPfind significantly outperforms other state-of-the-art methods in predicting the top ranked target for each drug. We demonstrate the utility of DASPfind by predicting 15 novel DTIs over a set of ion channel proteins, and confirming 12 out of these 15 DTIs through experimental evidence reported in literature and online drug databases. The second method (DASPfind+) modifies DASPfind in order to increase the confidence and reliability of the resultant predictions. Based on the structure of the drug-target interaction (DTI) networks, we introduced an optimization scheme that incrementally alters the network structure locally for each drug to achieve more robust top 1 ranked predictions. Moreover, we explored effects of several similarity measures between the targets on the prediction

    15. Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

      International Nuclear Information System (INIS)

      May, Felicity EB

      2014-01-01

      The incidence of breast cancer continues to rise: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-related receptor alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-related receptor alpha is an orphan receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-related receptor alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen receptor alpha and estrogen-related receptor alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel

    16. Drug Discovery Targeting Serotonin G Protein-Coupled Receptors in the Treatment of Neuropsychiatric Disorders

      Science.gov (United States)

      Felsing, Daniel E.

      Clinical data show that activation of 5-HT2C G protein-coupled receptors (GPCRs) can treat obesity (lorcaserin/BelviqRTM) and psychotic disorders (aripiprazole/Abilify.), including schizophrenia. 5-HT2C GPCRs are members of the 5-HT2 sub-family of 5-HT GPCRs, which include 5-HT2A, 5-HT2B, and 5-HT 2C GPCRs. 5-HT2C is structurally similar to 5-HT2A and 5-HT2B GPCRs, but activation of 5-HT2A and/or 5-HT 2B causes deleterious effects, including hallucinations and cardiac valvulopathy. Thus, there is a challenge to develop drugs that selectively activate only 5-HT2C. Prolonged activation of GPCRs by agonists reduces their function via a regulatory process called desensitization. This has clinical relevance, as 45% of drugs approved by the FDA target GPCRs, and agonist drugs (e.g., morphine) typically lose efficacy over time due to desensitization, which invites tolerance. Agonists that cause less desensitization may show extended clinical efficacy as well as a more acceptable clinical dose range. We hypothesized that structurally distinct agonists of the 5-HT2C receptor may cause varying degrees of desensitization by stabilizing unique 5-HT2C receptor conformations. Discovery of 5-HT2C agonists that exhibit minimal desensitization is therapeutically relevant for the pharmacotherapeutic treatment of chronic diseases such as obesity and psychotic disorders. The 5-HT7 receptor has recently been discovered as a druggable target, and selective activation of the 5-HT7 receptor has been shown to alleviate locomotor deficits in mouse models of Rett Syndrome. Additionally, buspirone has been shown to display therapeutically relevant affinity at 5-HT 1A and is currently in phase II clinical trials to treat stereotypy in children with autism. The 5-PAT chemical scaffold shows high affinity towards the 5-HT7 and 5-HT1A receptors. Modulations around the 5-phenyl moiety were able to improve selectivity in binding towards the 5-HT 7 receptor, whereas modulations of the alkyl chains

    17. Small Molecule Target Identification using Drug Affinity Responsive Target Stability (DARTS)

      OpenAIRE

      Lomenick, Brett Eugene

      2013-01-01

      Small molecule target identification is a monumental task. Knowledge of the binding interactions between small molecule compounds and cellular macromolecules such as proteins is crucial for understanding their biological properties and mechanisms of action, yet discovering these interactions remains a considerable challenge. To overcome the limitations of current target ID methods, we developed a novel technique that can identify direct binding interactions using the native, unmodified comp...

    18. A colon targeted drug delivery system based on alginate modificated graphene oxide for colorectal liver metastasis.

      Science.gov (United States)

      Zhang, Bin; Yan, Yayuan; Shen, Qiujuan; Ma, Dong; Huang, Langhuan; Cai, Xiang; Tan, Shaozao

      2017-10-01

      A major problem associated with colon cancer is liver metastasis. A colon-targeted drug delivery system is one way to address this problem after the resection of colorectal cancer. However, traditional drug delivery systems face many challenges, such as an inability to control the release rate, inaccurate targeting, susceptibility to the microenvironment and poor stability. Here, we report the development of a graphene oxide (GO)-based, sodium alginate (ALG) functionalized colon-targeting drug delivery system, that is loaded with 5-fluorouracil (5-FU) as the anti-cancer drug (denoted as GO-ALG/5-FU). Our results demonstrate that the as-prepared drug delivery system possesses a much lower toxicity and better colon-targeting controlled-release behaviours. We show that GO-ALG/5-FU significantly inhibited tumour growth and liver metastasis and prolonged the survival time of mice. We anticipate that our assay will help improve basic research of colon-targeted drug delivery systems and provide a new way to treat colon cancer liver metastasis. Copyright © 2017 Elsevier B.V. All rights reserved.

    19. Improved prediction of drug-target interactions using regularized least squares integrating with kernel fusion technique

      International Nuclear Information System (INIS)

      Hao, Ming; Wang, Yanli; Bryant, Stephen H.

      2016-01-01

      Identification of drug-target interactions (DTI) is a central task in drug discovery processes. In this work, a simple but effective regularized least squares integrating with nonlinear kernel fusion (RLS-KF) algorithm is proposed to perform DTI predictions. Using benchmark DTI datasets, our proposed algorithm achieves the state-of-the-art results with area under precision–recall curve (AUPR) of 0.915, 0.925, 0.853 and 0.909 for enzymes, ion channels (IC), G protein-coupled receptors (GPCR) and nuclear receptors (NR) based on 10 fold cross-validation. The performance can further be improved by using a recalculated kernel matrix, especially for the small set of nuclear receptors with AUPR of 0.945. Importantly, most of the top ranked interaction predictions can be validated by experimental data reported in the literature, bioassay results in the PubChem BioAssay database, as well as other previous studies. Our analysis suggests that the proposed RLS-KF is helpful for studying DTI, drug repositioning as well as polypharmacology, and may help to accelerate drug discovery by identifying novel drug targets. - Graphical abstract: Flowchart of the proposed RLS-KF algorithm for drug-target interaction predictions. - Highlights: • A nonlinear kernel fusion algorithm is proposed to perform drug-target interaction predictions. • Performance can further be improved by using the recalculated kernel. • Top predictions can be validated by experimental data.

    20. Improved prediction of drug-target interactions using regularized least squares integrating with kernel fusion technique

      Energy Technology Data Exchange (ETDEWEB)

      Hao, Ming; Wang, Yanli, E-mail: ywang@ncbi.nlm.nih.gov; Bryant, Stephen H., E-mail: bryant@ncbi.nlm.nih.gov

      2016-02-25

      Identification of drug-target interactions (DTI) is a central task in drug discovery processes. In this work, a simple but effective regularized least squares integrating with nonlinear kernel fusion (RLS-KF) algorithm is proposed to perform DTI predictions. Using benchmark DTI datasets, our proposed algorithm achieves the state-of-the-art results with area under precision–recall curve (AUPR) of 0.915, 0.925, 0.853 and 0.909 for enzymes, ion channels (IC), G protein-coupled receptors (GPCR) and nuclear receptors (NR) based on 10 fold cross-validation. The performance can further be improved by using a recalculated kernel matrix, especially for the small set of nuclear receptors with AUPR of 0.945. Importantly, most of the top ranked interaction predictions can be validated by experimental data reported in the literature, bioassay results in the PubChem BioAssay database, as well as other previous studies. Our analysis suggests that the proposed RLS-KF is helpful for studying DTI, drug repositioning as well as polypharmacology, and may help to accelerate drug discovery by identifying novel drug targets. - Graphical abstract: Flowchart of the proposed RLS-KF algorithm for drug-target interaction predictions. - Highlights: • A nonlinear kernel fusion algorithm is proposed to perform drug-target interaction predictions. • Performance can further be improved by using the recalculated kernel. • Top predictions can be validated by experimental data.

    1. A metabolic network approach for the identification and prioritization of antimicrobial drug targets.

      Science.gov (United States)

      Chavali, Arvind K; D'Auria, Kevin M; Hewlett, Erik L; Pearson, Richard D; Papin, Jason A

      2012-03-01

      For many infectious diseases, novel treatment options are needed in order to address problems with cost, toxicity and resistance to current drugs. Systems biology tools can be used to gain valuable insight into pathogenic processes and aid in expediting drug discovery. In the past decade, constraint-based modeling of genome-scale metabolic networks has become widely used. Focusing on pathogen metabolic networks, we review in silico strategies used to identify effective drug targets and highlight recent successes as well as limitations associated with such computational analyses. We further discuss how accounting for the host environment and even targeting the host may offer new therapeutic options. These systems-level approaches are beginning to provide novel avenues for drug targeting against infectious agents. Copyright © 2011 Elsevier Ltd. All rights reserved.

    2. Genome-scale metabolic models as platforms for identification of novel genes as antimicrobial drug targets.

      Science.gov (United States)

      Mienda, Bashir Sajo; Salihu, Rabiu; Adamu, Aliyu; Idris, Shehu

      2018-03-01

      The growing number of multidrug-resistant pathogenic bacteria is becoming a world leading challenge for the scientific community and for public health. However, advances in high-throughput technologies and whole-genome sequencing of bacterial pathogens make the construction of bacterial genome-scale metabolic models (GEMs) increasingly realistic. The use of GEMs as an alternative platforms will expedite identification of novel unconditionally essential genes and enzymes of target organisms with existing and forthcoming GEMs. This approach will follow the existing protocol for construction of high-quality GEMs, which could ultimately reduce the time, cost and labor-intensive processes involved in identification of novel antimicrobial drug targets in drug discovery pipelines. We discuss the current impact of existing GEMs of selected multidrug-resistant pathogenic bacteria for identification of novel antimicrobial drug targets and the challenges of closing the gap between genome-scale metabolic modeling and conventional experimental trial-and-error approaches in drug discovery pipelines.

    3. Receptor binding peptides for target-selective delivery of nanoparticles encapsulated drugs.

      Science.gov (United States)

      Accardo, Antonella; Aloj, Luigi; Aurilio, Michela; Morelli, Giancarlo; Tesauro, Diego

      2014-01-01

      Active targeting by means of drug encapsulated nanoparticles decorated with targeting bioactive moieties represents the next frontier in drug delivery; it reduces drug side effects and increases the therapeutic index. Peptides, based on their chemical and biological properties, could have a prevalent role to direct drug encapsulated nanoparticles, such as liposomes, micelles, or hard nanoparticles, toward the tumor tissues. A considerable number of molecular targets for peptides are either exclusively expressed or overexpressed on both cancer vasculature and cancer cells. They can be classified into three wide categories: integrins; growth factor receptors (GFRs); and G-protein coupled receptors (GPCRs). Therapeutic agents based on nanovectors decorated with peptides targeting membrane receptors belonging to the GPCR family overexpressed by cancer cells are reviewed in this article. The most studied targeting membrane receptors are considered: somatostatin receptors; cholecystokinin receptors; receptors associated with the Bombesin like peptides family; luteinizing hormone-releasing hormone receptors; and neurotensin receptors. Nanovectors of different sizes and shapes (micelles, liposomes, or hard nanoparticles) loaded with doxorubicin or other cytotoxic drugs and externally functionalized with natural or synthetic peptides are able to target the overexpressed receptors and are described based on their formulation and in vitro and in vivo behaviors.

    4. Drug targets in dormant Mycobacterium tuberculosis: can the conquest against tuberculosis become a reality?

      Science.gov (United States)

      Gupta, Vivek Kumar; Kumar, M Madhan; Singh, Dharmendra; Bisht, Deepa; Sharma, Shweta

      2018-02-01

      Targeting M. tuberculosis (Mtb) in latent form of infection is a major obstacle and big challenge in tuberculosis (TB) eradication by current chemotherapy. A better understanding of the physiology of Mtb and of the metabolic state of the bacillus during the dormancy, is a primary need in finding drug targets against non replicating persistent (NRP) form of the Mtb. Identification of potential drug targets against dormant state of Mtb is critically important to achieve the goal of complete eradication for shortening of anti-TB therapy. The metabolic processes functioning in dormant Mtb in providing cell viability and protecting Mtb from sterilization by the hostile environment can be explored as drug targets. This review discusses about the potential drug targets in dormant tubercle bacilli, anti-dormancy inhibitors and the strategies which can be pursued for maximizing success if these targets are exploited for killing the dormant bacilli. This has important implications as the currently available arsenal of drugs suffers from the demerit of achieving sterilizing killing of mycobacteria. This lacuna can be overcome if the proposed strategies for eliminating dormant bacteria are combined along with the existing treatment modalities for the extirpation of bacilli.

    5. Moonlighting adenosine deaminase: a target protein for drug development.

      Science.gov (United States)

      Cortés, Antoni; Gracia, Eduard; Moreno, Estefania; Mallol, Josefa; Lluís, Carme; Canela, Enric I; Casadó, Vicent

      2015-01-01

      Interest in adenosine deaminase (ADA) in the context of medicine has mainly focused on its enzymatic activity. This is justified by the importance of the reaction catalyzed by ADA not only for the intracellular purine metabolism, but also for the extracellular purine metabolism as well, because of its capacity as a regulator of the concentration of extracellular adenosine that is able to activate adenosine receptors (ARs). In recent years, other important roles have been described for ADA. One of these, with special relevance in immunology, is the capacity of ADA to act as a costimulator, promoting T-cell proliferation and differentiation mainly by interacting with the differentiation cluster CD26. Another role is the ability of ADA to act as an allosteric modulator of ARs. These receptors have very general physiological implications, particularly in the neurological system where they play an important role. Thus, ADA, being a single chain protein, performs more than one function, consistent with the definition of a moonlighting protein. Although ADA has never been associated with moonlighting proteins, here we consider ADA as an example of this family of multifunctional proteins. In this review, we discuss the different roles of ADA and their pathological implications. We propose a mechanism by which some of their moonlighting functions can be coordinated. We also suggest that drugs modulating ADA properties may act as modulators of the moonlighting functions of ADA, giving them additional potential medical interest. © 2014 Wiley Periodicals, Inc.

    6. Targeting the dopamine D3 receptor: an overview of drug design strategies.

      Science.gov (United States)

      Cortés, Antoni; Moreno, Estefanía; Rodríguez-Ruiz, Mar; Canela, Enric I; Casadó, Vicent

      2016-07-01

      Dopamine is a neurotransmitter widely distributed in both the periphery and the central nervous system (CNS). Its physiological effects are mediated by five closely related G protein-coupled receptors (GPCRs) that are divided into two major subclasses: the D1-like (D1, D5) and the D2-like (D2, D3, D4) receptors. D3 receptors (D3Rs) have the highest density in the limbic areas of the brain, which are associated with cognitive and emotional functions. These receptors are therefore attractive targets for therapeutic management. This review summarizes the functional and pharmacological characteristics of D3Rs, including the design and clinical relevance of full agonists, partial agonists and antagonists, as well as the capacity of these receptors to form active homodimers, heterodimers or higher order receptor complexes as pharmacological targets in several neurological and neurodegenerative disorders. The high sequence homology between D3R and the D2-type challenges the development of D3R-selective compounds. The design of new D3R-preferential ligands with improved physicochemical properties should provide a better pharmacokinetic/bioavailability profile and lesser toxicity than is found with existing D3R ligands. It is also essential to optimize D3R affinity and, especially, D3R vs. D2-type binding and functional selectivity ratios. Developing allosteric and bitopic ligands should help to improve the D3R selectivity of these drugs. As most evidence points to the ability of GPCRs to form homomers and heteromers, the most promising therapeutic strategy in the future is likely to involve the application of heteromer-selective drugs. These selective ligands would display different affinities for a given receptor depending on the receptor partners within the heteromer. Therefore, designing novel compounds that specifically target and modulate D1R-D3R heteromers would be an interesting approach for the treatment of levodopa (L-DOPA)-induced dyskinesias.

    7. Hyaluronic acid modified mesoporous carbon nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells

      Science.gov (United States)

      Wan, Long; Jiao, Jian; Cui, Yu; Guo, Jingwen; Han, Ning; Di, Donghua; Chang, Di; Wang, Pu; Jiang, Tongying; Wang, Siling

      2016-04-01

      In this paper, hyaluronic acid (HA) functionalized uniform mesoporous carbon spheres (UMCS) were synthesized for targeted enzyme responsive drug delivery using a facile electrostatic attraction strategy. This HA modification ensured stable drug encapsulation in mesoporous carbon nanoparticles in an extracellular environment while increasing colloidal stability, biocompatibility, cell-targeting ability, and controlled cargo release. The cellular uptake experiments of fluorescently labeled mesoporous carbon nanoparticles, with or without HA functionalization, demonstrated that HA-UMCS are able to specifically target cancer cells overexpressing CD44 receptors. Moreover, the cargo loaded doxorubicin (DOX) and verapamil (VER) exhibited a dual pH and hyaluronidase-1 responsive release in the tumor microenvironment. In addition, VER/DOX/HA-UMCS exhibited a superior therapeutic effect on an in vivo HCT-116 tumor in BALB/c nude mice. In summary, it is expected that HA-UMCS will offer a new method for targeted co-delivery of drugs to tumors overexpressing CD44 receptors.

    8. Photopatternable Magnetic Hollowbots by Nd-Fe-B Nanocomposite for Potential Targeted Drug Delivery Applications

      Directory of Open Access Journals (Sweden)

      Hui Li

      2018-04-01

      Full Text Available In contrast to traditional drug administration, targeted drug delivery can prolong, localize, target and have a protected drug interaction with the diseased tissue. Drug delivery carriers, such as polymeric micelles, liposomes, dendrimers, nanotubes, and so on, are hard to scale-up, costly, and have short shelf life. Here we show the novel fabrication and characterization of photopatternable magnetic hollow microrobots that can potentially be utilized in microfluidics and drug delivery applications. These magnetic hollowbots can be fabricated using standard ultraviolet (UV lithography with low cost and easily accessible equipment, which results in them being easy to scale up, and inexpensive to fabricate. Contact-free actuation of freestanding magnetic hollowbots were demonstrated by using an applied 900 G external magnetic field to achieve the movement control in an aqueous environment. According to the movement clip, the average speed of the magnetic hollowbots was estimated to be 1.9 mm/s.

    9. Inhibition of Glutamine Synthetase: A Potential Drug Target in Mycobacterium tuberculosis

      Directory of Open Access Journals (Sweden)

      Sherry L. Mowbray

      2014-08-01

      Full Text Available Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Globally, tuberculosis is second only to AIDS in mortality and the disease is responsible for over 1.3 million deaths each year. The impractically long treatment schedules (generally 6–9 months and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multi-, extensively- and totally-drug resistant strains. The development of new classes of anti-tuberculosis drugs and new drug targets is of global importance, since attacking the bacterium using multiple strategies provides the best means to prevent resistance. This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy.

    10. Inhibition of glutamine synthetase: a potential drug target in Mycobacterium tuberculosis.

      Science.gov (United States)

      Mowbray, Sherry L; Kathiravan, Muthu K; Pandey, Abhishek A; Odell, Luke R

      2014-08-26

      Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Globally, tuberculosis is second only to AIDS in mortality and the disease is responsible for over 1.3 million deaths each year. The impractically long treatment schedules (generally 6-9 months) and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multi-, extensively- and totally-drug resistant strains. The development of new classes of anti-tuberculosis drugs and new drug targets is of global importance, since attacking the bacterium using multiple strategies provides the best means to prevent resistance. This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy.

    11. Pure drug and polymer based nanotechnologies for the improved solubility, stability, bioavailability and targeting of anti-HIV drugs.

      Science.gov (United States)

      Sharma, Puneet; Garg, Sanjay

      2010-03-18

      The impact of human immunodeficiency virus (HIV) infection has been devastating with nearly 7400 new infections every day. Although, the advent of highly active antiretroviral therapy (HAART) has made a tremendous contribution in reducing the morbidity and mortality in developed countries, the situation in developing countries is still grim with millions of people being infected by this disease. The new advancements in the field of nanotechnology based drug delivery systems hold promise to improve the situation. These nanoscale systems have been successfully employed in other diseases such as cancer, and therefore, we now have a better understanding of the practicalities and technicalities associated with their clinical development. Nanotechnology based approaches offer some unique opportunities specifically for the improvement of water solubility, stability, bioavailability and targeting of antiretroviral drugs. This review presents discussion on the contribution of pure drug and polymer based nanotechnologies for the delivery anti-HIV drugs. Copyright 2009 Elsevier B.V. All rights reserved.

    12. A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

      Directory of Open Access Journals (Sweden)

      John C. Leach

      2016-03-01

      Full Text Available The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA, was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA+ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells.

    13. Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs.

      Science.gov (United States)

      Amir, Eitan; Seruga, Bostjan; Martinez-Lopez, Joaquin; Kwong, Ryan; Pandiella, Atanasio; Tannock, Ian F; Ocaña, Alberto

      2011-06-20

      The relationship between market pricing of new anticancer drugs and the magnitude of clinical benefit caused by them has not been reported. Randomized clinical trials (RCTs) that evaluated approved new agents for solid tumors by the U.S. Food and Drug administration since the year 2000 were assessed. Hazard ratios (HRs) and 95% CIs were extracted for time-to-event end points described for each RCT. HRs were pooled for three groups: agents directed against a specific molecular target, for which the target population is selected by a biomarker (group A); less specific biologic targeted agents (group B); and chemotherapeutic agents (group C). Monthly market prices of these different drugs were compared. For overall survival (OS), the pooled HR was 0.69 (95% CI, 0.59 to 0.81) for group A (six drugs, six trials); it was 0.78 (95% CI, 0.74 to 0.83) for group B (seven drugs, 14 trials); and it was 0.84 (95% CI, 0.79 to 0.90) for group C (eight drugs, 12 trials). For progression-free survival (PFS), the pooled HR was 0.42 (95% CI, 0.36 to 0.49) for group A (six drugs, seven trials); it was 0.57 (95% CI, 0.51 to 0.64) for group B (seven drugs, 14 trials); and it was 0.75 (95% CI, 0.66 to 0.85) for group C (six drugs, 10 trials). Tests for heterogeneity between subgroups were highly significant for PFS (P prices for standard doses of drugs were $5375 for group A, $5644 for group B, and $6584 for group C (P = .87). New agents with specific molecular targets are clinically the most beneficial, but their monthly market prices are not significantly different from those of other anticancer agents.

    14. Sol-Gel Behavior of Hydroxypropyl Methylcellulose (HPMC in Ionic Media Including Drug Release

      Directory of Open Access Journals (Sweden)

      Sunil C. Joshi

      2011-10-01

      Full Text Available Sol-gel transformations in HPMC (hydroxypropyl methylcellulose are being increasingly studied because of their role in bio-related applications. The thermo-reversible behavior of HPMC is particularly affected by its properties and concentration in solvent media, nature of additives, and the thermal environment it is exposed to. This article contains investigations on the effects of salt additives in Hofmeister series on the HPMC gelation. Various findings regarding gelation with salt ions as well as with the ionic and non-ionic surfactants are presented. The gel formation in physiological salt fluids such as simulated gastric and intestine fluids is also examined with the interest in oral drug delivery systems. The processes of swelling, dissolution and dispersion of HPMC tablets in simulated bio-fluids are explored and the release of a drug from the tablet affected by such processes is studied. Explanations are provided based on the chemical structure and the molecular binding/association of HPMC in a media. The test results at the body or near-body temperature conditions helped in understanding the progress of the gelation process within the human body environment. The detailed interpretation of various molecule level interactions unfolded the sol-gel mechanisms and the influence of a few other factors. The obtained test data and the established mathematical models are expected to serve as a guide in customizing applications of HPMC hydrogels.

    15. Sol-Gel Behavior of Hydroxypropyl Methylcellulose (HPMC) in Ionic Media Including Drug Release

      Science.gov (United States)

      Joshi, Sunil C.

      2011-01-01

      Sol-gel transformations in HPMC (hydroxypropyl methylcellulose) are being increasingly studied because of their role in bio-related applications. The thermo-reversible behavior of HPMC is particularly affected by its properties and concentration in solvent media, nature of additives, and the thermal environment it is exposed to. This article contains investigations on the effects of salt additives in Hofmeister series on the HPMC gelation. Various findings regarding gelation with salt ions as well as with the ionic and non-ionic surfactants are presented. The gel formation in physiological salt fluids such as simulated gastric and intestine fluids is also examined with the interest in oral drug delivery systems. The processes of swelling, dissolution and dispersion of HPMC tablets in simulated bio-fluids are explored and the release of a drug from the tablet affected by such processes is studied. Explanations are provided based on the chemical structure and the molecular binding/association of HPMC in a media. The test results at the body or near-body temperature conditions helped in understanding the progress of the gelation process within the human body environment. The detailed interpretation of various molecule level interactions unfolded the sol-gel mechanisms and the influence of a few other factors. The obtained test data and the established mathematical models are expected to serve as a guide in customizing applications of HPMC hydrogels. PMID:28824113

    16. Hepatitis B virus reverse transcriptase - Target of current antiviral therapy and future drug development.

      Science.gov (United States)

      Clark, Daniel N; Hu, Jianming

      2015-11-01

      Hepatitis B virus (HBV) infections rely on the proper functioning of the viral polymerase enzyme, a specialized reverse transcriptase (RT) with multiple activities. All currently approved antiviral drugs for the treatment of chronic HBV infection, except for interferon, target the RT and belong to the same chemical class - they are all nucleoside analogs. Viral DNA synthesis is carried out by the RT enzyme in several different steps, each with distinct RT conformational requirements. In principle, each stage may be targeted by distinct antiviral drugs. In particular, the HBV RT has the unique ability to initiate viral DNA synthesis using itself as a protein primer in a novel protein priming reaction. In order to help identify RT inhibitors and study their mechanisms of action, a number of experimental systems have been developed, each varying in its ability to dissect the protein priming stage and subsequent stages of viral DNA synthesis at the molecular level. Two of the most effective drugs to date, entecavir and tenofovir, can inhibit both the protein priming and the subsequent DNA elongation stages of HBV DNA synthesis. Interestingly, clevudine, a thymidine analog, can inhibit both protein priming and DNA elongation in a non-competitive manner and without being incorporated into the viral DNA. Thus, a nucleoside RT inhibitor (NRTI) can functionally mimic a non-NRTI (NNRTI) in its inhibition of the HBV RT. Therefore, novel NRTIs as well as NNRTIs may be developed to inhibit the DNA synthesis activity of the HBV RT. Furthermore, additional activities of the RT that are also essential to HBV replication, including specific recognition of the viral RNA and its packaging into viral nucleocapsids, may be exploited for antiviral development. To achieve a more potent inhibition of viral replication and ultimately cure chronic HBV infection, the next generation of anti-HBV therapies will likely need to include NRTIs, NNRTIs, and other agents that target the viral RT as

    17. New treatment options and emerging drugs for axial spondyloarthritis: biological and targeted synthetic agents.

      Science.gov (United States)

      Toussirot, Eric

      2017-02-01

      Ankylosing spondylitis (AS) and axial spondyloarthritis (ax SpA) are chronic inflammatory diseases mainly involving the axial skeleton. Pharmacological treatments for AS and ax SpA usually include local glucocorticoid injections, NSAIDs and anti-TNFα agents. Since around 30% to 40% of patients are non responders or intolerant to anti-TNFα agents, we need new therapeutic options for AS and ax SpA. Areas covered: This review describes the new biological agents that can be used or are in development for AS or ax SpA as well as emerging synthetic targeted drugs. Expert opinion: Based on the rationale of the involvement of the IL-23/Th17 axis in AS, novel biological agents have been developed and include secukinumab, an anti-IL-17A agent and ustekinumab, an anti-IL-23 antibody. New compounds in the class of synthetic drugs are apremilast, a PDE4 inhibitor, and inhibitors of kinase pathways. Secukinumab gave positive results in the treatment of AS. Ustekinumab yielded promising results in AS in an open labeled study. Apremilast is not effective in AS while results with kinase inhibitors are preliminary. Future studies will clarify the place of secukinumab in the therapeutic management of AS, its influence on radiographic progression and its effects on the non radiographic form of the disease.

    18. Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.

      Directory of Open Access Journals (Sweden)

      Juan D Unciti-Broceta

      2015-06-01

      Full Text Available African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.

    19. Current status of hyphenated mass spectrometry in studies of the metabolism of drugs of abuse, including doping agents.

      Science.gov (United States)

      Meyer, Markus R; Maurer, Hans H

      2012-01-01

      This paper reviews scientific contributions on the identification and/or quantification of metabolites of drugs of abuse in in vitro assays or various body samples using hyphenated mass spectrometry. Gas chromatography-mass spectrometry (GC-MS) as well as liquid chromatography-mass spectrometry (LC-MS) approaches are considered and discussed if they have been reported in the last five years and are relevant to clinical and forensic toxicology or doping control. Workup and artifact formation are discussed, and typical examples of studies of the metabolism of designer drugs, doping agents, herbal drugs, and synthetic cannabinoids are provided. Procedures for quantifying metabolites in body samples for pharmacokinetic studies or in enzyme incubations for enzyme kinetic studies are also reviewed. In conclusion, the reviewed papers showed that both GC-MS and LC-MS still have important roles to play in research into the metabolism of drugs of abuse, including doping agents.

    20. Drug-loaded nanocarriers: passive targeting and crossing of biological barriers.

      Science.gov (United States)

      Rabanel, J M; Aoun, V; Elkin, I; Mokhtar, M; Hildgen, P

      2012-01-01

      Poor bioavailability and poor pharmacokinetic characteristics are some of the leading causes of drug development failure. Therefore, poorly-soluble drugs, fragile proteins or nucleic acid products may benefit from their encapsulation in nanosized vehicles, providing enhanced solubilization, protection against degradation, and increased access to pathological compartments. A key element for the success of drug-loaded nanocarriers is their ability to either cross biological barriers themselves, or allow loaded drugs to traverse them to achieve optimal pharmacological action at pathological sites. Depending on the mode of administration, nanocarriers may have to cross different physiological barriers in their journey towards their target. In this review, the crossing of biological barriers by passive targeting strategies will be presented for intravenous delivery (vascular endothelial lining, particularly for tumor vasculature and blood brain barrier targeting), oral administration (gastrointestinal lining), and upper airway administration (pulmonary epithelium). For each specific barrier, background information will be provided on the structure and biology of the tissues involved as well as available pathways for nano-objects or loaded drugs (diffusion and convection through fenestration, transcytosis, tight junction crossing, etc.). The determinants of passive targeting - size, shape, surface chemistry, surface patterning of nanovectors - will be discussed in light of current results. Perspectives on each mode of administration will be presented. The focus will be on polymeric nanoparticles and dendrimers, although advances in liposome technology will be also reported as they represent the largest body in the drug delivery literature.

    1. Age-Dependent Cellular and Behavioral Deficits Induced by Molecularly Targeted Drugs Are Reversible.

      Science.gov (United States)

      Scafidi, Joseph; Ritter, Jonathan; Talbot, Brooke M; Edwards, Jorge; Chew, Li-Jin; Gallo, Vittorio

      2018-04-15

      Newly developed targeted anticancer drugs inhibit signaling pathways commonly altered in adult and pediatric cancers. However, as these pathways are also essential for normal brain development, concerns have emerged of neurologic sequelae resulting specifically from their application in pediatric cancers. The neural substrates and age dependency of these drug-induced effects in vivo are unknown, and their long-term behavioral consequences have not been characterized. This study defines the age-dependent cellular and behavioral effects of these drugs on normally developing brains and determines their reversibility with post-drug intervention. Mice at different postnatal ages received short courses of molecularly targeted drugs in regimens analagous to clinical treatment. Analysis of rapidly developing brain structures important for sensorimotor and cognitive function showed that, while adult administration was without effect, earlier neonatal administration of targeted therapies attenuated white matter oligodendroglia and hippocampal neuronal development more profoundly than later administration, leading to long-lasting behavioral deficits. This functional impairment was reversed by rehabilitation with physical and cognitive enrichment. Our findings demonstrate age-dependent, reversible effects of these drugs on brain development, which are important considerations as treatment options expand for pediatric cancers. Significance: Targeted therapeutics elicit age-dependent long-term consequences on the developing brain that can be ameliorated with environmental enrichment. Cancer Res; 78(8); 2081-95. ©2018 AACR . ©2018 American Association for Cancer Research.

    2. Update on medical and regulatory issues pertaining to compounded and FDA-approved drugs, including hormone therapy.

      Science.gov (United States)

      Pinkerton, JoAnn V; Pickar, James H

      2016-02-01

      We review the historical regulation of drug compounding, concerns about widespread use of non-Food and Drug Admiistration (FDA)-approved compounded bioidentical hormone therapies (CBHTs), which do not have proper labeling and warnings, and anticipated impact of the 2013 Drug Quality and Security Act (DQSA) on compounding. US government websites were searched for documents concerning drug compounding regulation and oversight from 1938 (passage of Federal Food, Drug, and Cosmetic Act [FDCA]) through 2014, including chronologies, Congressional testimony, FDA guidelines and enforcements, and reports. The FDCA and DQSA were reviewed. PubMed and Google were searched for articles on compounded drugs, including CBHT. Congress explicitly granted the FDA limited oversight of compounded drugs in a 1997 amendment to the FDCA, but the FDA has encountered obstacles in exercising that authority. After 64 patient deaths and 750 adversely affected patients from the 2012 meningitis outbreak due to contaminated compounded steroid injections, Congress passed the DQSA, authorizing the FDA to create a voluntary registration for facilities that manufacture and distribute sterile compounded drugs in bulk and reinforcing FDCA regulations for traditional compounding. Given history and current environment, concerns remain about CBHT product regulation and their lack of safety and efficacy data. The DQSA and its reinforcement of §503A of the FDCA solidifies FDA authority to enforce FDCA provisions against compounders of CBHT. The new law may improve compliance and accreditation by the compounding industry; support state and FDA oversight; and prevent the distribution of misbranded, adulterated, or inconsistently compounded medications, and false and misleading claims, thus reducing public health risk.

    3. Polysaccharide-based micro/nanocarriers for oral colon-targeted drug delivery.

      Science.gov (United States)

      Zhang, Lin; Sang, Yuan; Feng, Jing; Li, Zhaoming; Zhao, Aili

      2016-08-01

      Oral colon-targeted drug delivery has attracted many researchers because of its distinct advantages of increasing the bioavailability of the drug at the target site and reducing the side effects. Polysaccharides that are precisely activated by the physiological environment of the colon hold greater promise for colon targeting. Considerable research efforts have been directed towards developing polysaccharide-based micro/nanocarriers. Types of polysaccharides for colon targeting and in vitro/in vivo assessments of polysaccharide-based carriers for oral colon-targeted drug delivery are summarised. Polysaccharide-based microspheres have gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon (colon cancer, inflammatory bowel disease (IBD), amoebiasis and irritable bowel syndrome (IBS)), but also for it's potential for the delivery of anti-rheumatoid arthritis and anti-chronic stable angina drugs. Besides, Polysaccharide-based micro/nanocarriers such as microbeads, microcapsules, microparticles, nanoparticles, nanogels and nanospheres are also introduced in this review.

    4. Natural material-decorated mesoporous silica nanoparticle container for multifunctional membrane-controlled targeted drug delivery

      Directory of Open Access Journals (Sweden)

      Hu Y

      2017-11-01

      Full Text Available Yan Hu,1 Lei Ke,2 Hao Chen,1 Ma Zhuo,1 Xinzhou Yang,1 Dan Zhao,1 Suying Zeng,1 Xincai Xiao1 1Department of Pharmaceutics, School of Pharmaceutical Science, South-Central University for Nationalities, 2Department of Medicinal Chemistry, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China Abstract: To avoid the side effects caused by nonspecific targeting, premature release, weak selectivity, and poor therapeutic efficacy of current nanoparticle-based systems used for drug delivery, we fabricated natural material-decorated nanoparticles as a multifunctional, membrane-controlled targeted drug delivery system. The nanocomposite material coated with a membrane was biocompatible and integrated both specific tumor targeting and responsiveness to stimulation, which improved transmission efficacy and controlled drug release. Mesoporous silica nanoparticles (MSNs, which are known for their biocompatibility and high drug-loading capacity, were selected as a model drug container and carrier. The membrane was established by the polyelectrolyte composite method from chitosan (CS which was sensitive to the acidic tumor microenvironment, folic acid-modified CS which recognizes the folate receptor expressed on the tumor cell surface, and a CD44 receptor-targeted polysaccharide hyaluronic acid. We characterized the structure of the nanocomposite as well as the drug release behavior under the control of the pH-sensitive membrane switch and evaluated the antitumor efficacy of the system in vitro. Our results provide a basis for the design and fabrication of novel membrane-controlled nanoparticles with improved tumor-targeting therapy. Keywords: multifunctional, membrane-controlled, natural materials, mesoporous silica nanoparticles, targeted drug delivery

    5. Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration

      Science.gov (United States)

      Gu, Wenyi; Wu, Chengtie; Chen, Jiezhong; Xiao, Yin

      2013-01-01

      Nanotechnology is a vigorous research area and one of its important applications is in biomedical sciences. Among biomedical applications, targeted drug delivery is one of the most extensively studied subjects. Nanostructured particles and scaffolds have been widely studied for increasing treatment efficacy and specificity of present treatment approaches. Similarly, this technique has been used for treating bone diseases including bone regeneration. In this review, we have summarized and highlighted the recent advancement of nanostructured particles and scaffolds for the treatment of cancer bone metastasis, osteosarcoma, bone infections and inflammatory diseases, osteoarthritis, as well as for bone regeneration. Nanoparticles used to deliver deoxyribonucleic acid and ribonucleic acid molecules to specific bone sites for gene therapies are also included. The investigation of the implications of nanoparticles in bone diseases have just begun, and has already shown some promising potential. Further studies have to be conducted, aimed specifically at assessing targeted delivery and bioactive scaffolds to further improve their efficacy before they can be used clinically. PMID:23836972

    6. Measurement of drug-target engagement in live cells by two-photon fluorescence anisotropy imaging.

      Science.gov (United States)

      Vinegoni, Claudio; Fumene Feruglio, Paolo; Brand, Christian; Lee, Sungon; Nibbs, Antoinette E; Stapleton, Shawn; Shah, Sunil; Gryczynski, Ignacy; Reiner, Thomas; Mazitschek, Ralph; Weissleder, Ralph

      2017-07-01

      The ability to directly image and quantify drug-target engagement and drug distribution with subcellular resolution in live cells and whole organisms is a prerequisite to establishing accurate models of the kinetics and dynamics of drug action. Such methods would thus have far-reaching applications in drug development and molecular pharmacology. We recently presented one such technique based on fluorescence anisotropy, a spectroscopic method based on polarization light analysis and capable of measuring the binding interaction between molecules. Our technique allows the direct characterization of target engagement of fluorescently labeled drugs, using fluorophores with a fluorescence lifetime larger than the rotational correlation of the bound complex. Here we describe an optimized protocol for simultaneous dual-channel two-photon fluorescence anisotropy microscopy acquisition to perform drug-target measurements. We also provide the necessary software to implement stream processing to visualize images and to calculate quantitative parameters. The assembly and characterization part of the protocol can be implemented in 1 d. Sample preparation, characterization and imaging of drug binding can be completed in 2 d. Although currently adapted to an Olympus FV1000MPE microscope, the protocol can be extended to other commercial or custom-built microscopes.

    7. Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: A review.

      Science.gov (United States)

      Kanamala, Manju; Wilson, William R; Yang, Mimi; Palmer, Brian D; Wu, Zimei

      2016-04-01

      As the mainstay in the treatment of various cancers, chemotherapy plays a vital role, but still faces many challenges, such as poor tumour selectivity and multidrug resistance (MDR). Targeted drug delivery using nanotechnology has provided a new strategy for addressing the limitations of the conventional chemotherapy. In the last decade, the volume of research published in this area has increased tremendously, especially with functional nano drug delivery systems (nanocarriers). Coupling a specific stimuli-triggered drug release mechanism with these delivery systems is one of the most prevalent approaches for improving therapeutic outcomes. Among the various stimuli, pH triggered delivery is regarded as the most general strategy, targeting the acidic extracellular microenvironment and intracellular organelles of solid tumours. In this review, we discuss recent advances in the development of pH-sensitive nanocarriers for tumour-targeted drug delivery. The review focuses on the chemical design of pH-sensitive biomaterials, which are used to fabricate nanocarriers for extracellular and/or intracellular tumour site-specific drug release. The pH-responsive biomaterials bring forth conformational changes in these nanocarriers through various mechanisms such as protonation, charge reversal or cleavage of a chemical bond, facilitating tumour specific cell uptake or drug release. A greater understanding of these mechanisms will help to design more efficient drug delivery systems to address the challenges encountered in conventional chemotherapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

    8. Tumor-targeting delivery of herb-based drugs with cell-penetrating/tumor-targeting peptide-modified nanocarriers.

      Science.gov (United States)

      Kebebe, Dereje; Liu, Yuanyuan; Wu, Yumei; Vilakhamxay, Maikhone; Liu, Zhidong; Li, Jiawei

      2018-01-01

      Cancer has become one of the leading causes of mortality globally. The major challenges of conventional cancer therapy are the failure of most chemotherapeutic agents to accumulate selectively in tumor cells and their severe systemic side effects. In the past three decades, a number of drug delivery approaches have been discovered to overwhelm the obstacles. Among these, nanocarriers have gained much attention for their excellent and efficient drug delivery systems to improve specific tissue/organ/cell targeting. In order to enhance targeting efficiency further and reduce limitations of nanocarriers, nanoparticle surfaces are functionalized with different ligands. Several kinds of ligand-modified nanomedicines have been reported. Cell-penetrating peptides (CPPs) are promising ligands, attracting the attention of researchers due to their efficiency to transport bioactive molecules intracellularly. However, their lack of specificity and in vivo degradation led to the development of newer types of CPP. Currently, activable CPP and tumor-targeting peptide (TTP)-modified nanocarriers have shown dramatically superior cellular specific uptake, cytotoxicity, and tumor growth inhibition. In this review, we discuss recent advances in tumor-targeting strategies using CPPs and their limitations in tumor delivery systems. Special emphasis is given to activable CPPs and TTPs. Finally, we address the application of CPPs and/or TTPs in the delivery of plant-derived chemotherapeutic agents.

    9. The Antibiotic Resistant Target Seeker (ARTS), an exploration engine for antibiotic cluster prioritization and novel drug target discovery

      DEFF Research Database (Denmark)

      Alanjary, Mohammad; Kronmiller, Brent; Adamek, Martina

      2017-01-01

      With the rise of multi-drug resistant pathogens and the decline in number of potential new antibiotics in development there is a fervent need to reinvigorate the natural products discovery pipeline. Most antibiotics are derived from secondary metabolites produced by microorganisms and plants....... To avoid suicide, an antibiotic producer harbors resistance genes often found within the same biosynthetic gene cluster (BGC) responsible for manufacturing the antibiotic. Existing mining tools are excellent at detecting BGCs or resistant genes in general, but provide little help in prioritizing...... and identifying gene clusters for compounds active against specific and novel targets. Here we introduce the 'Antibiotic Resistant Target Seeker' (ARTS) available at https://arts.ziemertlab.com. ARTS allows for specific and efficient genome mining for antibiotics with interesting and novel targets. The aim...

    10. A Tale of Two Drug Targets: The Evolutionary History of BACE1 and BACE2

      Directory of Open Access Journals (Sweden)

      Christopher eSouthan

      2013-12-01

      Full Text Available The beta amyloid (APP cleaving enzyme (BACE1 has been a drug target for Alzheimer's Disease (AD since 1999 with lead inhibitors now entering clinical trials. In 2011, the paralogue, BACE2, became a new target for type II diabetes (T2DM having been identified as a TMEM27 secretase regulating pancreatic β cell function. However, the normal roles of both enzymes are unclear. This study outlines their evolutionary history and new opportunities for functional genomics. We identified 30 homologues (UrBACEs in basal phyla including Placozoans, Cnidarians, Choanoflagellates, Porifera, Echinoderms, Annelids, Mollusks and Ascidians (but not Ecdysozoans. UrBACEs are predominantly single copy, show 35% to 45% protein sequence identity with mammalian BACE1, are approximately 100 residues longer than cathepsin paralogues with an aspartyl protease domain flanked by a signal peptide and a C-terminal transmembrane domain. While multiple paralogues in Trichoplax and Monosiga pre-date the nervous system, duplication of the UrBACE in fish gave rise to BACE1 and BACE2 in the vertebrate lineage. The latter evolved more rapidly as the former maintained the emergent neuronal role. In mammals, Ka/Ks for BACE2 is higher than BACE1 but low ratios for both suggest purifying selection. The 5’ exons show higher Ka/Ks than the catalytic section. Model organism genomes show the absence of certain BACE human substrates when the UrBACE is present. Experiments could thus reveal undiscovered substrates and roles. The human protease double-target status means that evolutionary trajectories and functional shifts associated with different substrates will have implications for the development of clinical candidates for both AD and T2DM. A rational basis for inhibition specificity ratios and assessing target-related side effects will be facilitated by a more complete picture of BACE1 and BACE2 functions informed by their evolutionary context.

    11. Drug-target interaction prediction via class imbalance-aware ensemble learning.

      Science.gov (United States)

      Ezzat, Ali; Wu, Min; Li, Xiao-Li; Kwoh, Chee-Keong

      2016-12-22

      Multiple computational methods for predicting drug-target interactions have been developed to facilitate the drug discovery process. These methods use available data on known drug-target interactions to train classifiers with the purpose of predicting new undiscovered interactions. However, a key challenge regarding this data that has not yet been addressed by these methods, namely class imbalance, is potentially degrading the prediction performance. Class imbalance can be divided into two sub-problems. Firstly, the number of known interacting drug-target pairs is much smaller than that of non-interacting drug-target pairs. This imbalance ratio between interacting and non-interacting drug-target pairs is referred to as the between-class imbalance. Between-class imbalance degrades prediction performance due to the bias in prediction results towards the majority class (i.e. the non-interacting pairs), leading to more prediction errors in the minority class (i.e. the interacting pairs). Secondly, there are multiple types of drug-target interactions in the data with some types having relatively fewer members (or are less represented) than others. This variation in representation of the different interaction types leads to another kind of imbalance referred to as the within-class imbalance. In within-class imbalance, prediction results are biased towards the better represented interaction types, leading to more prediction errors in the less represented interaction types. We propose an ensemble learning method that incorporates techniques to address the issues of between-class imbalance and within-class imbalance. Experiments show that the proposed method improves results over 4 state-of-the-art methods. In addition, we simulated cases for new drugs and targets to see how our method would perform in predicting their interactions. New drugs and targets are those for which no prior interactions are known. Our method displayed satisfactory prediction performance and was

    12. Identifying co-targets to fight drug resistance based on a random walk model

      Directory of Open Access Journals (Sweden)

      Chen Liang-Chun

      2012-01-01

      Full Text Available Abstract Background Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. Results We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. Conclusions With gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance.

    13. Riboswitches: discovery of drugs that target bacterial gene-regulatory RNAs

      Science.gov (United States)

      Deigan, Katherine E.; Ferré-D’Amaré, Adrian R.

      2011-01-01

      Conspectus Riboswitches, which were discovered in the first years of the XXI century, are gene-regulatory mRNA domains that respond to the intracellular concentration of a variety of metabolites and second messengers. They control essential genes in many pathogenic bacteria, and represent a new class of biomolecular target for the development of antibiotics and chemical-biological tools. Five mechanisms of gene regulation are known for riboswitches. Most bacterial riboswitches modulate transcription termination or translation initiation in response to ligand binding. All known examples of eukaryotic riboswitches and some bacterial riboswitches control gene expression by alternative splicing. The glmS riboswitch, widespread in Gram-positive bacteria, is a catalytic RNA activated by ligand binding. Its self-cleavage destabilizes the mRNA of which it is part. Finally, one example of trans-acting riboswitch is known. Three-dimensional (3D) structures have been determined of representatives of thirteen structurally distinct riboswitch classes, providing atomic-level insight into their mechanisms of ligand recognition. While cellular and viral RNAs in general have attracted interest as potential drug targets, riboswitches show special promise due to the diversity and sophistication of small molecule recognition strategies on display in their ligand binding pockets. Moreover, uniquely among known structured RNA domains, riboswitches evolved to recognize small molecule ligands. Structural and biochemical advances in the study of riboswitches provide an impetus for the development of methods for the discovery of novel riboswitch activators and inhibitors. Recent rational drug design efforts focused on select riboswitch classes have yielded a small number of candidate antibiotic compounds, including one active in a mouse model of Staphylococcus aureus infection. The development of high-throughput methods suitable for riboswitch-specific drug discovery is ongoing. A fragment

    14. HIV Model Parameter Estimates from Interruption Trial Data including Drug Efficacy and Reservoir Dynamics

      Science.gov (United States)

      Luo, Rutao; Piovoso, Michael J.; Martinez-Picado, Javier; Zurakowski, Ryan

      2012-01-01

      Mathematical models based on ordinary differential equations (ODE) have had significant impact on understanding HIV disease dynamics and optimizing patient treatment. A model that characterizes the essential disease dynamics can be used for prediction only if the model parameters are identifiable from clinical data. Most previous parameter identification studies for HIV have used sparsely sampled data from the decay phase following the introduction of therapy. In this paper, model parameters are identified from frequently sampled viral-load data taken from ten patients enrolled in the previously published AutoVac HAART interruption study, providing between 69 and 114 viral load measurements from 3–5 phases of viral decay and rebound for each patient. This dataset is considerably larger than those used in previously published parameter estimation studies. Furthermore, the measurements come from two separate experimental conditions, which allows for the direct estimation of drug efficacy and reservoir contribution rates, two parameters that cannot be identified from decay-phase data alone. A Markov-Chain Monte-Carlo method is used to estimate the model parameter values, with initial estimates obtained using nonlinear least-squares methods. The posterior distributions of the parameter estimates are reported and compared for all patients. PMID:22815727

    15. Drug Targets for Cardiovascular-Safe Anti-Inflammatory: In Silico Rational Drug Studies.

      Directory of Open Access Journals (Sweden)

      Sajad Shahbazi

      Full Text Available Cyclooxygenase-2 (COX-2 plays an important role in memory consolidation and synaptic activity, the most fundamental functions of the brain. It converts arachidonic acid to prostaglandin endoperoxide H2. In contrast, if over-expressed, it causes inflammation in response to cytokine, pro-inflammatory molecule, and growth factor. Anti-inflammatory agents, by allosteric or competitive inhibition of COX-2, alleviate the symptoms of inflammation. Coxib family drugs, particularly celecoxib, are the most famous anti-inflammatory agents available in the market showing significant inhibitory effect on COX-2 activity. Due to high cardiovascular risk of this drug group, recent researches are focused on the investigation of new safer drugs for anti-inflammatory diseases. Natural compounds, particularly, phytochemicals are found to be good candidates for drug designing and discovery. In the present study, we performed in silico studies to quantitatively scrutinize the molecular interaction of curcumin and its structural analogs with COX-2, COX-1, FXa and integrin αIIbβIII to investigate their therapeutic potential as a cardiovascular-safe anti-inflammatory medicine (CVSAIM. The results of both ADMET and docking study indicated that out of all the 39 compounds studied, caffeic acid had remarkable interaction with proteins involved in inflammatory response. It was also found to inhibit the proteins that are involved in thrombosis, thereby, having the potential to be developed as therapeutic agent.

    16. Multifunctional Polymer Nanoparticles for Dual Drug Release and Cancer Cell Targeting

      Directory of Open Access Journals (Sweden)

      Yu-Han Wen

      2017-06-01

      Full Text Available Multifunctional polymer nanoparticles have been developed for cancer treatment because they could be easily designed to target cancer cells and to enhance therapeutic efficacy according to cancer hallmarks. In this study, we synthesized a pH-sensitive polymer, poly(methacrylic acid-co-histidine/doxorubicin/biotin (HBD in which doxorubicin (DOX was conjugated by a hydrazone bond to encapsulate an immunotherapy drug, imiquimod (IMQ, to form dual cancer-targeting and dual drug-loaded nanoparticles. At low pH, polymeric nanoparticles could disrupt and simultaneously release DOX and IMQ. Our experimental results show that the nanoparticles exhibited pH-dependent drug release behavior and had an ability to target cancer cells via biotin and protonated histidine.

    17. Drug Target Optimization in Chronic Myeloid Leukemia Using Innovative Computational Platform

      Science.gov (United States)

      Chuang, Ryan; Hall, Benjamin A.; Benque, David; Cook, Byron; Ishtiaq, Samin; Piterman, Nir; Taylor, Alex; Vardi, Moshe; Koschmieder, Steffen; Gottgens, Berthold; Fisher, Jasmin

      2015-02-01

      Chronic Myeloid Leukemia (CML) represents a paradigm for the wider cancer field. Despite the fact that tyrosine kinase inhibitors have established targeted molecular therapy in CML, patients often face the risk of developing drug resistance, caused by mutations and/or activation of alternative cellular pathways. To optimize drug development, one needs to systematically test all possible combinations of drug targets within the genetic network that regulates the disease. The BioModelAnalyzer (BMA) is a user-friendly computational tool that allows us to do exactly that. We used BMA to build a CML network-model composed of 54 nodes linked by 104 interactions that encapsulates experimental data collected from 160 publications. While previous studies were limited by their focus on a single pathway or cellular process, our executable model allowed us to probe dynamic interactions between multiple pathways and cellular outcomes, suggest new combinatorial therapeutic targets, and highlight previously unexplored sensitivities to Interleukin-3.

    18. Progress and Challenges in Developing Aptamer-Functionalized Targeted Drug Delivery Systems

      Directory of Open Access Journals (Sweden)

      Feng Jiang

      2015-10-01

      Full Text Available Aptamers, which can be screened via systematic evolution of ligands by exponential enrichment (SELEX, are superior ligands for molecular recognition due to their high selectivity and affinity. The interest in the use of aptamers as ligands for targeted drug delivery has been increasing due to their unique advantages. Based on their different compositions and preparation methods, aptamer-functionalized targeted drug delivery systems can be divided into two main categories: aptamer-small molecule conjugated systems and aptamer-nanomaterial conjugated systems. In this review, we not only summarize recent progress in aptamer selection and the application of aptamers in these targeted drug delivery systems but also discuss the advantages, challenges and new perspectives associated with these delivery systems.

    19. Nanotechnology-based drug delivery treatments and specific targeting therapy for age-related macular degeneration

      Directory of Open Access Journals (Sweden)

      Tai-Chi Lin

      2015-11-01

      Full Text Available Nanoparticles combined with cells, drugs, and specially designed genes provide improved therapeutic efficacy in studies and clinical setting, demonstrating a new era of treatment strategy, especially in retinal diseases. Nanotechnology-based drugs can provide an essential platform for sustaining, releasing and a specific targeting design to treat retinal diseases. Poly-lactic-co-glycolic acid is the most widely used biocompatible and biodegradable polymer approved by the Food and Drug Administration. Many studies have attempted to develop special devices for delivering small-molecule drugs, proteins, and other macromolecules consistently and slowly. In this article, we first review current progress in the treatment of age-related macular degeneration. Then, we discuss the function of vascular endothelial growth factor (VEGF and the pharmacological effects of anti-VEGF-A antibodies and soluble or modified VEGF receptors. Lastly, we summarize the combination of antiangiogenic therapy and nanomedicines, and review current potential targeting therapy in age-related macular degeneration.

    20. Iontophoresis of minoxidil sulphate loaded microparticles, a strategy for follicular drug targeting?

      Science.gov (United States)

      Gelfuso, Guilherme M; Barros, M Angélica de Oliveira; Delgado-Charro, M Begoña; Guy, Richard H; Lopez, Renata F V

      2015-10-01

      The feasibility of targeting drugs to hair follicles by a combination of microencapsulation and iontophoresis has been evaluated. Minoxidil sulphate (MXS), which is used in the treatment of alopecia, was selected as a relevant drug with respect to follicular penetration. The skin permeation and disposition of MXS encapsulated in chitosan microparticles (MXS-MP) was evaluated in vitro after passive and iontophoretic delivery. Uptake of MXS was quantified at different exposure times in the stratum corneum (SC) and hair follicles. Microencapsulation resulted in increased (6-fold) drug accumulation in the hair follicles relative to delivery from a simple MXS solution. Application of iontophoresis enhanced follicular delivery for both the solution and the microparticle formulations. It appears, therefore, that microencapsulation and iontophoresis can act synergistically to enhance topical drug targeting to hair follicles. Copyright © 2015 Elsevier B.V. All rights reserved.

    1. To neither target, capture, surveille, nor wage war: On-going need for attention to metaphor theory in care and prevention for people who use drugs.

      Science.gov (United States)

      Perlman, David C; Jordan, Ashly E

      2017-01-01

      Metaphors, and the frames they evoke, potently influence how people understand issues. These concepts of discourse, metaphor, and framing have been productively used in a range of studies including in the field of addiction. In public health and clinical discourse on people who use drugs, use of terms such as "targeting," "surveilling," and "capturing," along with "war on drugs" frames and referring to drug treatment as "substitution" may reinforce negative perceptions of people who use drugs. Avoiding military metaphors and explicitly leveraging metaphors that emphasize humanity, social cohesion, and agency have the potential to improve public health for people who use drugs.

    2. Studies in Multifunctional Drug Development: Preparation and Evaluation of 11beta-Substituted Estradiol-Drug Conjugates, Cell Membrane Targeting Imaging Agents, and Target Multifunctional Nanoparticles

      Science.gov (United States)

      Dao, KinhLuan Lenny D.

      Cancer is the second leading cause of death after cardiovascular disease in the United State. Despite extensive research in development of antitumor drugs, most of these therapeutic entities often possess nonspecific toxicity, thus they can only be used to treat tumors in higher doses or more frequently. Because of the cytotoxicity and severe side effects, the drug therapeutic window normally is limited. Beside the toxicity issue, antitumor drug are also not selectively taken up by tumor cells, thus the necessitating concentrations that would eradicate the tumor can often not be used. In addition, tumor cells tend to develop resistance against the anticancer drugs after prolonged treatment. Therefore, alleviating the systemic cytotoxicity and side effects, improving in tumor selectivity, high potency, and therapeutic efficacy are still major obstacles in the area of anticancer drug development. A more promising approach for developing a selective agent for cancer is to conjugate a potent therapeutic drug, or an imaging agent with a targeting group, such as antibody or a high binding-specificity small molecule, that selectively recognize the overexpressed antigens or proteins on tumor cells. My research combines several approaches to describe this strategy via using different targeting molecules to different diseases, as well as different potent cytotoxic drugs for different therapies. Three studies related to the preparation and biological evaluation of new therapeutic agents, such as estradiol-drug hybrids, cell membrane targeted molecular imaging agents, and multifunctional NPs will be discussed. The preliminary results of these studies indicated that our new reagents achieved their initial objectives and can be further improved for optimized synthesis and in vivo experiments. The first study describes the method in which we employed a modular assembly approach to synthesize a novel 11beta-substituted steroidal anti-estrogen. The key intermediate was synthesized

    3. Development of New Drugs for an Old Target — The Penicillin Binding Proteins

      Directory of Open Access Journals (Sweden)

      André Luxen

      2012-10-01

      Full Text Available The widespread use of β-lactam antibiotics has led to the worldwide appearance of drug-resistant strains. Bacteria have developed resistance to β-lactams by two main mechanisms: the production of β-lactamases, sometimes accompanied by a decrease of outer membrane permeability, and the production of low-affinity, drug resistant Penicillin Binding Proteins (PBPs. PBPs remain attractive targets for developing new antibiotic agents because they catalyse the last steps of the biosynthesis of peptidoglycan, which is unique to bacteria, and lies outside the cytoplasmic membrane. Here we summarize the “current state of the art” of non-β-lactam inhibitors of PBPs, which have being developed in an attempt to counter the emergence of β-lactam resistance. These molecules are not susceptible to hydrolysis by β-lactamases and thus present a real alternative to β-lactams. We present transition state analogs such as boronic acids, which can covalently bind to the active serine residue in the catalytic site. Molecules containing ring structures different from the β-lactam-ring like lactivicin are able to acylate the active serine residue. High throughput screening methods, in combination with virtual screening methods and structure based design, have allowed the development of new molecules. Some of these novel inhibitors are active against major pathogens, including methicillin-resistant Staphylococcus aureus (MRSA and thus open avenues new for the discovery of novel antibiotics.

    4. CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM.

      Directory of Open Access Journals (Sweden)

      Anjan Debnath

      2017-12-01

      Full Text Available Primary Amoebic Meningoencephalitis (PAM is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (but likely underreported the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug 'repurposing'-a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51 target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially 'druggable' target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM.

    5. CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)

      Science.gov (United States)

      Debnath, Anjan; Calvet, Claudia M.; Aksenov, Alexander; Abagyan, Ruben; Nes, W. David; McKerrow, James H.

      2017-01-01

      Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered “rare” (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug ‘repurposing’—a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially ‘druggable’ target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM. PMID:29284029

    6. CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM).

      Science.gov (United States)

      Debnath, Anjan; Calvet, Claudia M; Jennings, Gareth; Zhou, Wenxu; Aksenov, Alexander; Luth, Madeline R; Abagyan, Ruben; Nes, W David; McKerrow, James H; Podust, Larissa M

      2017-12-01

      Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug 'repurposing'-a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially 'druggable' target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM.

    7. Pluronic F127 nanomicelles engineered with nuclear localized functionality for targeted drug delivery

      International Nuclear Information System (INIS)

      Li, Yong-Yong; Li, Lan; Dong, Hai-Qing; Cai, Xiao-Jun; Ren, Tian-Bin

      2013-01-01

      PKKKRKV (Pro-Lys-Lys-Lys-Arg-Lys-Val, PV7), a seven amino acid peptide, has emerged as one of the primary nuclear localization signals that can be targeted into cell nucleus via the nuclear import machinery. Taking advantage of chemical diversity and biological activities of this short peptide sequence, in this study, Pluronic F127 nanomicelles engineered with nuclear localized functionality were successfully developed for intracellular drug delivery. These nanomicelles with the size ∼ 100 nm were self-assembled from F127 polymer that was flanked with two PV7 sequences at its both terminal ends. Hydrophobic anticancer drug doxorubicin (DOX) with inherent fluorescence was chosen as the model drug, which was found to be efficiently encapsulated into nanomicelles with the encapsulation efficiency at 72.68%. In comparison with the non-functionalized namomicelles, the microscopic observation reveals that PV7 functionalized nanomicelles display a higher cellular uptake, especially into the nucleus of HepG2 cells, due to the nuclear localization signal effects. Both cytotoxicity and apoptosis studies show that the DOX-loaded nanomicelles were more potent than drug nanomicelles without nuclear targeting functionality. It was thus concluded that PV7 functionalized nanomicelles could be a potentially alternative vehicle for nuclear targeting drug delivery. - Highlights: ► A new nuclear targeted drug delivery system based on micelles is developed. ► This micellar system features a core-shell structure with the size peaked at 100 nm. ► PV7, a short peptide sequence, is adopted as a nuclear targeting ligand. ► PV7 functionalized drug loaded micelles are more potent in killing tumor cells

    8. Drug-target interaction prediction using ensemble learning and dimensionality reduction.

      Science.gov (United States)

      Ezzat, Ali; Wu, Min; Li, Xiao-Li; Kwoh, Chee-Keong

      2017-10-01

      Experimental prediction of drug-target interactions is expensive, time-consuming and tedious. Fortunately, computational methods help narrow down the search space for interaction candidates to be further examined via wet-lab techniques. Nowadays, the number of attributes/features for drugs and targets, as well as the amount of their interactions, are increasing, making these computational methods inefficient or occasionally prohibitive. This motivates us to derive a reduced feature set for prediction. In addition, since ensemble learning techniques are widely used to improve the classification performance, it is also worthwhile to design an ensemble learning framework to enhance the performance for drug-target interaction prediction. In this paper, we propose a framework for drug-target interaction prediction leveraging both feature dimensionality reduction and ensemble learning. First, we conducted feature subspacing to inject diversity into the classifier ensemble. Second, we applied three different dimensionality reduction methods to the subspaced features. Third, we trained homogeneous base learners with the reduced features and then aggregated their scores to derive the final predictions. For base learners, we selected two classifiers, namely Decision Tree and Kernel Ridge Regression, resulting in two variants of ensemble models, EnsemDT and EnsemKRR, respectively. In our experiments, we utilized AUC (Area under ROC Curve) as an evaluation metric. We compared our proposed methods with various state-of-the-art methods under 5-fold cross validation. Experimental results showed EnsemKRR achieving the highest AUC (94.3%) for predicting drug-target interactions. In addition, dimensionality reduction helped improve the performance of EnsemDT. In conclusion, our proposed methods produced significant improvements for drug-target interaction prediction. Copyright © 2017 Elsevier Inc. All rights reserved.

    9. Simulating Serial-Target Antibacterial Drug Synergies Using Flux Balance Analysis

      DEFF Research Database (Denmark)

      Krueger, Andrew S.; Munck, Christian; Dantas, Gautam

      2016-01-01

      Flux balance analysis (FBA) is an increasingly useful approach for modeling the behavior of metabolic systems. However, standard FBA modeling of genetic knockouts cannot predict drug combination synergies observed between serial metabolic targets, even though such synergies give rise to some...... the possibility for more accurate genome-scale predictions of drug synergies, which can be used to suggest treatments for infections and other diseases....

    10. Drug Target Identification and Elucidation of Natural Inhibitors for : An Study

      Directory of Open Access Journals (Sweden)

      Surya Narayan Rath

      2016-12-01

      Full Text Available Environmental microbes like Bordetella petrii has been established as a causative agent for various infectious diseases in human. Again, development of drug resistance in B. petrii challenged to combat against the infection. Identification of potential drug target and proposing a novel lead compound against the pathogen has a great aid and value. In this study, bioinformatics tools and technology have been applied to suggest a potential drug target by screening the proteome information of B. petrii DSM 12804 (accession No. PRJNA28135 from genome database of National Centre for Biotechnology information. In this regards, the inhibitory effect of nine natural compounds like ajoene (Allium sativum, allicin (A. sativum, cinnamaldehyde (Cinnamomum cassia, curcumin (Curcuma longa, gallotannin (active component of green tea and red wine, isoorientin (Anthopterus wardii, isovitexin (A. wardii, neral (Melissa officinalis, and vitexin (A. wardii have been acknowledged with anti-bacterial properties and hence tested against identified drug target of B. petrii by implicating computational approach. The in silico studies revealed the hypothesis that lpxD could be a potential drug target and with recommendation of a strong inhibitory effect of selected natural compounds against infection caused due to B. petrii, would be further validated through in vitro experiments.

    11. The Proteomics Big Challenge for Biomarkers and New Drug-Targets Discovery

      Science.gov (United States)

      Savino, Rocco; Paduano, Sergio; Preianò, Mariaimmacolata; Terracciano, Rosa

      2012-01-01

      In the modern process of drug discovery, clinical, functional and chemical proteomics can converge and integrate synergies. Functional proteomics explores and elucidates the components of pathways and their interactions which, when deregulated, lead to a disease condition. This knowledge allows the design of strategies to target multiple pathways with combinations of pathway-specific drugs, which might increase chances of success and reduce the occurrence of drug resistance. Chemical proteomics, by analyzing the drug interactome, strongly contributes to accelerate the process of new druggable targets discovery. In the research area of clinical proteomics, proteome and peptidome mass spectrometry-profiling of human bodily fluid (plasma, serum, urine and so on), as well as of tissue and of cells, represents a promising tool for novel biomarker and eventually new druggable targets discovery. In the present review we provide a survey of current strategies of functional, chemical and clinical proteomics. Major issues will be presented for proteomic technologies used for the discovery of biomarkers for early disease diagnosis and identification of new drug targets. PMID:23203042

    12. Magnetic graphene oxide as a carrier for targeted delivery of chemotherapy drugs in cancer therapy

      Energy Technology Data Exchange (ETDEWEB)

      Huang, Ya-Shu [Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan, ROC (China); Lu, Yu-Jen [Department of Neurosurgery, Chang Gung Memorial Hospital, Kwei-San, Taoyuan 33305, Taiwan, ROC (China); Chen, Jyh-Ping, E-mail: jpchen@mail.cgu.edu.tw [Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan, ROC (China); Department of Plastic and Reconstructive Surgery and Craniofacial Research Center, Chang Gung Memorial Hospital, Kwei-San, Taoyuan 33305, Taiwan, ROC (China); Graduate Institute of Health Industry and Technology, Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kwei-San, Taoyuan 33302, Taiwan, ROC (China); Department of Materials Engineering, Ming Chi University of Technology, Tai-Shan, New Taipei City 24301, Taiwan, ROC (China)

      2017-04-01

      A magnetic targeted functionalized graphene oxide (GO) complex is constituted as a nanocarrier for targeted delivery and pH-responsive controlled release of chemotherapy drugs to cancer cells. Magnetic graphene oxide (mGO) was prepared by chemical co-precipitation of Fe{sub 3}O{sub 4} magnetic nanoparticles on GO nano-platelets. The mGO was successively modified by chitosan and mPEG-NHS through covalent bindings to synthesize mGOC-PEG. The polyethylene glycol (PEG) moiety is expected to prolong the circulation time of mGO by reducing the reticuloendothelial system clearance. Irinotecan (CPT-11) or doxorubicin (DOX) was loaded to mGOC-PEG through π-π stacking interactions for magnetic targeted delivery of the cancer chemotherapy drug. The best values of loading efficiency and loading content of CPT-11 were 54% and 2.7% respectively; whereas for DOX, they were 65% and 393% The pH-dependent drug release profile was further experimented at different pHs, in which ~60% of DOX was released at pH 5.4 and ~10% was released at pH 7.4. In contrast, ~90% CPT-11 was released at pH 5.4 and ~70% at pH 7.4. Based on the drug loading and release characteristics, mGOC-PEG/DOX was further chosen for in vitro cytotoxicity tests against U87 human glioblastoma cell line. The IC50 value of mGOC-PEG/DOX was found to be similar to that of free DOX but was reduced dramatically when subject to magnetic targeting. It is concluded that with the high drug loading and pH-dependent drug release properties, mGOC-PEG will be a promising drug carrier for targeted delivery of chemotherapy drugs in cancer therapy. - Highlights: • mGO was prepared by chemical co-precipitation of Fe{sub 3}O{sub 4} MNP on GO nano-platelets. • mGO was further modified by chitosan and mPEG-NHS to synthesize mGOC-PEG. • mGOC-PEG showed higher drug loading of doxorubicin (DOX) than irinotecan. • mGOC-PEG showed pH-responsive controlled release of chemotherapy drugs. • Magnetic targeting enhanced cytotoxicity of

    13. Magnetic graphene oxide as a carrier for targeted delivery of chemotherapy drugs in cancer therapy

      International Nuclear Information System (INIS)

      Huang, Ya-Shu; Lu, Yu-Jen; Chen, Jyh-Ping

      2017-01-01

      A magnetic targeted functionalized graphene oxide (GO) complex is constituted as a nanocarrier for targeted delivery and pH-responsive controlled release of chemotherapy drugs to cancer cells. Magnetic graphene oxide (mGO) was prepared by chemical co-precipitation of Fe 3 O 4 magnetic nanoparticles on GO nano-platelets. The mGO was successively modified by chitosan and mPEG-NHS through covalent bindings to synthesize mGOC-PEG. The polyethylene glycol (PEG) moiety is expected to prolong the circulation time of mGO by reducing the reticuloendothelial system clearance. Irinotecan (CPT-11) or doxorubicin (DOX) was loaded to mGOC-PEG through π-π stacking interactions for magnetic targeted delivery of the cancer chemotherapy drug. The best values of loading efficiency and loading content of CPT-11 were 54% and 2.7% respectively; whereas for DOX, they were 65% and 393% The pH-dependent drug release profile was further experimented at different pHs, in which ~60% of DOX was released at pH 5.4 and ~10% was released at pH 7.4. In contrast, ~90% CPT-11 was released at pH 5.4 and ~70% at pH 7.4. Based on the drug loading and release characteristics, mGOC-PEG/DOX was further chosen for in vitro cytotoxicity tests against U87 human glioblastoma cell line. The IC50 value of mGOC-PEG/DOX was found to be similar to that of free DOX but was reduced dramatically when subject to magnetic targeting. It is concluded that with the high drug loading and pH-dependent drug release properties, mGOC-PEG will be a promising drug carrier for targeted delivery of chemotherapy drugs in cancer therapy. - Highlights: • mGO was prepared by chemical co-precipitation of Fe 3 O 4 MNP on GO nano-platelets. • mGO was further modified by chitosan and mPEG-NHS to synthesize mGOC-PEG. • mGOC-PEG showed higher drug loading of doxorubicin (DOX) than irinotecan. • mGOC-PEG showed pH-responsive controlled release of chemotherapy drugs. • Magnetic targeting enhanced cytotoxicity of m

    14. Colon-targeted oral drug delivery systems: design trends and approaches.

      Science.gov (United States)

      Amidon, Seth; Brown, Jack E; Dave, Vivek S

      2015-08-01

      Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.

    15. Crowd Sourcing a New Paradigm for Interactome Driven Drug Target Identification in Mycobacterium tuberculosis

      Science.gov (United States)

      Rohira, Harsha; Bhat, Ashwini G.; Passi, Anurag; Mukherjee, Keya; Choudhary, Kumari Sonal; Kumar, Vikas; Arora, Anshula; Munusamy, Prabhakaran; Subramanian, Ahalyaa; Venkatachalam, Aparna; S, Gayathri; Raj, Sweety; Chitra, Vijaya; Verma, Kaveri; Zaheer, Salman; J, Balaganesh; Gurusamy, Malarvizhi; Razeeth, Mohammed; Raja, Ilamathi; Thandapani, Madhumohan; Mevada, Vishal; Soni, Raviraj; Rana, Shruti; Ramanna, Girish Muthagadhalli; Raghavan, Swetha; Subramanya, Sunil N.; Kholia, Trupti; Patel, Rajesh; Bhavnani, Varsha; Chiranjeevi, Lakavath; Sengupta, Soumi; Singh, Pankaj Kumar; Atray, Naresh; Gandhi, Swati; Avasthi, Tiruvayipati Suma; Nisthar, Shefin; Anurag, Meenakshi; Sharma, Pratibha; Hasija, Yasha; Dash, Debasis; Sharma, Arun; Scaria, Vinod; Thomas, Zakir; Chandra, Nagasuma; Brahmachari, Samir K.; Bhardwaj, Anshu

      2012-01-01

      A decade since the availability of Mycobacterium tuberculosis (Mtb) genome sequence, no promising drug has seen the light of the day. This not only indicates the challenges in discovering new drugs but also suggests a gap in our current understanding of Mtb biology. We attempt to bridge this gap by carrying out extensive re-annotation and constructing a systems level protein interaction map of Mtb with an objective of finding novel drug target candidates. Towards this, we synergized crowd sourcing and social networking methods through an initiative ‘Connect to Decode’ (C2D) to generate the first and largest manually curated interactome of Mtb termed ‘interactome pathway’ (IPW), encompassing a total of 1434 proteins connected through 2575 functional relationships. Interactions leading to gene regulation, signal transduction, metabolism, structural complex formation have been catalogued. In the process, we have functionally annotated 87% of the Mtb genome in context of gene products. We further combine IPW with STRING based network to report central proteins, which may be assessed as potential drug targets for development of drugs with least possible side effects. The fact that five of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lends credence to our unique approach. PMID:22808064

    16. Repurposed FDA-approved drugs targeting genes influencing aging can extend lifespan and healthspan in rotifers.

      Science.gov (United States)

      Snell, Terry W; Johnston, Rachel K; Matthews, Amelia B; Zhou, Hongyi; Gao, Mu; Skolnick, Jeffrey

      2018-04-01

      Pharmaceutical interventions can slow aging in animals, and have advantages because their dose can be tightly regulated and the timing of the intervention can be closely controlled. They also may complement environmental interventions like caloric restriction by acting additively. A fertile source for therapies slowing aging is FDA approved drugs whose safety has been investigated. Because drugs bind to several protein targets, they cause multiple effects, many of which have not been characterized. It is possible that some of the side effects of drugs prescribed for one therapy may have benefits in retarding aging. We used computationally guided drug screening for prioritizing drug targets to produce a short list of candidate compounds for in vivo testing. We applied the virtual ligand screening approach FINDSITE comb for screening potential anti-aging protein targets against FDA approved drugs listed in DrugBank. A short list of 31 promising compounds was screened using a multi-tiered approach with rotifers as an animal model of aging. Primary and secondary survival screens and cohort life table experiments identified four drugs capable of extending rotifer lifespan by 8-42%. Exposures to 1 µM erythromycin, 5 µM carglumic acid, 3 µM capecitabine, and 1 µM ivermectin, extended rotifer lifespan without significant effect on reproduction. Some drugs also extended healthspan, as estimated by mitochondria activity and mobility (swimming speed). Our most promising result is that rotifer lifespan was extended by 7-8.9% even when treatment was started in middle age.

    17. Open-source chemogenomic data-driven algorithms for predicting drug-target interactions.

      Science.gov (United States)

      Hao, Ming; Bryant, Stephen H; Wang, Yanli

      2018-02-06

      While novel technologies such as high-throughput screening have advanced together with significant investment by pharmaceutical companies during the past decades, the success rate for drug development has not yet been improved prompting researchers looking for new strategies of drug discovery. Drug repositioning is a potential approach to solve this dilemma. However, experimental identification and validation of potential drug targets encoded by the human genome is both costly and time-consuming. Therefore, effective computational approaches have been proposed to facilitate drug repositioning, which have proved to be successful in drug discovery. Doubtlessly, the availability of open-accessible data from basic chemical biology research and the success of human genome sequencing are crucial to develop effective in silico drug repositioning methods allowing the identification of potential targets for existing drugs. In this work, we review several chemogenomic data-driven computational algorithms with source codes publicly accessible for predicting drug-target interactions (DTIs). We organize these algorithms by model properties and model evolutionary relationships. We re-implemented five representative algorithms in R programming language, and compared these algorithms by means of mean percentile ranking, a new recall-based evaluation metric in the DTI prediction research field. We anticipate that this review will be objective and helpful to researchers who would like to further improve existing algorithms or need to choose appropriate algorithms to infer potential DTIs in the projects. The source codes for DTI predictions are available at: https://github.com/minghao2016/chemogenomicAlg4DTIpred. Published by Oxford University Press 2018. This work is written by US Government employees and is in the public domain in the US.

    18. Hydrogels synthesised through photoinitiator-free photopolymerisation technique for delivering drugs including a tumour-tracing porphyrin

      International Nuclear Information System (INIS)

      Ng, Loo-Teck; Swami, Salesh; Gordon-Thomson, Clare

      2006-01-01

      Hydrogels were synthesised using the photoinitiator-free photopolymerisation technique involving interactions between donor/acceptor pairs for delivering drugs of different molecular weights including a porphyrin used as a tumour-tracing agent. N-(5-hydroxy) pentylmaleimide, an acceptor, formed hydrogels with N-vinyl-2-pyrrolidinone, 2-hydroxyethyl methacrylate and N-vinylcaprolactum. Glucosamine, an effective H-donor in enhancing polymerisation as shown by Differential Photocalorimetric results, was found unsuitable for hydrogel preparation. Drugs of different molecular weights releasing at the same rate was discussed. The hydrogels were found to have no toxic effects and were biocompatible with a human keratinocyte cell line

    19. ACHIEVEMENT OF TARGET BLOOD PRESSURE LEVEL IN HYPERTENSIVE PATIENTS WITH AMLODIDINE: ORIGINAL DRUG VERSUS GENERIC

      Directory of Open Access Journals (Sweden)

      S. Yu. Martsevich

      2016-01-01

      Full Text Available Aim. To evaluate antihypertensive effects of new generic amlodipine (Stamlo M in comparison with original amlodipine (Norvasc in monotherapy and in combination with angiotensin converting enzyme (ACE inhibitor and diuretic in patients with arterial hypertension (HT of 1-2 degree.Material and methods. 60 patients with HT of 1-2 degree were included in the open randomized parallel comparative study. Patients were split into 2 groups. Study duration was 10 weeks. Efficacy control, dose correction, addition of ACE inhibitor and diuretic was performed each 2 weeks.Results. The significant antihypertensive effect of monotherapy was observed in both groups already by the 2-4 weeks of therapy. Significant differences between amlodipines in influence on blood pressure (BP level and heart rate was not found. Monotherapy with generic amlodipine (10 mg OD provided target BP level more than in half of patients. Achievement of target BP levels was found in 89% and 96% of patients treated with generic and original amlodipine, respectively, when they were combined with lisinopril (10 mg OD and hydrochlorothiazide (12,5 mg OD.Conclusion. New generic amlodipine (Stamlo M is an effective and safe antihypertensive drug comparable with original amlodipine in clinical efficacy.

    20. Guidelines to PET measurements of the target occupancy in the brain for drug development

      Energy Technology Data Exchange (ETDEWEB)

      Takano, Akihiro; Varrone, Andrea; Gulyas, Balazs; Halldin, Christer [Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Stockholm (Sweden); Salvadori, Piero [CNR Istituto di Fisiologia Clinica, Pisa (Italy); Gee, Antony [Kings College London, Department of Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); Windhorst, Albert; Lammertsma, Adriaan A. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Vercouillie, Johnny [Universite Francois Rabelais de Tours, UMR Inserm U930, Tours (France); Bormans, Guy [KU Leuven, Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, Leuven (Belgium)

      2016-11-15

      This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations. (orig.)

    1. Combined targeting of STAT3 and STAT5: a novel approach to overcome drug resistance in chronic myeloid leukemia

      Science.gov (United States)

      Gleixner, Karoline V.; Schneeweiss, Mathias; Eisenwort, Gregor; Berger, Daniela; Herrmann, Harald; Blatt, Katharina; Greiner, Georg; Byrgazov, Konstantin; Hoermann, Gregor; Konopleva, Marina; Waliul, Islam; Cumaraswamy, Abbarna A.; Gunning, Patrick T.; Maeda, Hiroshi; Moriggl, Richard; Deininger, Michael; Lion, Thomas; Andreeff, Michael; Valent, Peter

      2017-01-01

      In chronic myeloid leukemia, resistance against BCR-ABL1 tyrosine kinase inhibitors can develop because of BCR-ABL1 mutations, activation of additional pro-oncogenic pathways, and stem cell resistance. Drug combinations covering a broad range of targets may overcome resistance. CDDO-Me (bardoxolone methyl) is a drug that inhibits the survival of leukemic cells by targeting different pro-survival molecules, including STAT3. We found that CDDO-Me inhibits proliferation and survival of tyrosine kinase inhibitor-resistant BCR-ABL1+ cell lines and primary leukemic cells, including cells harboring BCR-ABL1T315I or T315I+ compound mutations. Furthermore, CDDO-Me was found to block growth and survival of CD34+/CD38− leukemic stem cells (LSC). Moreover, CDDO-Me was found to produce synergistic growth-inhibitory effects when combined with BCR-ABL1 tyrosine kinase inhibitors. These drug-combinations were found to block multiple signaling cascades and molecules, including STAT3 and STAT5. Furthermore, combined targeting of STAT3 and STAT5 by shRNA and STAT5-targeting drugs also resulted in synergistic growth-inhibition, pointing to a new efficient concept of combinatorial STAT3 and STAT5 inhibition. However, CDDO-Me was also found to increase the expression of heme-oxygenase-1, a heat-shock-protein that triggers drug resistance and cell survival. We therefore combined CDDO-Me with the heme-oxygenase-1 inhibitor SMA-ZnPP, which also resulted in synergistic growth-inhibitory effects. Moreover, SMA-ZnPP was found to sensitize BCR-ABL1+ cells against the combination ‘CDDO-Me+ tyrosine kinase inhibitor’. Together, combined targeting of STAT3, STAT5, and heme-oxygenase-1 overcomes resistance in BCR-ABL1+ cells, including stem cells and highly resistant sub-clones expressing BCR-ABL1T315I or T315I-compound mutations. Whether such drug-combinations are effective in tyrosine kinase inhibitor-resistant patients with chronic myeloid leukemia remains to be elucidated. PMID:28596283

    2. Effective treatment of glioblastoma requires crossing the blood–brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine

      Science.gov (United States)

      Kim, Sang-Soo; Harford, Joe B.; Pirollo, Kathleen F.; Chang, Esther H.

      2015-01-01

      Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Both therapeutic resistance and restricted permeation of drugs across the blood–brain barrier (BBB) play a major role in the poor prognosis of GBM patients. Accumulated evidence suggests that in many human cancers, including GBM, therapeutic resistance can be attributed to a small fraction of cancer cells known as cancer stem cells (CSCs). CSCs have been shown to have stem cell-like properties that enable them to evade traditional cytotoxic therapies, and so new CSC-directed anti-cancer therapies are needed. Nanoparticles have been designed to selectively deliver payloads to relevant target cells in the body, and there is considerable interest in the use of nanoparticles for CSC-directed anti-cancer therapies. Recent advances in the field of nanomedicine offer new possibilities for overcoming CSC-mediated therapeutic resistance and thus significantly improving management of GBM. In this review, we will examine the current nanomedicine approaches for targeting CSCs and their therapeutic implications. The inhibitory effect of various nanoparticle-based drug delivery system towards CSCs in GBM tumors is the primary focus of this review. PMID:26116770

    3. Effective treatment of glioblastoma requires crossing the blood-brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine.

      Science.gov (United States)

      Kim, Sang-Soo; Harford, Joe B; Pirollo, Kathleen F; Chang, Esther H

      2015-12-18

      Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Both therapeutic resistance and restricted permeation of drugs across the blood-brain barrier (BBB) play a major role in the poor prognosis of GBM patients. Accumulated evidence suggests that in many human cancers, including GBM, therapeutic resistance can be attributed to a small fraction of cancer cells known as cancer stem cells (CSCs). CSCs have been shown to have stem cell-like properties that enable them to evade traditional cytotoxic therapies, and so new CSC-directed anti-cancer therapies are needed. Nanoparticles have been designed to selectively deliver payloads to relevant target cells in the body, and there is considerable interest in the use of nanoparticles for CSC-directed anti-cancer therapies. Recent advances in the field of nanomedicine offer new possibilities for overcoming CSC-mediated therapeutic resistance and thus significantly improving management of GBM. In this review, we will examine the current nanomedicine approaches for targeting CSCs and their therapeutic implications. The inhibitory effect of various nanoparticle-based drug delivery system towards CSCs in GBM tumors is the primary focus of this review. Copyright © 2015 Elsevier Inc. All rights reserved.

    4. DNA replication proteins as potential targets for antimicrobials in drug-resistant bacterial pathogens.

      Science.gov (United States)

      van Eijk, Erika; Wittekoek, Bert; Kuijper, Ed J; Smits, Wiep Klaas

      2017-05-01

      With the impending crisis of antimicrobial resistance, there is an urgent need to develop novel antimicrobials to combat difficult infections and MDR pathogenic microorganisms. DNA replication is essential for cell viability and is therefore an attractive target for antimicrobials. Although several antimicrobials targeting DNA replication proteins have been developed to date, gyrase/topoisomerase inhibitors are the only class widely used in the clinic. Given the numerous essential proteins in the bacterial replisome that may serve as a potential target for inhibitors and the relative paucity of suitable compounds, it is evident that antimicrobials targeting the replisome are underdeveloped so far. In this review, we report on the diversity of antimicrobial compounds targeting DNA replication and highlight some of the challenges in developing new drugs that target this process. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

    5. Drug delivery to the human and mouse uterus using immunoliposomes targeted to the oxytocin receptor.

      Science.gov (United States)

      Paul, Jonathan W; Hua, Susan; Ilicic, Marina; Tolosa, Jorge M; Butler, Trent; Robertson, Sarah; Smith, Roger

      2017-03-01

      The ability to provide safe and effective pharmacotherapy during obstetric complications, such as preterm labor or postpartum hemorrhage, is hampered by the systemic toxicity of therapeutic agents leading to adverse side effects in the mother and fetus. Development of novel strategies to target tocolytic and uterotonic agents specifically to uterine myocytes would improve therapeutic efficacy while minimizing the risk of side effects. Ligand-targeted liposomes have emerged as a reliable and versatile platform for targeted drug delivery to specific cell types, tissues or organs. Our objective was to develop a targeted drug delivery system for the uterus utilizing an immunoliposome platform targeting the oxytocin receptor. We conjugated liposomes to an antibody that recognizes an extracellular domain of the oxytocin receptor. We then examined the ability of oxytocin receptor-targeted liposomes to deliver contraction-blocking (nifedipine, salbutamol and rolipram) or contraction-enhancing (dofetilide) agents to strips of spontaneously contracting myometrial tissue in vitro (human and mouse). We evaluated the ability of oxytocin receptor-targeted liposomes to localize to uterine tissue in vivo, and assessed if targeted liposomes loaded with indomethacin were capable of preventing lipopolysaccharide-induced preterm birth in mice. Oxytocin receptor-targeted liposomes loaded with nifedipine, salbutamol or rolipram consistently abolished human myometrial contractions in vitro, while oxytocin receptor-targeted liposomes loaded with dofetilide increased contraction duration. Nontargeted control liposomes loaded with these agents had no effect. Similar results were observed in mouse uterine strips. Following in vivo administration to pregnant mice, oxytocin receptor-targeted liposomes localized specifically to the uterine horns and mammary tissue. Targeting increased localization to the uterus 7-fold. Localization was not detected in the maternal brain or fetus. Targeted

    6. Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR-Mycobacterium tuberculosis Strains

      Directory of Open Access Journals (Sweden)

      H. M. Adnan Hameed

      2018-04-01

      Full Text Available Tuberculosis (TB is a formidable infectious disease that remains a major cause of death worldwide today. Escalating application of genomic techniques has expedited the identification of increasing number of mutations associated with drug resistance in Mycobacterium tuberculosis. Unfortunately the prevalence of bacillary resistance becomes alarming in many parts of the world, with the daunting scenarios of multidrug-resistant tuberculosis (MDR-TB, extensively drug-resistant tuberculosis (XDR-TB and total drug-resistant tuberculosis (TDR-TB, due to number of resistance pathways, alongside some apparently obscure ones. Recent advances in the understanding of the molecular/ genetic basis of drug targets and drug resistance mechanisms have been steadily made. Intriguing findings through whole genome sequencing and other molecular approaches facilitate the further understanding of biology and pathology of M. tuberculosis for the development of new therapeutics to meet the immense challenge of global health.

    7. Applicability of bioanalysis of multiple analytes in drug discovery and development: review of select case studies including assay development considerations.

      Science.gov (United States)

      Srinivas, Nuggehally R

      2006-05-01

      The development of sound bioanalytical method(s) is of paramount importance during the process of drug discovery and development culminating in a marketing approval. Although the bioanalytical procedure(s) originally developed during the discovery stage may not necessarily be fit to support the drug development scenario, they may be suitably modified and validated, as deemed necessary. Several reviews have appeared over the years describing analytical approaches including various techniques, detection systems, automation tools that are available for an effective separation, enhanced selectivity and sensitivity for quantitation of many analytes. The intention of this review is to cover various key areas where analytical method development becomes necessary during different stages of drug discovery research and development process. The key areas covered in this article with relevant case studies include: (a) simultaneous assay for parent compound and metabolites that are purported to display pharmacological activity; (b) bioanalytical procedures for determination of multiple drugs in combating a disease; (c) analytical measurement of chirality aspects in the pharmacokinetics, metabolism and biotransformation investigations; (d) drug monitoring for therapeutic benefits and/or occupational hazard; (e) analysis of drugs from complex and/or less frequently used matrices; (f) analytical determination during in vitro experiments (metabolism and permeability related) and in situ intestinal perfusion experiments; (g) determination of a major metabolite as a surrogate for the parent molecule; (h) analytical approaches for universal determination of CYP450 probe substrates and metabolites; (i) analytical applicability to prodrug evaluations-simultaneous determination of prodrug, parent and metabolites; (j) quantitative determination of parent compound and/or phase II metabolite(s) via direct or indirect approaches; (k) applicability in analysis of multiple compounds in select

    8. Doxorubicin loaded PVA coated iron oxide nanoparticles for targeted drug delivery

      International Nuclear Information System (INIS)

      Kayal, S.; Ramanujan, R.V.

      2010-01-01

      Magnetic drug targeting is a drug delivery system that can be used in locoregional cancer treatment. Coated magnetic particles, called carriers, are very useful for delivering chemotherapeutic drugs. Magnetic carriers were synthesized by coprecipitation of iron oxide followed by coating with polyvinyl alcohol (PVA). Characterization was carried out using X-ray diffraction, TEM, TGA, FTIR and VSM techniques. The magnetic core of the carriers was magnetite (Fe 3 O 4 ), with average size of 10 nm. The room temperature VSM measurements showed that magnetic particles were superparamagnetic. The amount of PVA bound to the iron oxide nanoparticles were estimated by thermogravimetric analysis (TGA) and the attachment of PVA to the iron oxide nanoparticles was confirmed by FTIR analysis. Doxorubicin (DOX) drug loading and release profiles of PVA coated iron oxide nanoparticles showed that up to 45% of adsorbed drug was released in 80 h, the drug release followed the Fickian diffusion-controlled process. The binding of DOX to the PVA was confirmed by FTIR analysis. The present findings show that DOX loaded PVA coated iron oxide nanoparticles are promising for magnetically targeted drug delivery.

    9. [Economic Loss of Remaining Contents in Molecular Target Drug Preparation and the Simulation for Cost Saving].

      Science.gov (United States)

      Usami, Eiseki; Kimura, Michio; Fukuoka, Tomohiro; Okada, Kazutomo; Yoshimura, Tomoaki

      2016-06-01

      While preparing an anticancer drug, even if it is an expensive molecular target drug, the remainder is not divided and saved for use in other patients; instead, it is discarded, resulting in waste of medical resources. In this study, we examined the economic loss in terms of medical costs by calculating the discarded amounts of 12 commonly used molecular target drugs at Ogaki Municipal Hospital, Japan between January 2012 and December 2014. We found, on average, that drugs valued at ¥ 52,593,182 were discarded annually. In particular, the discarded amounts of relatively expensive drugs, such as bevacizumab, bortezomib, and rituximab, were valued at ¥ 16,646,300, ¥ 15,866,289, and ¥ 8,401,324, respectively. Among these, the average amount of waste per administration of bortezomib was particularly expensive, at a cost of ¥ 67,325. Bortezomib is a commonly used treatment, resulting in excessive cumulative discarded cost. In an effort to save cost, we should consider using small capacity standard injections. Development of a simulation that used the remaining drug contents from only 1 day showed that bevacizumab alone accounts for an average cost saving of ¥1 2,542,191(75.3%) per year. This study suggests that effectively utilizing the remaining drug contents would ensure efficient use of medical resources, thereby reducing economic losses.

    10. Relationship among reaction rate, release rate and efficiency of nanomachine-based targeted drug delivery.

      Science.gov (United States)

      Zhao, Qingying; Li, Min; Luo, Jun

      2017-12-04

      In nanomachine applications towards targeted drug delivery, drug molecules released by nanomachines propagate and chemically react with tumor cells in aqueous environment. If the nanomachines release drug molecules faster than the tumor cells react, it will result in loss and waste of drug molecules. It is a potential issue associated with the relationship among reaction rate, release rate and efficiency. This paper aims to investigate the relationship among reaction rate, release rate and efficiency based on two drug reception models. We expect to pave a way for designing a control method of drug release. We adopted two analytical methods that one is drug reception process based on collision with tumors and another is based on Michaelis Menten enzymatic kinetics. To evaluate the analytical formulations, we used the well-known simulation framework N3Sim to establish simulations. The analytical results of the relationship among reaction rate, release rate and efficiency is obtained, which match well with the numerical simulation results in a 3-D environment. Based upon two drug reception models, the results of this paper would be beneficial for designing a control method of nanomahine-based drug release.

    11. Natural products used as a chemical library for protein-protein interaction targeted drug discovery.

      Science.gov (United States)

      Jin, Xuemei; Lee, Kyungro; Kim, Nam Hee; Kim, Hyun Sil; Yook, Jong In; Choi, Jiwon; No, Kyoung Tai

      2018-01-01

      Protein-protein interactions (PPIs), which are essential for cellular processes, have been recognized as attractive therapeutic targets. Therefore, the construction of a PPI-focused chemical library is an inevitable necessity for future drug discovery. Natural products have been used as traditional medicines to treat human diseases for millennia; in addition, their molecular scaffolds have been used in diverse approved drugs and drug candidates. The recent discovery of the ability of natural products to inhibit PPIs led us to use natural products as a chemical library for PPI-targeted drug discovery. In this study, we collected natural products (NPDB) from non-commercial and in-house databases to analyze their similarities to small-molecule PPI inhibitors (iPPIs) and FDA-approved drugs by using eight molecular descriptors. Then, we evaluated the distribution of NPDB and iPPIs in the chemical space, represented by the molecular fingerprint and molecular scaffolds, to identify the promising scaffolds, which could interfere with PPIs. To investigate the ability of natural products to inhibit PPI targets, molecular docking was used. Then, we predicted a set of high-potency natural products by using the iPPI-likeness score based on a docking score-weighted model. These selected natural products showed high binding affinities to the PPI target, namely XIAP, which were validated in an in vitro experiment. In addition, the natural products with novel scaffolds might provide a promising starting point for further medicinal chemistry developments. Overall, our study shows the potency of natural products in targeting PPIs, which might help in the design of a PPI-focused chemical library for future drug discovery. Copyright © 2017 Elsevier Inc. All rights reserved.

    12. Kinetic target-guided synthesis in drug discovery and chemical biology: a comprehensive facts and figures survey.

      Science.gov (United States)

      Bosc, Damien; Jakhlal, Jouda; Deprez, Benoit; Deprez-Poulain, Rebecca

      2016-01-01

      For the last 15 years, kinetic target-guided syntheses, including in situ click chemistry, have been used as alternative methods to find ligands to therapeutically relevant proteins. In this review, a comprehensive survey of biological targets used in kinetic target-guided synthesis covers historical and recent examples. The chemical reactions employed and practical aspects, including controls, library sizes and product detection, are presented. A particular focus is on the reagents and warhead selection and design with a critical overview of the challenges encountered. As protein supply remains a key success factor, it appears that increased efforts should be taken toward miniaturization in order to expand the scope of this strategy and qualify it as a fully fledged drug discovery tool.

    13. Editorial: Current status and perspective on drug targets in tubercle bacilli and drug design of antituberculous agents based on structure-activity relationship.

      Science.gov (United States)

      Tomioka, Haruaki

      2014-01-01

      Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. However, the development of new drugs for the treatment and prophylaxis of TB, particularly those truly active against dormant and persistent types of tubercle bacilli, has been slow, although some promising drugs, such as diarylquinoline TMC207, nitroimidazopyran PA-824, nitroimidazo-oxazole Delamanid (OPC-67683), oxazolidinone PNU-100480, ethylene diamine SQ-109, and pyrrole derivative LL3858, are currently under phase 1 to 3 clinical trials. Therefore, novel types of antituberculous drug, which act on unique drug targets in Mycobacterium tuberculosis (MTB) pathogens, particularly drug targets related to the establishment of mycobacterial dormancy in the host's macrophages, are urgently needed. In this context, it should be noted that current anti-TB drugs mostly target the metabolic reactions and proteins which are essential for the growth of MTB in extracellular milieus. It may also be promising to develop another type of drug that exerts an inhibitory action against bacterial virulence factors which cross-talk and interfere with signaling pathways of MTB-infected immunocompetent host cells, such as lymphocytes, macrophages, and NK cells, thereby changing the intracellular milieus that are favorable to intramacrophage survival and the growth of infected bacilli. This special issue contains ten review articles, dealing with recent approaches to identify and establish novel drug targets in MTB for the development of new and unique antitubercular drugs, including those related to mycobacterial dormancy and crosstalk with cellular signaling pathways. In addition, this special issue contains some review papers with special reference to the drug design based on quantitative structure-activity relationship (QSAR) analysis, especially three-dimensional (3D)-QSAR. New, critical information on the entire genome of MTB and mycobacterial virulence genes is

    14. Managing anthelmintic resistance-Variability in the dose of drug reaching the target worms influences selection for resistance?

      Science.gov (United States)

      Leathwick, Dave M; Luo, Dongwen

      2017-08-30

      The concentration profile of anthelmintic reaching the target worms in the host can vary between animals even when administered doses are tailored to individual liveweight at the manufacturer's recommended rate. Factors contributing to variation in drug concentration include weather, breed of animal, formulation and the route by which drugs are administered. The implications of this variability for the development of anthelmintic resistance was investigated using Monte-Carlo simulation. A model framework was established where 100 animals each received a single drug treatment. The 'dose' of drug allocated to each animal (i.e. the concentration-time profile of drug reaching the target worms) was sampled at random from a distribution of doses with mean m and standard deviation s. For each animal the dose of drug was used in conjunction with pre-determined dose-response relationships, representing single and poly-genetic inheritance, to calculate efficacy against susceptible and resistant genotypes. These data were then used to calculate the overall change in resistance gene frequency for the worm population as a result of the treatment. Values for m and s were varied to reflect differences in both mean dose and the variability in dose, and for each combination of these 100,000 simulations were run. The resistance gene frequency in the population after treatment increased as m decreased and as s increased. This occurred for both single and poly-gene models and for different levels of dominance (survival under treatment) of the heterozygote genotype(s). The results indicate that factors which result in lower and/or more variable concentrations of active reaching the target worms are more likely to select for resistance. The potential of different routes of anthelmintic administration to play a role in the development of anthelmintic resistance is discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

    15. Applications of Dynamic Clamp to Cardiac Arrhythmia Research: Role in Drug Target Discovery and Safety Pharmacology Testing.

      Science.gov (United States)

      Ortega, Francis A; Grandi, Eleonora; Krogh-Madsen, Trine; Christini, David J

      2017-01-01

      Dynamic clamp, a hybrid-computational-experimental technique that has been used to elucidate ionic mechanisms underlying cardiac electrophysiology, is emerging as a promising tool in the discovery of potential anti-arrhythmic targets and in pharmacological safety testing. Through the injection of computationally simulated conductances into isolated cardiomyocytes in a real-time continuous loop, dynamic clamp has greatly expanded the capabilities of patch clamp outside traditional static voltage and current protocols. Recent applications include fine manipulation of injected artificial conductances to identify promising drug targets in the prevention of arrhythmia and the direct testing of model-based hypotheses. Furthermore, dynamic clamp has been used to enhance existing experimental models by addressing their intrinsic limitations, which increased predictive power in identifying pro-arrhythmic pharmacological compounds. Here, we review the recent advances of the dynamic clamp technique in cardiac electrophysiology with a focus on its future role in the development of safety testing and discovery of anti-arrhythmic drugs.

    16. Magnetic Nanoparticles as Intraocular Drug Delivery System to Target Retinal Pigmented Epithelium (RPE

      Directory of Open Access Journals (Sweden)

      Martina Giannaccini

      2014-01-01

      Full Text Available One of the most challenging efforts in drug delivery is the targeting of the eye. The eye structure and barriers render this organ poorly permeable to drugs. Quite recently the entrance of nanoscience in ocular drug delivery has improved the penetration and half-life of drugs, especially in the anterior eye chamber, while targeting the posterior chamber is still an open issue. The retina and the retinal pigment epithelium/choroid tissues, located in the posterior eye chamber, are responsible for the majority of blindness both in childhood and adulthood. In the present study, we used magnetic nanoparticles (MNPs as a nanotool for ocular drug delivery that is capable of specific localization in the retinal pigmented epithelium (RPE layer. We demonstrate that, following intraocular injection in Xenopus embryos, MNPs localize specifically in RPE where they are retained for several days. The specificity of the localization did not depend on particle size and surface properties of the MNPs used in this work. Moreover, through similar experiments in zebrafish, we demonstrated that the targeting of RPE by the nanoparticles is not specific for the Xenopus species.

    17. Haptic guided virtual reality simulation for targeted drug delivery using nano-containers manipulation.

      Science.gov (United States)

      Hassan, Syed; Shah, Mohsin; Yoon, Sung Chul; Ullah, Ikram; Kim, Myeong Ok; Yoon, Jungwon

      2013-07-01

      When dealing with nano targeted drug delivery process the significant area of virtual reality application can be visualizing real time process and simulating it at nano-scale, since the effectiveness of a drug primarily depends on the affected cell and targeted doze. This paper proposes virtual reality (VR) as a tool to analyze and simulate nanoparticles (NPs) manipulation, in this paper amorphous NPs are analyzed and simulated in virtual environment. Haptic guides virtualizing the atomic force microscope (AFM) is applied in the virtual environment which allows the operators to sense and touch the NPs when evaluating its structure, drug release time, and behavioral study. Cisplatin was loaded as a modal drug to the self-assembled amorphous copolymer P(3HV-co-4HB)-b-mPEG NPs, where the efficiency and bioavailability of Cisplatin was further investigated. The prepared NPs when simulated in virtual environment proved to show good biocompatibility. Results showed that amorphous polymeric NPs could be efficient vehicles for the constant and targeted delivery of toxic anticancer drugs.

    18. HIV life cycle and potential targets for drug activity | Miller | Southern ...

      African Journals Online (AJOL)

      HIV life cycle and potential targets for drug activity. S Miller. Abstract. No Abstract. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians · for Authors · FAQ's · More about AJOL ...

    19. Transportproteiner som drug-targets hos Plasmodium falciparum. Nye perspektiver i behandlingen af malaria

      DEFF Research Database (Denmark)

      Ellekvist, Peter; Colding, Hanne

      2006-01-01

      to identify, clone and characterise a number of these transport proteins from the parasite. Since the P. falciparum transport proteins differ from their human homologues, they may provide potential drug targets in the treatment of malaria. An example of a P. falciparum transport protein which seems promising...

    20. Impacts of Blood-Brain Barrier in Drug Delivery and Targeting of Brain Tumors

      Directory of Open Access Journals (Sweden)

      Yadollah Omidi

      2012-02-01

      Full Text Available Introduction: Entry of blood circulating agents into the brain is highly selectively controlled by specific transport machineries at the blood brain barrier (BBB, whose excellent barrier restrictiveness make brain drug delivery and targeting very challenging. Methods: Essential information on BBB cellular microenvironment were reviewed and discussed towards impacts of BBB on brain drug delivery and targeting. Results: Brain capillary endothelial cells (BCECs form unique biological structure and architecture in association with astrocytes and pericytes, in which microenvironment the BCECs express restrictive tight junctional complexes that block the paracellular inward/outward traverse of biomolecules/compounds. These cells selectively/specifically control the transportation process through carrier and/or receptor mediated transport machineries that can also be exploited for the delivery of pharmaceuticals into the brain. Intelligent molecular therapies should be designed using such transport machineries for the efficient delivery of designated drugs into the brain. For better clinical outcomes, these smart pharmaceuticals should be engineered as seamless nanosystems to provide simultaneous imaging and therapy (multimodal theranostics. Conclusion: The exceptional functional presence of BBB selectively controls inward and outward transportation mechanisms, thus advanced smart multifunctional nanomedicines are needed for the effective brain drug delivery and targeting. Fully understanding the biofunctions of BBB appears to be a central step for engineering of intelligent seamless therapeutics consisting of homing device for targeting, imaging moiety for detecting, and stimuli responsive device for on-demand liberation of therapeutic agent.

    1. Polymeric nanomedicines for image-guided drug delivery and tumor-targeted combination therapy

      Czech Academy of Sciences Publication Activity Database

      Lammers, T.; Šubr, Vladimír; Ulbrich, Karel; Hennink, W. E.; Storm, G.; Kiessling, F.

      2010-01-01

      Roč. 5, č. 3 (2010), s. 197-212 ISSN 1748-0132 R&D Projects: GA MŠk 1M0505 Institutional research plan: CEZ:AV0Z40500505 Keywords : nanomedicine s * drug targeting * polymer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 11.750, year: 2010

    2. Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging

      Czech Academy of Sciences Publication Activity Database

      Theek, B.; Gremse, F.; Kunjachan, S.; Fokong, S.; Pola, Robert; Pechar, Michal; Deckers, R.; Storm, G.; Ehling, J.; Kiessling, F.; Lammers, T.

      2014-01-01

      Roč. 182, 28 May (2014), s. 83-89 ISSN 0168-3659 R&D Projects: GA ČR GCP207/12/J030 Institutional support: RVO:61389013 Keywords : drug targeting * nanomedicine * theranostics Subject RIV: CD - Macromolecular Chemistry Impact factor: 7.705, year: 2014

    3. Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs

      DEFF Research Database (Denmark)

      Madsen, Karsten K; White, H Steve; Schousboe, Arne

      2010-01-01

      Epileptic seizure activity is associated with an imbalance between excitatory and inhibitory synaptic activities. The latter is mediated by GABA, and several currently used antiepileptic drugs target entities of the GABAergic synapse such as the receptors or the inactivation mechanism consisting...... of transmembrane transport and enzymatic degradation. The development of tiagabine selectively inhibiting the GABA transporter GAT1 constitutes a proof of concept that the GABA transporters are interesting drug targets in the context of antiepileptic drugs. The review provides a detailed analysis of the role...... of such transporters pointing in particular to an interesting role of the transporters located extrasynaptically. It is suggested that the betaine-GABA transporter BGT1 should receive particular interest in this context as the GABA analogue EF 1502 (N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-4-(methylamino)-4...

    4. In Silico Identification of Proteins Associated with Drug-induced Liver Injury Based on the Prediction of Drug-target Interactions.

      Science.gov (United States)

      Ivanov, Sergey; Semin, Maxim; Lagunin, Alexey; Filimonov, Dmitry; Poroikov, Vladimir

      2017-07-01

      Drug-induced liver injury (DILI) is the leading cause of acute liver failure as well as one of the major reasons for drug withdrawal from clinical trials and the market. Elucidation of molecular interactions associated with DILI may help to detect potentially hazardous pharmacological agents at the early stages of drug development. The purpose of our study is to investigate which interactions with specific human protein targets may cause DILI. Prediction of interactions with 1534 human proteins was performed for the dataset with information about 699 drugs, which were divided into three categories of DILI: severe (178 drugs), moderate (310 drugs) and without DILI (211 drugs). Based on the comparison of drug-target interactions predicted for different drugs' categories and interpretation of those results using clustering, Gene Ontology, pathway and gene expression analysis, we identified 61 protein targets associated with DILI. Most of the revealed proteins were linked with hepatocytes' death caused by disruption of vital cellular processes, as well as the emergence of inflammation in the liver. It was found that interaction of a drug with the identified targets is the essential molecular mechanism of the severe DILI for the most of the considered pharmaceuticals. Thus, pharmaceutica