WorldWideScience

Sample records for categorical structure-activity relationship

  1. Categorization of fragrance contact allergens for prioritization of preventive measures: clinical and experimental data and consideration of structure-activity relationships.

    Science.gov (United States)

    Uter, Wolfgang; Johansen, Jeanne D; Börje, Anna; Karlberg, Ann-Therese; Lidén, Carola; Rastogi, Suresh; Roberts, David; White, Ian R

    2013-10-01

    Contact allergy to fragrances is still relatively common, affecting ∼ 16% of patients patch tested for suspected allergic contact dermatitis, considering all current screening allergens. The objective of the review is to systematically retrieve, evaluate and classify evidence on contact allergy to fragrances, in order to arrive at recommendations for targeting of primary and secondary prevention. Besides published evidence on contact allergy in humans, animal data (local lymph node assay), annual use volumes and structure-activity relationships (SARs) were considered for an algorithmic categorization of substances as contact allergens. A total of 54 individual chemicals and 28 natural extracts (essential oils) can be categorized as established contact allergens in humans, including all 26 substances previously identified as contact allergens (SCCNFP/0017/98). Twelve of the 54 individual chemicals are considered to be of special concern, owing to the high absolute number of reported cases of contact allergy (>100). Additionally, 18 single substances and one natural mixture are categorized as established contact allergens in animals. SARs, combined with limited human evidence, contributed to the categorization of a further 26 substances as likely contact allergens. In conclusion, the presence of 127 single fragrance substances and natural mixtures should, owing to their skin sensitizing properties, be disclosed, for example on the label. As an additional preventive measure, the maximum use concentration of 11 substances of special concern should be limited to 100 ppm. The substance hydroxyisohexyl 3-cyclohexene carboxaldehyde and the two ingredients chloroatranol and atranol in the natural extracts Evernia prunastri and Evernia furfuracea should not be present in cosmetic products.

  2. Structure activity relationships of spiramycins.

    Science.gov (United States)

    Omura, S; Sano, H; Sunazuka, T

    1985-07-01

    Sixty-six derivatives of spiramycin I and neospiramycin I were synthesized and evaluated by four parameters, MIC, affinity to ribosomes (ID50), therapeutic effect in mice and retention time in HPLC. Among the derivatives, 3,3'',4''-tri-O-propionyl- and 3,4''-di-O-acetyl-3''-O-butyrylspiramycin I showed the highest therapeutic effect which was superior to acetylspiramycin. Structure activity relationships of spiramycins are discussed.

  3. Structure-activity relationship studies of argiotoxins

    DEFF Research Database (Denmark)

    Poulsen, Mette H; Lucas, Simon; Bach, Tinna B;

    2013-01-01

    Argiotoxin-636 (ArgTX-636), a natural product from the spider Argiope lobata, is a potent but nonselective open-channel blocker of ionotropic glutamate (iGlu) receptors. Here, three series of analogues were designed to exploit selectivity among iGlu receptors, taking advantage of a recently devel......, respectively. Thus, the first structure-activity relationship study of ArgTX-636 has been carried out and has provided lead compounds for probing the ion channel region of iGlu receptors....... developed solid-phase synthetic methodology for the synthesis of ArgTX-636 and analogues. Initially, the importance of secondary amino groups in the polyamine chain was studied by the synthesis of systematically modified ArgTX-636 analogues, which were evaluated for pharmacological activity at NMDA and AMPA...

  4. Peptide Bacteriocins--Structure Activity Relationships.

    Science.gov (United States)

    Etayash, Hashem; Azmi, Sarfuddin; Dangeti, Ramana; Kaur, Kamaljit

    2015-01-01

    With the growing concerns in the scientific and health communities over increasing levels of antibiotic resistance, antimicrobial peptide bacteriocins have emerged as promising alternatives to conventional small molecule antibiotics. A substantial attention has recently focused on the utilization of bacteriocins in food preservation and health safety. Despite the fact that a large number of bacteriocins have been reported, only a few have been fully characterized and structurally elucidated. Since knowledge of the molecular structure is a key for understanding the mechanism of action and therapeutic effects of peptide, we centered our focus in this review on the structure-activity relationships of bacteriocins with a particular focus in seven bacteriocins, namely, nisin, microcin J25, microcin B17, microcin C, leucocin A, sakacin P, and pediocin PA-1. Significant structural changes responsible for the altered activity of the recent bacteriocin analogues are discussed here.

  5. Structure-activity relationships of bumetanide derivatives

    DEFF Research Database (Denmark)

    Pedersen, Kasper Lykke; Töllner, Kathrin; Römermann, Kerstin;

    2015-01-01

    of diuretics such as bumetanide. Bumetanide was discovered by screening ∼5000 3-amino-5-sulfamoylbenzoic acid derivatives, long before NKCC2 was identified in the kidney. Therefore, structure-activity studies on effects of bumetanide derivatives on NKCC2 are not available. EXPERIMENTAL APPROACH: In this study...

  6. A genetic algorithm for structure-activity relationships: software implementation

    CERN Document Server

    Jantschi, Lorentz

    2009-01-01

    The design and the implementation of a genetic algorithm are described. The applicability domain is on structure-activity relationships expressed as multiple linear regressions and predictor variables are from families of structure-based molecular descriptors. An experiment to compare different selection and survival strategies was designed and realized. The genetic algorithm was run using the designed experiment on a set of 206 polychlorinated biphenyls searching on structure-activity relationships having known the measured octanol-water partition coefficients and a family of molecular descriptors. The experiment shows that different selection and survival strategies create different partitions on the entire population of all possible genotypes.

  7. Antiproliferative and Structure Activity Relationships of Amaryllidaceae Alkaloids.

    Science.gov (United States)

    Cedrón, Juan C; Ravelo, Ángel G; León, Leticia G; Padrón, José M; Estévez-Braun, Ana

    2015-07-30

    The antiproliferative activity of a set of seven natural Amaryllidaceae alkaloids and 32 derivatives against four cancer cell lines (A2780, SW1573, T47-D and WiDr) was determined. The best antiproliferative activities were achieved with alkaloids derived from pancracine (2), haemanthamine (6) and haemantidine (7). For each skeleton, some structure-activity relationships were outlined.

  8. Structure activity relationship of selective GABA uptake inhibitors

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Jørgensen, Lars; Madsen, Karsten K;

    2015-01-01

    A series of β-amino acids with lipophilic diaromatic side chain was synthesized and characterized pharmacologically on mouse γ-amino butyric acid (GABA) transporter subtypes mGAT1-4 in order to investigate structure activity relationships (SAR) for mGAT2 (corresponding to hBGT-1). Variation...

  9. Partitioning and lipophilicity in quantitative structure-activity relationships.

    OpenAIRE

    Dearden, J. C.

    1985-01-01

    The history of the relationship of biological activity to partition coefficient and related properties is briefly reviewed. The dominance of partition coefficient in quantitation of structure-activity relationships is emphasized, although the importance of other factors is also demonstrated. Various mathematical models of in vivo transport and binding are discussed; most of these involve partitioning as the primary mechanism of transport. The models describe observed quantitative structure-ac...

  10. Structure-Activity Relationships in Nitro-Aromatic Compounds

    Science.gov (United States)

    Vogt, R. A.; Rahman, S.; Crespo-Hernández, C. E.

    Many nitro-aromatic compounds show mutagenic and carcinogenic properties, posing a potential human health risk. Despite this potential health hazard, nitro-aromatic compounds continue to be emitted into ambient air from municipal incinerators, motor vehicles, and industrial power plants. As a result, understanding the structural and electronic factors that influence mutagenicity in nitro-aromatic compounds has been a long standing objective. Progress toward this goal has accelerated over the years, in large part due to the synergistic efforts among toxicology, computational chemistry, and statistical modeling of toxicological data. The concerted influence of several structural and electronic factors in nitro-aromatic compounds makes the development of structure-activity relationships (SARs) a paramount challenge. Mathematical models that include a regression analysis show promise in predicting the mutagenic activity of nitro-aromatic compounds as well as in prioritizing compounds for which experimental data should be pursued. A major challenge of the structure-activity models developed thus far is their failure to apply beyond a subset of nitro-aromatic compounds. Most quantitative structure-activity relationship papers point to statistics as the most important confirmation of the validity of a model. However, the experimental evidence shows the importance of the chemical knowledge in the process of generating models with reasonable applicability. This chapter will concisely summarize the structural and electronic factors that influence the mutagenicity in nitro-aromatic compounds and the recent efforts to use quantitative structure-activity relationships to predict those physicochemical properties.

  11. Structure-activity relationship of crustacean peptide hormones.

    Science.gov (United States)

    Katayama, Hidekazu

    2016-01-01

    In crustaceans, various physiological events, such as molting, vitellogenesis, and sex differentiation, are regulated by peptide hormones. To understanding the functional sites of these hormones, many structure-activity relationship (SAR) studies have been published. In this review, the author focuses the SAR of crustacean hyperglycemic hormone-family peptides and androgenic gland hormone and describes the detailed results of our and other research groups. The future perspectives will be also discussed.

  12. Structure-activity relationships of benzothiazole GPR35 antagonists.

    Science.gov (United States)

    Abdalhameed, Manahil M; Zhao, Pingwei; Hurst, Dow P; Reggio, Patricia H; Abood, Mary E; Croatt, Mitchell P

    2017-02-01

    The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both ends of the scaffold. The activities of the analogues illustrate the importance of all three segments of the compound.

  13. Structure and Structure-activity Relationship of Functional Organic Molecules

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    @@ Research theme The group is made up of junior scientists from the State Key Laboratory of Elemento-organic Chemistry, Nankai University.The scientists focus their studis on the structure and structure-activity relationship of functional organic molecules not only because it has been the basis of their research, but also because the functional study of organic compounds is now a major scientific issue for organic chemists around the world.

  14. Structure-Activity Relationship of Fluoroquinolones Against K. pneumoniae

    Science.gov (United States)

    Li, Xiao-hong; Zhang, Rui-zhou; Cheng, Xin-lu; Yang, Xiang-dong

    2007-04-01

    The structure-activity relationship of fluoroquinolones, which show anti-K. pneumoniae activity, was studied by using principal component analysis (PCA) and hierarchical cluster analysis (HCA). The PCA results showed that the lowest unoccupied molecular orbital energy, energy difference between the highest occupied and the lowest unoccupied molecular orbital, dipole moment, net atomic charge on atom I, molecular polarizability, partition coefficient and molecular refractivity of these compounds are responsible for the separation between high-activity and low-activity groups. The HCA results were similar to those obtained with PCA. By using the chemometric results, four synthetic compounds were analyzed through PCA and HCA, and three of them are proposed as active molecules against K. pneumoniae which is consistent with the results of clinical experiments. The methodologies of PCA and HCA provide a reliable rule for classifying new fluoroquinolones with anti-K. pneumoniae activity.

  15. Structure-activity relationship of endomorphins and their analogs

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    To study the structure-activity relationship of endomorphins (EMs), the action of opioid receptor binding (AORB), analgesic activity and vasodilator effects of EMs and their eight analogs were investigated, which were prepared by rationally replacing the 2-/3-amino acid (Aa) of EMs. The results showed: (ⅰ) The 2-Aa was comparatively more related to the selectivity of EMs while the 3-Aa to their affinity; (ⅱ) the analgesia and vasodilatation of EMs and their analogs were not completely dictated by their AORB (in vitro), the action of [D-Pro2]EM-2 was unusual; (ⅲ) EMs lost their analgesia in the central nervous system and their vasodilatation in the circulatory system with different mechanisms; the former was due to the degradation of some peptidase, and the latter possibly due to the feedback inhibi-tion.

  16. Structure-activity relationship studies of citalopram derivatives

    DEFF Research Database (Denmark)

    Larsen, M Andreas B; Plenge, Per; Andersen, Jacob;

    2016-01-01

    towards the S2 site. EXPERIMENTAL APPROACH: We performed a systematic structure-activity relationship study based on the scaffold of citalopram and the structurally closely related congener, talopram, that shows low-affinity S1 binding in SERT. The role of the four chemical substituents, which distinguish......-activity relationship study revealed a di-methyl citalopram, which binds to the S1 site with an affinity of 6.4 [4.7;8.8] μM (mean[SEM interval]) and shows an allosteric potency of 3.6 [3.3;3.8] μM, thus bearing ~2-fold selectivity for the allosteric site relative to the S1 site in SERT. CONCLUSIONS AND IMPLICATIONS....... The antidepressant drug citalopram displays high-affinity S1 binding and low-affinity S2 binding. To elucidate a possible therapeutic role of allosteric inhibition of SERT a drug that specifically targets the allosteric site is required. The purpose of this study was to find a compound bearing higher selectivity...

  17. Review of Quantitative Structure - Activity Relationships for Acute Mammalian Toxicity

    Directory of Open Access Journals (Sweden)

    Iglika Lessigiarska

    2006-12-01

    Full Text Available This paper reviews Quantitative Structure-Activity Relationship (QSAR models for acute mammalian toxicity published in the last decade. A number of QSAR models based on cytotoxicity data from mammalian cell lines are also included because of their possible use as a surrogate system for predicting acute toxicity to mammals. On the basis of the review, the following conclusions can be made: i a relatively small number of models for in vivo toxicity are published in the literature. This is due to the nature of the endpoint - acute systemic toxicity is usually related to whole body phenomena and therefore is very complex. The complexity of the mechanisms involved leads to difficulties in the QSAR modelling; ii most QSAR models identify hydrophobicity as a parameter of high importance for the modelled toxicity. In addition, many models indicate the role of the electronic and steric effects; iii most of the literature-based models are restricted to single chemical classes. Models based on more heterogeneous data sets are those incorporated in expert systems. In general, the QSAR models for mammalian toxicity identified in this review are considered useful for investigating the mechanisms of toxicity of defined chemical classes. However, for predictive purposes in the regulatory assessment of chemicals most of the models require additional information to satisfy internationally agreed validation principles. In addition, the development of new models covering larger chemical domains would be useful for the regulatory assessment of chemicals.

  18. Structure activity relationships to assess new chemicals under TSCA

    Energy Technology Data Exchange (ETDEWEB)

    Auletta, A.E. [Environmental Protection Agency, Washington, DC (United States)

    1990-12-31

    Under Section 5 of the Toxic Substances Control Act (TSCA), manufacturers must notify the US Environmental Protection Agency (EPA) 90 days before manufacturing, processing, or importing a new chemical substance. This is referred to as a premanufacture notice (PMN). The PMN must contain certain information including chemical identity, production volume, proposed uses, estimates of exposure and release, and any health or environmental test data that are available to the submitter. Because there is no explicit statutory authority that requires testing of new chemicals prior to their entry into the market, most PMNs are submitted with little or no data. As a result, EPA has developed special techniques for hazard assessment of PMN chemicals. These include (1) evaluation of available data on the chemical itself, (2) evaluation of data on analogues of the PMN, or evaluation of data on metabolites or analogues of metabolites of the PMN, (3) use of quantitative structure activity relationships (QSARs), and (4) knowledge and judgement of scientific assessors in the interpretation and integration of the information developed in the course of the assessment. This approach to evaluating potential hazards of new chemicals is used to identify those that are most in need of addition review of further testing. It should not be viewed as a replacement for testing. 4 tabs.

  19. The structure-activity relationship in herbicidal monosubstituted sulfonylureas

    Energy Technology Data Exchange (ETDEWEB)

    Li, Zheng-Ming; Ma, Yi; Guddat, Luke; Cheng, Pei-Quan; Wang, Jian-Guo; Pang, Siew S; Dong, Yu-Hui; Lai, Cheng-Ming; Wang, Ling-Xiu; Jia, Guo-Feng; Li, Yong-Hong; Wang, Su-Hua; Liu, Jie; Zhao, Wei-Guang; Wang, Bao-Lei [Nankai; (Queens); (Chinese Aca. Sci.)

    2012-05-24

    The herbicide sulfonylurea (SU) belongs to one of the most important class of herbicides worldwide. It is well known for its ecofriendly, extreme low toxicity towards mammals and ultralow dosage application. The original inventor, G Levitt, set out structure-activity relationship (SAR) guidelines for SU structural design to attain superhigh bioactivity. A new approach to SU molecular design has been developed. After the analysis of scores of SU products by X-ray diffraction methodology and after greenhouse herbicidal screening of 900 novel SU structures synthesized in the authors laboratory, it was found that several SU structures containing a monosubstituted pyrimidine moiety retain excellent herbicidal characteristics, which has led to partial revision of the Levitt guidelines. Among the novel SU molecules, monosulfuron and monosulfuron-ester have been developed into two new herbicides that have been officially approved for field application and applied in millet and wheat fields in China. A systematic structural study of the new substrate-target complex and the relative mode of action in comparison with conventional SU has been carried out. A new mode of action has been postulated.

  20. Structure-activity relationship of nerve-highlighting fluorophores.

    Directory of Open Access Journals (Sweden)

    Summer L Gibbs

    Full Text Available Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR absorption and emission, would be of immediate benefit to patients and surgeons. Currently, there are only three classes of small molecule organic fluorophores that penetrate the blood nerve barrier and bind to nerve tissue when administered systemically. Of these three classes, the distyrylbenzenes (DSBs are particularly attractive for further study. Although not presently in the NIR range, DSB fluorophores highlight all nerve tissue in mice, rats, and pigs after intravenous administration. The purpose of the current study was to define the pharmacophore responsible for nerve-specific uptake and retention, which would enable future molecules to be optimized for NIR optical properties. Structural analogs of the DSB class of small molecules were synthesized using combinatorial solid phase synthesis and commercially available building blocks, which yielded more than 200 unique DSB fluorophores. The nerve-specific properties of all DSB analogs were quantified using an ex vivo nerve-specific fluorescence assay on pig and human sciatic nerve. Results were used to perform quantitative structure-activity relationship (QSAR modeling and to define the nerve-specific pharmacophore. All DSB analogs with positive ex vivo fluorescence were tested for in vivo nerve specificity in mice to assess the effect of biodistribution and clearance on nerve fluorescence signal. Two new DSB fluorophores with the highest nerve to muscle ratio were tested in pigs to confirm scalability.

  1. Synthetic and structure-activity relationship of insecticidal bufadienolides.

    Science.gov (United States)

    Hidayat, Ace Tatang; Zainuddin, Achmad; Dono, Danar; Hermawan, Wawan; Hayashi, Hideo; Supratman, Unang

    2014-07-01

    A new synthetic analog of bufadienolide, methyl isobryophyllinate A (1), and a known synthetic analog, methyl isobersaldegenate-1,3,5-orthoacetate (2), were obtained by methanolysis of bryophyllin A (3) and bersaldegenin-1,3,5-orthoacetate (5) in basic solution. Structure-insecticidal activity relationship studies revealed both orthoacetate and alpha-pyrone moieties seemed to be essential structural elements for exhibiting insecticidal activity, whereas oxygenated substituents in the C ring enhanced the insecticidal activity against the third instar larvae of silkworm (Bombyx mori).

  2. Activity Landscape Plotter: A Web-based Application for the Analysis of Structure-Activity Relationships.

    Science.gov (United States)

    González-Medina, Mariana; Méndez-Lucio, Oscar; Medina-Franco, Jose Luis

    2017-02-24

    Activity landscape modeling is a powerful method for the quantitative analysis of structure-activity relationships. This cheminformatics area is in continuous growth and several quantitative and visual approaches are constantly being developed. However, these approaches often fall into disuse due to their limited access. Herein, we present Activity Landscape Plotter as the first freely available web-based tool to automatically analyze structure-activity relationships of compound data sets. Based on the concept of activity landscape modeling, the online service performs pair-wise structure and activity relationships from an input data set supplied by the user. For visual analysis, Activity Landscape Plotter generates Structure-Activity Similarity and Dual Activity Difference maps. The user can interactively navigate through the maps and export all the pairwise structure-activity information as comma delimited files. Activity Landscape Plotter is freely accessible at https://unam-shiny-difacquim.shinyapps.io/ActLSmaps/.

  3. Quantitative Structure-Activity Relationships and Docking Studies of Calcitonin Gene-Related Peptide Antagonists

    DEFF Research Database (Denmark)

    Jenssen, Håvard; Mehrabian, Mohadeseh; Kyani, Anahita

    2012-01-01

    Defining the role of calcitonin gene-related peptide in migraine pathogenesis could lead to the application of calcitonin gene-related peptide antagonists as novel migraine therapeutics. In this work, quantitative structure-activity relationship modeling of biological activities of a large range...... of calcitonin gene-related peptide antagonists was performed using a panel of physicochemical descriptors. The computational studies evaluated different variable selection techniques and demonstrated shuffling stepwise multiple linear regression to be superior over genetic algorithm-multiple linear regression....... The linear quantitative structure-activity relationship model revealed better statistical parameters of cross-validation in comparison with the non-linear support vector regression technique. Implementing only five peptide descriptors into this linear quantitative structure-activity relationship model...

  4. Structure-activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

    DEFF Research Database (Denmark)

    Mungalpara, Jignesh; Zachariassen, Zack G; Thiele, Stefanie;

    2013-01-01

    , and autoimmune diseases. While the structure-activity relationships for Arg(1), Arg(2), and Gly(4) are well established, less is understood about the roles of the aromatic residues 2-Nal(3) and D-Tyr(5). Here we report further structure-activity relationship studies of these two positions, which showed that (i......The cyclopentapeptide CXCR4 antagonist FC131 (cyclo(-Arg(1)-Arg(2)-2-Nal(3)-Gly(4)-D-Tyr(5)-), 2; 2-Nal = 3-(2-naphthyl)alanine) represents an excellent starting point for development of novel drug-like ligands with therapeutic potential in HIV, cancer, stem-cell mobilization, inflammation...

  5. Relationships between Categorical Perception of Phonemes, Phoneme Awareness, and Visual Attention Span in Developmental Dyslexia.

    Science.gov (United States)

    Zoubrinetzky, Rachel; Collet, Gregory; Serniclaes, Willy; Nguyen-Morel, Marie-Ange; Valdois, Sylviane

    2016-01-01

    We tested the hypothesis that the categorical perception deficit of speech sounds in developmental dyslexia is related to phoneme awareness skills, whereas a visual attention (VA) span deficit constitutes an independent deficit. Phoneme awareness tasks, VA span tasks and categorical perception tasks of phoneme identification and discrimination using a d/t voicing continuum were administered to 63 dyslexic children and 63 control children matched on chronological age. Results showed significant differences in categorical perception between the dyslexic and control children. Significant correlations were found between categorical perception skills, phoneme awareness and reading. Although VA span correlated with reading, no significant correlations were found between either categorical perception or phoneme awareness and VA span. Mediation analyses performed on the whole dyslexic sample suggested that the effect of categorical perception on reading might be mediated by phoneme awareness. This relationship was independent of the participants' VA span abilities. Two groups of dyslexic children with a single phoneme awareness or a single VA span deficit were then identified. The phonologically impaired group showed lower categorical perception skills than the control group but categorical perception was similar in the VA span impaired dyslexic and control children. The overall findings suggest that the link between categorical perception, phoneme awareness and reading is independent from VA span skills. These findings provide new insights on the heterogeneity of developmental dyslexia. They suggest that phonological processes and VA span independently affect reading acquisition.

  6. The application of structure-activity relationships in human hazard assessment: a first approach

    NARCIS (Netherlands)

    Hulzebos EM; Janssen PAH; Maslankiewicz L; Meijerink MCM; Muller JJA; Pelgrom SMG; Verdam L; Vermeire TG; CSR

    2001-01-01

    In this report an overview is given of structure-activity relationships (SARs) described in literature that can be helpful for the daily human hazard evaluation of chemicals. SARs describe the relation between molecular structure and biological- or physical-chemical activity of the chemical. Chemica

  7. Neuritogenic activity of gangliosides from echinoderms and their structure-activity relationship.

    Science.gov (United States)

    Kaneko, Masafumi; Yamada, Koji; Miyamoto, Tomofumi; Inagaki, Masanori; Higuchi, Ryuichi

    2007-03-01

    The effects of the gangliosides isolated from echinoderms on the neuritogenesis of a rat pheochromocytoma cell line (PC-12 cells) in the presence of nerve growth factor were investigated. The results show that they displayed neuritogenic activity. Based on the observed results, a structure-activity relationship has been established.

  8. Environmental properties of long-chain alcohols. Structure-activity Relationship for Chronic Aquatic Toxicity

    DEFF Research Database (Denmark)

    Schaefers, Christoph; Sanderson, Hans; Boshof, Udo;

    2009-01-01

    Daphnia magna reproduction tests were performed with C10, C12, C14 and C15 alcohols to establish a structure-activity relationship of chronic effects of long-chain alcohols. The data generation involved substantial methodological efforts due to the exceptionally rapid biodegradability of the test...

  9. Is There a Relationship between Speech Identification in Noise and Categorical Perception in Children with Dyslexia?

    Science.gov (United States)

    Calcus, Axelle; Lorenzi, Christian; Collet, Gregory; Colin, Cécile; Kolinsky, Régine

    2016-01-01

    Purpose: Children with dyslexia have been suggested to experience deficits in both categorical perception (CP) and speech identification in noise (SIN) perception. However, results regarding both abilities are inconsistent, and the relationship between them is still unclear. Therefore, this study aimed to investigate the relationship between CP…

  10. Sphaeropsidones, phytotoxic dimedone methyl ethers produced by Diplodia cupressi: a structure-activity relationship study.

    Science.gov (United States)

    Evidente, Antonio; Maddau, Lucia; Scanu, Bruno; Andolfi, Anna; Masi, Marco; Motta, Andrea; Tuzi, Angela

    2011-04-25

    Sphaeropsidone and episphaeropsidone are two phytotoxic dimedone methyl ethers produced by Diplodia cupressi, the causal agent of a canker disease of cypress in the Mediterranean area. In this study, eight derivatives obtained by chemical modifications and two natural analogues were assayed for phytotoxic and antifungal activities, and a structure-activity relationship was examined. Each compound was tested on nonhost plants and on five fungal pathogenic species belonging to the genus Phytophthora. The results provide insights into structure-activity relationships within these compounds. It was found that the hydroxy group at C-5, the absolute C-5 configuration, the epoxy group, and the C-2 carbonyl group appear to be structural features important in conferring biological activity. The conversion of sphaeropsidone into the corresponding 1,4-dione derivative led to a compound showing greater antifungal activity than its precursor. This finding could be useful in devising new natural fungicides for practical application in agriculture.

  11. Aedes aegypti (Diptera: Culicidae) Biting Deterrence: Structure-Activity Relationship of Saturated and Unsaturated Fatty Acids

    Science.gov (United States)

    2012-11-01

    VECTOR CONTROL, PEST MANAGEMENT, RESISTANCE, REPELLENTS Aedes aegypti (Diptera: Culicidae) Biting Deterrence: Structure- Activity Relationship of...deterrent effects of a series of saturated and unsaturated fatty acids against Aedes aegypti (L), yellow fever mosquito (Diptera: Culicidae) using theK...greater thanDEET againstAe. aegypti and their relative repellency varied according to species tested. The MED values of 120 (C11:0), 145 (C12:0) and

  12. Quantum Chemical Study on Structure-activity Relationship of Several Kinds of Drugs

    Institute of Scientific and Technical Information of China (English)

    LI Xiao-Hong; CHENG Xin-Lu; ZHANG Rui-Zhou; YANG Xiang-Dong

    2005-01-01

    The structure-activity relationship of several drugs with similar structure has been investigated by using ab initio method.The relation between the dipole moments and biological activities of these drugs was judged after comparing their geometric structures, dipole moments and inhibitory concentrations.In principle, new drug molecule could be reasonably designed by altering the place of groups and ultimately, the potential drug could be screened by comparing the dipole moments of obtained molecules.

  13. Calculation of Quantitative Structure-Activity Relationship Descriptors of Artemisinin Derivatives

    Directory of Open Access Journals (Sweden)

    Jambalsuren Bayarmaa

    2008-06-01

    Full Text Available Quantitative structure-activity relationships are based on the construction of predictive models using a set of known molecules and associated activity value. This accurate methodology, developed with adequate mathematical and computational tools, leads to a faster, cheaper and more comprehensive design of new products, reducing the experimental synthesis and testing on animals. Preparation of the QSAR models of artemisinin derivatives was carried out by the genetic function algorithm (GFA method for 91 molecules. The results show some relationships to the observed antimalarial activities of the artemisinin derivatives. The most statistically signi fi cant regression equation obtained from the fi nal GFA relates to two molecular descriptors.

  14. Semantic Categorization and Reading Skill across Dutch Primary Grades: Development Yes, Relationship No

    Science.gov (United States)

    Gijsel, Martine A. R.; Ormel, Ellen A.; Hermans, Daan; Verhoeven, L.; Bosman, Anna M. T.

    2011-01-01

    In the present study, the development of semantic categorization and its relationship with reading was investigated across Dutch primary grade students. Three Exemplar-level tasks (Experiment 1) and two Superordinate-level tasks (Experiment 2) with different types of distracters (phonological, semantic and perceptual) were administered to assess…

  15. Semantic categorization and reading skill across Dutch primary grades: Development yes, relationship no

    NARCIS (Netherlands)

    Gijsel, M.A.R.; Ormel, E.A.; Hermans, D.; Verhoeven, L.T.W.; Bosman, A.M.T.

    2011-01-01

    In the present study, the development of semantic categorization and its relationship with reading was investigated across Dutch primary grade students. Three Exemplar-level tasks (Experiment 1) and two Superordinate-level tasks (Experiment 2) with different types of distracters (phonological, seman

  16. Flavonoids promoting HaCaT migration: I. Hologram quantitative structure-activity relationships.

    Science.gov (United States)

    Cho, Moonjae; Yoon, Hyuk; Park, Mijoo; Kim, Young Hwa; Lim, Yoongho

    2014-03-15

    Cell migration plays an important role in multicellular development and preservation. Because wound healing requires cell migration, compounds promoting cell migration can be used for wound repair therapy. Several plant-derived polyphenols are known to promote cell migration, which improves wound healing. Previous studies of flavonoids on cell lines have focused on their inhibitory effects and not on wound healing. In addition, studies of flavonoids on wound healing have been performed using mixtures. In this study, individual flavonoids were used for cellular migration measurements. Relationships between the cell migration effects of flavonoids and their structural properties have never been reported. Here, we investigated the migration of keratinocytes caused by 100 flavonoids and examined their relationships using hologram quantitative structure-activity relationships. The structural conditions responsible for efficient cell migration on keratinocyte cell lines determined from the current study will facilitate the design of flavonoids with improved activity.

  17. The Structure-Activity Relationship of the Antioxidant Peptides from Natural Proteins.

    Science.gov (United States)

    Zou, Tang-Bin; He, Tai-Ping; Li, Hua-Bin; Tang, Huan-Wen; Xia, En-Qin

    2016-01-12

    Peptides derived from dietary proteins, have been reported to display significant antioxidant activity, which may exert notably beneficial effects in promoting human health and in food processing. Recently, much research has focused on the generation, separation, purification and identification of novel peptides from various protein sources. Some researchers have tried to discover the structural characteristics of antioxidant peptides in order to lessen or avoid the tedious and aimless work involving the ongoing generated peptide preparation schemes. This review aims to summarize the current knowledge on the relationship between the structural features of peptides and their antioxidant activities. The relationship between the structure of the precursor proteins and their abilities to release antioxidant fragments will also be summarized and inferred. The preparation methods and antioxidant capacity evaluation assays of peptides and a prediction scheme of quantitative structure-activity relationship (QSAR) will also be pointed out and discussed.

  18. Study of the structure-activity relationships of parabens: a practical class

    Energy Technology Data Exchange (ETDEWEB)

    Fernandes, Joao Paulo dos Santos; Savino, Giovanna; Amarante, Andre Cortinas Goncalves, E-mail: joao.fernandes@mackenzie.br [Centro de Ciencias Biologicas e da Saude, Universidade Presbiteriana Mackenzie, Sao Paulo, SP (Brazil); Sousa, Milena Rodrigues de; Silva, Geane Ramos da [Universidade Camilo Castelo Branco, Sao Paulo, SP (Brazil); Cianciulli, Maria Eliza [Universidade do Grande ABC, Santo Andre, SP (Brazil); Correa, Michelle Fidelis; Ferrarini, Marcio [Centro Universitario Sao Camilo, Sao Paulo, SP (Brazil)

    2013-09-01

    Parabens are p-hydroxybenzoic acid esters widely used as preservatives. With the aim of teaching the structure-activity relationships (SAR) knowledge in a practical form, this paper proposed a practical class to view the SAR of parabens as antimicrobial agents. Methyl, ethyl, n-propyl, isopropyl and isopentyl paraben compounds were synthesized and their respective antimicrobial activities were assessed through determination of minimum inhibitory concentrations (MIC) against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 stains. With the MIC values, it was possible to verify their correlation with calculated lipophilicity (ClogP). This method can be applied in practical Medicinal Chemistry classes. (author)

  19. Synthesis and structure-activity relationships of potent 4-fluoro-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors.

    Science.gov (United States)

    Fukushima, Hiroshi; Hiratate, Akira; Takahashi, Masato; Mikami, Ayako; Saito-Hori, Masako; Munetomo, Eiji; Kitano, Kiyokazu; Chonan, Sumi; Saito, Hidetaka; Suzuki, Akio; Takaoka, Yuji; Yamamoto, Koji

    2008-04-01

    Dipeptidyl peptidase IV (DPP-IV) inhibitors are promising antidiabetic drugs, and several drugs are in the developmental stage. We previously reported that the introduction of fluorine to the 4-position of 2-cyanopyrrolidine enhanced the DPP-IV inhibitory effect. In the present report, we examined the structure-activity relationship (SAR) of 2-cyano-4-fluoropyrrolidine with N-substituted glycine at the 1-position. We report the identification of a potent and stable DPP-IV inhibitor (TS-021) with a long-term persistent plasma drug concentration and a potent antihyperglycemic activity.

  20. A computational quantitative structure-activity relationship study of carbamate anticonvulsants using quantum pharmacological methods.

    Science.gov (United States)

    Knight, J L; Weaver, D F

    1998-10-01

    A pattern recognition quantitative structure-activity relationship (QSAR) study has been performed to determine the molecular features of carbamate anticonvulsants which influence biological activity. Although carbamates, such as felbamate, have been used to treat epilepsy, their mechanisms of efficacy and toxicity are not completely understood. Quantum and classical mechanics calculations have been exploited to describe 46 carbamate drugs. Employing a principal component analysis and multiple linear regression calculations, five crucial structural descriptors were identified which directly relate to the bioactivity of the carbamate family. With the resulting mathematical model, the biological activity of carbamate analogues can be predicted with 85-90% accuracy.

  1. Structure-Activity Relationships on the Molecular Descriptors Family Project at the End

    Directory of Open Access Journals (Sweden)

    Lorentz JÄNTSCHI

    2007-12-01

    Full Text Available Molecular Descriptors Family (MDF on the Structure-Activity Relationships (SAR, a promising approach in investigation and quantification of the link between 2D and 3D structural information and the activity, and its potential in the analysis of the biological active compounds is summarized. The approach, attempts to correlate molecular descriptors family generated and calculated on a set of biological active compounds with their observed activity. The estimation as well as prediction abilities of the approach are presented. The obtained MDF SAR models can be used to predict the biological activity of unknown substrates in a series of compounds.

  2. Structure-activity relationship study of selective benzimidazole-based inhibitors of Cryptosporidium parvum IMPDH

    Science.gov (United States)

    Kirubakaran, Sivapriya; Gorla, Suresh Kumar; Sharling, Lisa; Zhang, Minjia; Liu, Xiaoping; Ray, Soumya S.; MacPherson, Iain S.; Striepen, Boris; Hedstrom, Lizbeth; Cuny, Gregory D.

    2012-01-01

    Cryptosporidium parasites are important waterborne pathogens of both humans and animals. The C. parvum and C. hominis genomes indicate that the only route to guanine nucleotides is via inosine 5'-monophosphate dehydrogenase (IMPDH). Thus the inhibition of the parasite IMPDH presents a potential strategy for treating Cryptosporidium infections. A selective benzimidazole-based inhibitor of C. parvum IMPDH (CpIMPDH) was previously identified in a high throughput screen. Here we report a structure-activity relationship study of benzimidazole-based compounds that resulted in potent and selective inhibitors of CpIMPDH. Several compounds display potent antiparasitic activity in vitro. PMID:22310229

  3. Quantitative structure-activity relationships for the Toxicity of Substituted Benzenes to Cyprinus carpio

    Institute of Scientific and Technical Information of China (English)

    GUANG-HUA LU; CHAO WANG; XING YUAN; PEI-ZHEN LAN

    2005-01-01

    Objective To measure the 96h-LC50 values of 32 substituted benzenes to the carp and to study the relationship between quantitative structure-activity and structural parameters of chemicals. Methods The acute toxicity values of 32 substituted benzenes to the carp were determined in a semistatic test. The energy of the lowest unoccupied molecular orbital, and the highest occupied molecular orbital, the dipole moment and the molecular weight of substituted benzenes were calculated by the quantum chemical method MOPAC6.0. Results The range of the toxicity of studied compounds was broad, and the most toxic compound was pentachlorophenol, while the least toxic compound was 4-methylaniline. By the stepwise regression analyses, a series of Quantitative structure-activity relationships (QSAR) equations were derived from all compounds and subclasses. The equation log1/LC50=0.759logP +2.222 (R2 (adj)=0.818) was found to fit well and the average predicted percentage error was 6.16%. Conclusion The toxicity of anilines and phenols to the carp could be modeled well by logP alone, whereas the toxicity of the halogenated benzenes and nitrobenznes not containing hydroxyl or amino group can be controlled by hydrophobic and electronic factors.

  4. Agropyrenol, a phytotoxic fungal metabolite, and its derivatives: a structure-activity relationship study.

    Science.gov (United States)

    Cimmino, Alessio; Zonno, Maria Chiara; Andolfi, Anna; Troise, Ciro; Motta, Andrea; Vurro, Maurizio; Evidente, Antonio

    2013-02-27

    Agropyrenol is a phytotoxic substituted salicylic aldehyde produced in liquid culture by Ascochyta agropyrina var. nana , a potential mycoherbicide proposed for the control of the perennial weed Elytrigia repens. In this study, six derivatives obtained by chemical modifications of the toxin were assayed for phytotoxic, antimicrobial, and zootoxic activities, and the structure-activity relationships were examined. Each compound was tested on non-host weedy and agrarian plants, fungi, Gram-positive and Gram-negative bacteria, and brine shrimp larvae. The results provide insights into the structure-activity relationships of agropyrenol. Both the double bond and the diol system of the 3,4-dihydroxypentenyl side chain as well as the aldehyde group at C-1 of the phenolic ring of agropyrenol proved to be important for the phytotoxicity. The lesser polar 3',4'-O,O'-isopropylidene of agropyrenol also showed significant zootoxic and slight antimicrobial activities. This finding could be useful in devising new natural herbicides for practical application in agriculture.

  5. Antiplasmodial Activity, Cytotoxicity and Structure-Activity Relationship Study of Cyclopeptide Alkaloids

    Directory of Open Access Journals (Sweden)

    Emmy Tuenter

    2017-02-01

    Full Text Available Cyclopeptide alkaloids are polyamidic, macrocyclic compounds, containing a 13-, 14-, or 15-membered ring. The ring system consists of a hydroxystyrylamine moiety, an amino acid, and a β-hydroxy amino acid; attached to the ring is a side chain, comprised of one or two more amino acid moieties. In vitro antiplasmodial activity was shown before for several compounds belonging to this class, and in this paper the antiplasmodial and cytotoxic activities of ten more cyclopeptide alkaloids are reported. Combining these results and the IC50 values that were reported by our group previously, a library consisting of 19 cyclopeptide alkaloids was created. A qualitative SAR (structure-activity relationship study indicated that a 13-membered macrocyclic ring is preferable over a 14-membered one. Furthermore, the presence of a β-hydroxy proline moiety could correlate with higher antiplasmodial activity, and methoxylation (or, to a lesser extent, hydroxylation of the styrylamine moiety could be important for displaying antiplasmodial activity. In addition, QSAR (quantitative structure-activity relationship models were developed, using PLS (partial least squares regression and MLR (multiple linear regression. On the one hand, these models allow for the indication of the most important descriptors (molecular properties responsible for the antiplasmodial activity. Additionally, predictions made for interesting structures did not contradict the expectations raised in the qualitative SAR study.

  6. Olfactory sensitivity and odor structure-activity relationships for aliphatic carboxylic acids in CD-1 mice.

    Science.gov (United States)

    Can Güven, Selçuk; Laska, Matthias

    2012-01-01

    Using a conditioning paradigm, the olfactory sensitivity of CD-1 mice for a homologous series of aliphatic n-carboxylic acids (ethanoic acid to n-octanoic acid) and several of their isomeric forms was investigated. With all 14 odorants, the animals significantly discriminated concentrations as low as 0.03 ppm (parts per million) from the solvent, and with four odorants the best-scoring animals even detected concentrations as low as 3 ppt (parts per trillion). Analysis of odor structure-activity relationships showed that the correlation between olfactory detection thresholds of the mice for the unbranched carboxylic acids and carbon chain length can best be described as a U-shaped function with the lowest threshold values at n-butanoic acid. A significant positive correlation between olfactory detection thresholds and carbon chain length of the carboxylic acids with their branching next to the functional carboxyl group was found. In contrast, no such correlation was found for carboxylic acids with their branching at the distal end of the carbon chain relative to the functional carboxyl group. Finally, a significant correlation was found between olfactory detection thresholds and the position of the branching of the carboxylic acids. Across-species comparisons suggest that mice are more sensitive for short-chained (C(2) to C(4)) aliphatic n-carboxylic acids than other mammalian species, but not for longer-chained ones (C(5) to C(8)). Further comparisons suggest that odor structure-activity relationships are both substance class- and species-specific.

  7. Nuclear receptor engineering based on novel structure activity relationships revealed by farnesyl pyrophosphate.

    Science.gov (United States)

    Goyanka, Ritu; Das, Sharmistha; Samuels, Herbert H; Cardozo, Timothy

    2010-11-01

    Nuclear receptors (NRs) comprise the second largest protein family targeted by currently available drugs, acting via specific ligand interactions within the ligand binding domain (LBD). Recently, farnesyl pyrophosphate (FPP) was shown to be a unique promiscuous NR ligand, activating a subset of NR family members and inhibiting wound healing in skin. The current study aimed at visualizing the unique basis of FPP interaction with multiple receptors in order to identify general structure-activity relationships that operate across the NR family. Docking of FPP to the 3D structures of the LBDs of a diverse set of NRs consistently revealed an electrostatic FPP pyrophosphate contact with an NR arginine conserved in the NR family, a hydrophobic farnesyl contact with NR helix-12 and a ligand binding pocket volume between 300 and 430 Å(3) as the minimal requirements for FPP activation of any NR. Lack of any of these structural features appears to render a given NR resistant to FPP activation. We used these structure-activity relationships to rationally design and successfully engineer several mutant human estrogen receptors that retain responsiveness to estradiol but no longer respond to FPP.

  8. Quantitative structure-activity relationships of antimicrobial fatty acids and derivatives against Staphylococcus aureus

    Institute of Scientific and Technical Information of China (English)

    Hui ZHANG; Lu ZHANG; Li-juan PENG; Xiao-wu DONG; Di WU; Vivian Chi-Hua WU; Feng-qin FENG

    2012-01-01

    Fatty acids and derivatives (FADs) are resources for natural antimicrobials.In order to screen for additional potent antimicrobial agents,the antimicrobial activities of FADs against Staphylococcus aureus were examined using a microplate assay.Monoglycerides of fatty acids were the most potent class of fatty acids,among which monotridecanoin possessed the most potent antimicrobial activity.The conventional quantitative structure-activity relationship (QSAR) and comparative molecular field analysis (CoMFA) were performed to establish two statistically reliable models (conventional QSAR:R2=0.942,Q2LOO=0.910; CoMFA:R2=0.979,Q2=0.588,respectively).Improved forecasting can be achieved by the combination of these two models that provide a good insight into the structureactivity relationships of the FADs and that may be useful to design new FADs as antimicrobial agents.

  9. Toxicity challenges in environmental chemicals: Prediction of human plasma protein binding through quantitative structure-activity relationship (QSAR) models

    Science.gov (United States)

    The present study explores the merit of utilizing available pharmaceutical data to construct a quantitative structure-activity relationship (QSAR) for prediction of the fraction of a chemical unbound to plasma protein (Fub) in environmentally relevant compounds. Independent model...

  10. Molecular Descriptors Family on Structure Activity Relationships 3. Antituberculotic Activity of some Polyhydroxyxanthones

    Directory of Open Access Journals (Sweden)

    Sorana BOLBOACĂ

    2005-06-01

    Full Text Available The antituberculotic activity of some polyhydroxyxanthones was estimated using the Molecular Descriptors Family on Structure Activity Relationships methodology. From a total number of 298110 real and distinct calculated descriptors, 94843 were significantly different and entered into multiple linear regression analysis. The best performing bi-varied model was obtained by use of all polyhydroxyxanthones. The MDF SAR model was validated splitting the molecules into training and test sets. A correlated correlations analysis was applied in other to compare the MDF SAR models with the previous SAR model. The prediction ability of antituberculotic activity of polyhydroxyxanthones with MDF SAR methodology is sustained by three arguments: leave-one-out procedure, training vs. test procedure, and the correlated correlations analysis. Looking at the bi-varied MDF SAR model, we can conclude that the antituberculotic activity of polyhydroxyxanthones is almost of geometrical nature (99% and is strongly dependent on partial atomic charge and group electronegativity.

  11. A descriptor of amino acids: SVRG and its application to peptide quantitative structure-activity relationship.

    Science.gov (United States)

    Tong, J; Che, T; Li, Y; Wang, P; Xu, X; Chen, Y

    2011-01-01

    In this work, a descriptor, SVRG (principal component scores vector of radial distribution function descriptors and geometrical descriptors), was derived from principal component analysis (PCA) of a matrix of two structural variables of coded amino acids, including radial distribution function index (RDF) and geometrical index. SVRG scales were then applied in three panels of peptide quantitative structure-activity relationships (QSARs) which were modelled by partial least squares regression (PLS). The obtained models with the correlation coefficient (R²(cum)), cross-validation correlation coefficient (Q²(LOO)) were 0.910 and 0.863 for 48 bitter-tasting dipeptides; 0.968 and 0.931 for 21 oxytocin analogues; and 0.992 and 0.954 for 20 thromboplastin inhibitors. Satisfactory results showed that SVRG contained much chemical information relating to bioactivities. The approach may be a useful structural expression methodology for studies on peptide QSAR.

  12. Structure-activity relationships of heteroaromatic esters as human rhinovirus 3C protease inhibitors.

    Science.gov (United States)

    Im, Isak; Lee, Eui Seung; Choi, Soo Jeong; Lee, Ju-Yeon; Kim, Yong-Chul

    2009-07-01

    Human rhinovirus 3C protease (HRV 3C(pro)) is known to be a promising target for development of therapeutic agents against the common cold because of the importance of the protease in viral replication as well as its expression in a large number of serotypes. To explore non-peptidic inhibitors of HRV 3C(pro), a series of novel heteroaromatic esters was synthesized and evaluated for inhibitory activity against HRV 3C(pro), to determine the structure-activity relationships. The most potent inhibitor, 7, with a 5-bromopyridinyl group, had an IC(50) value of 80nM. In addition, the binding mode of a novel analog, 19, with the 4-hydroxyquinolinone moiety, was explored by molecular docking, suggesting a new interaction in the S1 pocket.

  13. Cyclooxygenase active bioflavonoids from Balaton tart cherry and their structure activity relationships.

    Science.gov (United States)

    Wang, H; Nair, M G; Strasburg, G M; Booren, A M; Gray, I; Dewitt, D L

    2000-03-01

    Several flavonoids and isoflavonoids isolated from Balaton tart cherry were assayed for prostaglandin H endoperoxide synthase (PGHS-1) enzyme or cyclooxygenase isoform-1 (COX-1) activity. Genistein showed the highest COX-1 inhibitory activity among the isoflavonoids studied, with an IC50 value of 80 microM. Kaempferol gave the highest COX-1 inhibitory activity among the flavonoids tested, with an IC50 value of 180 microM. The structure-activity relationships of flavonoids and isoflavonoids revealed that hydroxyl groups at C4', C5 and C7 in isoflavonoids were essential for appreciable COX-1 inhibitory activity. Also, the C2-C3 double bond in flavonoids is important for COX-1 inhibitory activity. However, a hydroxyl group at the position decreased COX-1 inhibitory activity by flavonoids.

  14. A structure-activity relationship study of small-molecule inhibitors of GLI1-mediated transcription.

    Science.gov (United States)

    Actis, Marcelo; Connelly, Michele C; Mayasundari, Anand; Punchihewa, Chandanamali; Fujii, Naoaki

    2011-01-01

    We have previously reported ketoprofen amide compounds as inhibitors of GLI1-mediated transcription, an essential down-stream element of the Hedgehog (Hh) pathway. These compounds inhibited Gli-luciferase reporter in C3H10T1/2 cells that were exogenously transfected with GLI1 and in Rh30 cells that endogenously overexpress GLI1. Here we have designed new derivatives of these compounds aiming to explore the structure-activation relationship (SAR). By replacing the ketone carbonyl group of the ketoprofen moiety with an ether, amide, sulfonamide, or sulfone, we found several new compounds that are equipotent to the ketoprofen amide compounds. Among them, sulfone 30 inhibited Gli-luciferase reporter in C3H10T1/2 cells that were exogenously transfected with GLI1 and in Rh30 cells that endogenously overexpress GLI1.

  15. Quantitative Structure Activity Relationship of Cinnamaldehyde Compounds against Wood-Decaying Fungi

    Directory of Open Access Journals (Sweden)

    Dongmei Yang

    2016-11-01

    Full Text Available Cinnamaldehyde, of the genius Cinnamomum, is a major constituent of the bark of the cinnamon tree and possesses broad-spectrum antimicrobial activity. In this study, we used best multiple linear regression (BMLR to develop quantitative structure activity relationship (QSAR models for cinnamaldehyde derivatives against wood-decaying fungi Trametes versicolor and Gloeophyllun trabeum. Based on the two optimal QSAR models, we then designed and synthesized two novel cinnamaldehyde compounds. The QSAR models exhibited good correlation coefficients: R2Tv = 0.910 for Trametes versicolor and R2Gt = 0.926 for Gloeophyllun trabeum. Small errors between the experimental and calculated values of two designed compounds indicated that these two QSAR models have strong predictability and stability.

  16. New Quantitative Structure-Activity Relationship Models Improve Predictability of Ames Mutagenicity for Aromatic Azo Compounds.

    Science.gov (United States)

    Manganelli, Serena; Benfenati, Emilio; Manganaro, Alberto; Kulkarni, Sunil; Barton-Maclaren, Tara S; Honma, Masamitsu

    2016-10-01

    Existing Quantitative Structure-Activity Relationship (QSAR) models have limited predictive capabilities for aromatic azo compounds. In this study, 2 new models were built to predict Ames mutagenicity of this class of compounds. The first one made use of descriptors based on simplified molecular input-line entry system (SMILES), calculated with the CORAL software. The second model was based on the k-nearest neighbors algorithm. The statistical quality of the predictions from single models was satisfactory. The performance further improved when the predictions from these models were combined. The prediction results from other QSAR models for mutagenicity were also evaluated. Most of the existing models were found to be good at finding toxic compounds but resulted in many false positive predictions. The 2 new models specific for this class of compounds avoid this problem thanks to a larger set of related compounds as training set and improved algorithms.

  17. Structure-activity relationship of lysophosphatidylcholines in HL-60 human leukemia cells

    Institute of Scientific and Technical Information of China (English)

    Eun-heeLEE; Mi-ranYUN; Wei-hongWANG; JeeHJUNG; Dong-soonIM

    2004-01-01

    AIM: To explore the structure-activity relationship of lysophosphatidylcholine (LPC) and lysolipid molecules from a marine sponge and ladybirds. METHODS: We tested three synthetic LPCs and four natural lysolipids on Ca2+ mobilization in HL-60 human leukemia cells. RESULTS: We observed lysolipid-mediated Ca2+ mobilization. The activity was the same in both ester-and ether-linked lysolipids, and introduction of a double bond or methoxy group on the alkyl chain did not significantly modulate the activity. However, replacement of trimethylammonium moiety in the choline structure with ammonium moiety reduced the activity. Furthermore, change of the alkyl chain length influenced the Ca2+ response. CONCLUSION: LPC-induced Ca2+ mobilization might be dependent on the length of alkyl chain and the presence of choline moiety in HL-60 leukemia cells.

  18. Structure-activity relationship of lysophosphatidylcholines in HL-60 human leukemia cells

    Institute of Scientific and Technical Information of China (English)

    Eun-hee LEE; Mi-ran YUN; Wei-hong WANG; Jee H JUNG; Dong-soon IM

    2004-01-01

    AIM: To explore the structure-activity relationship of lysophosphatidylcholine (LPC) and lysolipid molecules from a marine sponge and ladybirds. METHODS: We tested three synthetic LPCs and four natural lysolipids on Ca2+mobilization in HL-60 human leukemia cells. RESULTS: We observed lysolipid-mediated Ca2+ mobilization. The activity was the same in both ester- and ether-linked lysolipids, and introduction of a double bond or methoxy group on the alkyl chain did not significantly modulate the activity. However, replacement of trimethylammonium moiety in the choline structure with ammonium moiety reduced the activity. Furthermore, change of the alkyl chain length influenced the Ca2+ response. CONCLUSION: LPC-induced Ca2+ mobilization might be dependent on the length of alkyl chain and the presence of choline moiety in HL-60 leukemia cells.

  19. In vivo toxicity of nitroaromatics: A comprehensive quantitative structure-activity relationship study.

    Science.gov (United States)

    Gooch, Aminah; Sizochenko, Natalia; Rasulev, Bakhtiyor; Gorb, Leonid; Leszczynski, Jerzy

    2017-02-07

    The toxicity data of 90 nitroaromatic compounds related to their 50% lethal dose concentration for rats (LD50) were analyzed to develop quantitative structure-activity relationship (QSAR) models. Quantum-chemically calculated descriptors together with molecular descriptors generated by DRAGON, PaDEL, and HiT-QSAR software were utilized to build QSAR models. Quality and validity of the models were determined by internal and external validation techniques. The results show that the toxicity of nitroaromatic compounds depends on various factors, such as the number of nitro-groups, the topological state, and the presence of certain structural fragments. The developed models based on the largest (to date) dataset of nitroaromatics in vivo toxicity showed a good predictive ability. The results provide important input that could be applied in a preliminary assessment of nitroaromatic compounds' toxicity to mammals. Environ Toxicol Chem 2017;9999:1-7. © 2017 SETAC.

  20. Structure-activity relationship (SAR) analysis of a family of steroids acutely controlling steroidogenesis.

    Science.gov (United States)

    Midzak, Andrew; Rammouz, Georges; Papadopoulos, Vassilios

    2012-11-01

    Steroids metabolically derive from lipid cholesterol, and vertebrate steroids additionally derive from the steroid pregnenolone. Pregnenolone is derived from cholesterol by hydrolytic cleavage of the aliphatic tail by mitochondrial cytochrome P450 enzyme CYP11A1, located in the inner mitochondrial membrane. Delivery of cholesterol to CYP11A1 comprises the principal control step of steroidogenesis, and requires a series of proteins spanning the mitochondrial double membranes. A critical member of this cholesterol translocation machinery is the integral outer mitochondrial membrane translocator protein (18kDa, TSPO), a high-affinity drug- and cholesterol-binding protein. The cholesterol-binding site of TSPO consists of a phylogenetically conserved cholesterol recognition/interaction amino acid consensus (CRAC). Previous studies from our group identified 5-androsten-3β,17,19-triol (19-Atriol) as drug ligand for the TSPO CRAC motif inhibiting cholesterol binding to CRAC domain and steroidogenesis. To further understand 19-Atriol's mechanism of action as well as the molecular recognition by the TSPO CRAC motif, we undertook structure-activity relationship (SAR) analysis of the 19-Atriol molecule with a variety of substituted steroids oxygenated at positions around the steroid backbone. We found that in addition to steroids hydroxylated at carbon C19, hydroxylations at C4, C7, and C11 contributed to inhibition of cAMP-mediated steroidogenesis in a minimal steroidogenic cell model. However, only substituted steroids with C19 hydroxylations exhibited specificity to TSPO, its CRAC motif, and mitochondrial cholesterol transport, as the C4, C7, and C11 hydroxylated steroids inhibited the metabolic transformation of cholesterol by CYP11A1. We thus provide new insights into structure-activity relationships of steroids inhibiting mitochondrial cholesterol transport and steroidogenic cholesterol metabolic enzymes.

  1. A Quantitative Structure-Activity Relationships (QSAR Study of Piperine Based Derivatives with Leishmanicidal Activity

    Directory of Open Access Journals (Sweden)

    Edilson Beserra Alencar Filho

    2017-04-01

    Full Text Available Leishmaniasis is a parasitic disease which represents a serious public health problem in developing countries. It is considered a neglected tropical disease, for which there is little initiative in the search for therapeutic alternatives by pharmaceutical industry. Natural products remain a great source of inspiration for obtaining bioactive molecules. In 2010, Singh and co-workers published the synthesis and in vitro biological activity of piperoyl-aminoacid conjugates, as well as of piperine, against cellular cultures of Leishmania donovani. The piperine is an alkaloid isolated from Piper nigrum that has many activities described in the literature. In this work, we present a Quantitative Structure-Activity Study of piperine derivatives tested by Singh and co-workers, aiming to highlight important molecular features for leishmanicidal activity, obtaining a mathematical model to predict the activity of new analogs. Compounds were submitted to a geometry optimization computational procedure at semiempirical level of quantum theory. Molecular descriptors for the set of compounds were calculated by E-Dragon online plataform, followed by a variable selection procedure using Ordered Predictors Selection algorithm. Validation parameters obtained showed that a good QSAR model, based on multiple linear regression, was obtained (R2 = 0.85; Q2 = 0.69, and the following conclusions regarding the structure-activity relationship were elucidated: Compounds with electronegative atoms on different substituent groups of analogs, absence of unsaturation on lateral chain, presence of ester instead of carboxyl, and large volumes (due the presence of additional aromatic rings trends to increase the activity against promastigote forms of leishmania. DOI: http://dx.doi.org/10.17807/orbital.v9i1.893

  2. Structure-activity relationships for perfluoroalkane-induced in vitro interference with rat liver mitochondrial respiration.

    Science.gov (United States)

    Wallace, K B; Kissling, G E; Melnick, R L; Blystone, C R

    2013-10-01

    Perfluorinated alkyl acids (PFAAs) represent a broad class of commercial products designed primarily for the coatings industry. However, detection of residues globally in a variety of species led to the discontinuation of production in the U.S. Although PFAAs cause activation of the PPARα and CAR nuclear receptors, interference with mitochondrial bioenergetics has been implicated as an alternative mechanism of cytotoxicity. Although the mechanisms by which the eight carbon chain PFAAs interfere with mitochondrial bioenergetics are fairly well described, the activities of the more highly substituted or shorter chain PFAAs are far less well characterized. The current investigation was designed to explore structure-activity relationships by which PFAAs interfere with mitochondrial respiration in vitro. Freshly isolated rat liver mitochondria were incubated with one of 16 different PFAAs, including perfluorinated carboxylic, acetic, and sulfonic acids, sulfonamides and sulfamido acetates, and alcohols. The effect on mitochondrial respiration was measured at five concentrations and dose-response curves were generated to describe the effects on state 3 and 4 respiration and respiratory control. With the exception of PFOS, all PFAAs at sufficiently high concentrations (>20μM) stimulated state 4 and inhibited state 3 respiration. Stimulation of state 4 respiration was most pronounced for the carboxylic acids and the sulfonamides, which supports prior evidence that the perfluorinated carboxylic and acetic acids induce the mitochondrial permeability transition, whereas the sulfonamides are protonophoric uncouplers of oxidative phosphorylation. In both cases, potency increased with increasing carbon number, with a prominent inflection point between the six and eight carbon congeners. The results provide a foundation for classifying PFAAs according to specific modes of mitochondrial activity and, in combination with toxicokinetic considerations, establishing structure-activity

  3. Structure-activity relationship between carboxylic acids and T cell cycle blockade.

    Science.gov (United States)

    Gilbert, Kathleen M; DeLoose, Annick; Valentine, Jimmie L; Fifer, E Kim

    2006-04-04

    This study was designed to examine the potential structure-activity relationship between carboxylic acids, histone acetylation and T cell cycle blockade. Toward this goal a series of structural homologues of the short-chain carboxylic acid n-butyrate were studied for their ability to block the IL-2-stimulated proliferation of cloned CD4+ T cells. The carboxylic acids were also tested for their ability to inhibit histone deacetylation. In addition, Western blotting was used to examine the relative capacity of the carboxlic acids to upregulate the cyclin kinase-dependent inhibitor p21cip1 in T cells. As shown earlier n-butyrate effectively inhibited histone deacetylation. The increased acetylation induced by n-butyrate was associated with the upregulation of the cyclin-dependent kinase inhibitor p21cip1 and the cell cycle blockade of CD4+ T cells. Of the other carboxylic acids studied, the short chain acids, C3-C5, without branching were the best inhibitors of histone deacetylase. This inhibition correlated with increased expression of the cell cycle blocker p21cip1, and the associated suppression of CD4+ T cell proliferation. The branched-chain carboxylic acids tested were ineffective in all the assays. These results underline the relationship between the ability of a carboxylic acid to inhibit histone deacetylation, and their ability to block T cell proliferation, and suggests that branching inhibits these effects.

  4. Identification of New Nonsteroidal RORα Ligands; Related Structure-Activity Relationships and Docking Studies.

    Science.gov (United States)

    Dubernet, Mathieu; Duguet, Nicolas; Colliandre, Lionel; Berini, Christophe; Helleboid, Stéphane; Bourotte, Marilyne; Daillet, Matthieu; Maingot, Lucie; Daix, Sébastien; Delhomel, Jean-François; Morin-Allory, Luc; Routier, Sylvain; Walczak, Robert

    2013-06-13

    A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key structure-activity relationships (SAR) were established, where benzyl and urea moieties were both identified as very important elements to maintain the activity. Most notably, the SAR were consistent with the binding mode of the compound 8 (S-isomer) in the RORα docking model that was developed in this program. As predicted by the model, the urea moiety is engaged in the formation of key hydrogen bonds with the backbone of Tyr380 and Asp382. The benzyl group is located in a wide hydrophobic pocket. The structural relationships reported in this letter will help in further optimization of this compound series and will provide novel synthetic probes helpful for elucidation of complex RORα physiopathology.

  5. Quantitative structure-activity relationships of selected phenols with non-monotonic dose-response curves

    Institute of Scientific and Technical Information of China (English)

    GAO ChangAn; ZHANG AiQian; LIN Yuan; YIN DaQiang; WANG LianSheng

    2009-01-01

    Particular non-monotonic dose-response curves of many endocrine disrupting chemicals (EDCs) suggest the existence of diverse toxicity mechanisms at different dose levels. As a result, the biologi-cal activities of EDCs cannot be simply exhibited by unique EC/LD<,50. values, and the quantitative structure-activity relationship (QSAR) analysis for non-monotonic dose-response relationship be-comes an unknown field in the environmental science. In this paper, nine phenols with inverted U-shaped dose-response curves in lymphocyte proliferation test of Carassius auratus were selected. The binding interactions between the phenols and several typical EDCs-related receptors were then explored in a molecular simulation study. The estrogen receptor (ER), androgen receptor (AR), thyroid hormone receptor (TR), bacterial O2 sensing FixL protein (FixL), aryl hydrocarbon receptor (AhR), and the peroxisome proliferator-activated receptor (PPAR) were the target receptors in the study. Linear regression QSAR models for the low and high exposure levels of the compounds were developed separately. The results indicated that the lymphocyte proliferation in the low-dose range might involve ER-mediated process, while the proliferation inhibition in the high dose range was dominated by the acute toxicity of phenols due to receptor occupancy and cell damage.

  6. Structure-Activity Relationship Analysis of the Thermal Stabilities of Nitroaromatic Compounds Following Different Decomposition Mechanisms.

    Science.gov (United States)

    Li, Jiazhong; Liu, Huanxiang; Huo, Xing; Gramatica, Paola

    2013-02-01

    The decomposition behavior of energetic materials is very important for the safety problems concerning their production, transportation, use and storage, because molecular decomposition is intimately connected to their explosive properties. Nitroaromatic compounds, particularly nitrobenzene derivatives, are often considered as prototypical energetic molecules, and some of them are commonly used as high explosives. Quantitative structure-activity relationship (QSAR) represents a potential tool for predicting the thermal stability properties of energetic materials. But it is reported that constructing general reliable models to predict their stability and their potential explosive properties is a very difficult task. In this work, we make our efforts to investigate the relationship between the molecular structures and corresponding thermal stabilities of 77 nitrobenzene derivatives with various substituent functional groups (in ortho, meta and/or para positions). The proposed best MLR model, developed by the new software QSARINS, based on Genetic Algorithm for variable selection and with various validation tools, is robust, stable and predictive with R(2) of 0.86, QLOO (2) of 0.79 and CCC of 0.90. The results indicated that, though difficult, it is possible to build predictive, externally validated QSAR models to estimate the thermal stability of nitroaromatic compounds.

  7. Synthesis and structure-activity relationship of thiobarbituric acid derivatives as potent inhibitors of urease.

    Science.gov (United States)

    Khan, Khalid Mohammed; Rahim, Fazal; Khan, Ajmal; Shabeer, Muhammad; Hussain, Shafqat; Rehman, Wajid; Taha, Muhammad; Khan, Momin; Perveen, Shahnaz; Choudhary, M Iqbal

    2014-08-01

    A series of thiobarbituric acid derivatives 1-27 were synthesized and evaluated for their urease inhibitory potential. Exciting results were obtained from the screening of these compounds 1-27. Compounds 5, 7, 8, 11, 16, 17, 22, 23 and 24 showed excellent urease inhibition with IC50 values 18.1 ± 0.52, 16.0 ± 0.45, 16.0 ± 0.22, 14.3 ± 0.27, 6.7 ± 0.27, 10.6 ± 0.17, 19.2 ± 0.29, 18.2 ± 0.76 and 1.61 ± 0.18 μM, respectively, much better than the standard urease inhibitor thiourea (IC₅₀=21 ± 0.11 μM). Compound 3, 4, 10, and 26 exhibited comparable activities to the standard with IC₅₀ values 21.4 ± 1.04 and 21.5 ± 0.61 μM, 22.8 ± 0.32, 25.2 ± 0.63, respectively. However the remaining compounds also showed prominent inhibitory potential The structure-activity relationship was established for these compounds. This study identified a novel class of urease inhibitors. The structures of all compounds were confirmed through spectroscopic techniques such as EI-MS and (1)H NMR.

  8. Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy.

    Science.gov (United States)

    Paraskar, Abhimanyu S; Soni, Shivani; Chin, Kenneth T; Chaudhuri, Padmaparna; Muto, Katherine W; Berkowitz, Julia; Handlogten, Michael W; Alves, Nathan J; Bilgicer, Basar; Dinulescu, Daniela M; Mashelkar, Raghunath A; Sengupta, Shiladitya

    2010-07-13

    Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O --> Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 +/- 0.16 microM) comparable to that of free cisplatin (3.87 +/- 0.37 microM), and superior to carboplatin (14.75 +/- 0.38 microM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras(LSL/+)/Pten(fl/fl) ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer.

  9. New Descriptors of Amino Acids and Its Applications to Peptide Quantitative Structure-activity Relationship

    Institute of Scientific and Technical Information of China (English)

    SHU Mao; HUO Dan-Qun; MEI Hua; LIANG Gui-Zhao; ZHANG Mei; LI Zhi-Liang

    2008-01-01

    A new set of descriptors, HSEHPCSV (component score vector of hydrophobic, steric, and electronic properties together with hydrogen bonding contributions), were derived from principal component analyses of 95 physicochemical variables of 20 natural amino acids separately according to different kinds of properties described, namely, hydrophobic, steric, and electronic properties as well as hydrogen bonding contributions. HSEHPCSV scales were then employed to express structures of angiotensin-converting enzyme inhibitors, bitter tasting thresholds and bactericidal 18 peptide, and to construct QSAR models based on partial least square (PLS). The results obtained are as follows: the multiple correlation coefficient (R2cum) of 0.846, 0.917 and 0.993, leave-one-out cross validated Q2cum of 0.835, 0.865 and 0.899, and root-mean-square error for estimated error (RMSEE) of 0.396, 0.187and 0.22, respectively. Satisfactory results showed that, as new amino acid scales, data of HSEHPCSV may be a useful structural expression methodology for the studies on peptide QSAR (quantitative structure-activity relationship) due to many advantages such as plentiful structural information, definite physical and chemical meaning and easy interpretation.

  10. Quantitative structure-activity relationships for nasal pungency thresholds of volatile organic compounds.

    Science.gov (United States)

    Hau, K M; Connell, D W; Richardson, B J

    1999-01-01

    A model was developed for describing the triggering of nasal pungency in humans, based on the partition of volatile organic compounds (VOCs) between the air phase and the biophase. Two partition parameters are used in the model: the water-air partition coefficient and the octanol-water partition coefficient. The model was validated using data from the literature, principally on alcohols, acetates and ketones. The model suggests that all test compounds, regardless of their chemical functional groups, bind to a common receptor site within the hydrophobic interior of the bilayer membrane of the trigeminal nerve endings. There is probably only a slight, non-specific interaction between the VOC molecule and the receptor molecule, whereas this type of non-specific interaction for the detection of odor is much stronger. In practical terms, the suggestion that all VOCs share a common irritation receptor site implies that nasal-pungency thresholds of individual VOCs may be additive. Quantitative structure-activity relationships (QSARs) for nasal-pungency thresholds were also developed from the model, which can be used to predict nasal-pungency thresholds of common VOCs. Although the present model does not offer additional precision over that of M.H. Abraham et al., 1996, Fundam. Appl. Toxicol. 31, 71-76, it requires fewer descriptors and offers a physiological basis to the QSAR. Another advantage of the present model is that it also provides a basis for comparison between the olfactory process and nasal pungency.

  11. Molecular Descriptors Family on Structure Activity Relationships 4. Molar Refraction of Cyclic Organophosphorus Compounds

    Directory of Open Access Journals (Sweden)

    Lorentz JÄNTSCHI

    2005-06-01

    Full Text Available The molecular descriptors family on structure activity relationships methodology was applied on ten cyclic organophosphorus compounds in order to predict theirs molar refraction. A number of 107692 significantly different MDF members enter into a multiple linear regression analysis. A pair of descriptors (lGDmSMt, lAmrfEt, which have the best performing ability in prediction of molar refraction of cyclic organophosphorus compounds, was found and a bi-varied MDF SAR model was built. After performing leave-one-out cross-validation, satisfactory result was obtained with cross-validation r2cv and r2 values of 0.9999 and 0.9999. The external validation of the bi-varied MDF SAR model and its ability in prediction of molar refraction of cyclic organophosphorus compounds is demonstrated by the results obtained in training vs. test experiment. The correlated correlation results proved us that the ability in prediction of molar refraction of cyclic organophosphorus compounds with bi-varied MDF SAR model is significantly better compared with the previous reported SAR (see pZ = 0.0 % from Steiger’s Z test. The results showed clearly that the molar refraction of cyclic organophosphorus compounds is almost of topological nature (99.99%, and is strongly dependent on atomic relative mass and atomic electronegativity.

  12. Structure-activity relationship studies on clinically relevant HIV-1 NNRTIs.

    Science.gov (United States)

    Rawal, R K; Murugesan, V; Katti, S B

    2012-01-01

    In addition to the nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs) and integrase inhibitors (INIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) have contributed significantly in the treatment of HIV-1 infections. More than 60 structurally different classes of compounds have been identified as NNRTIs, which are specifically inhibiting HIV-1 reverse transcriptase (RT). Five NNRTIs (nevirapine, delavirdine, efavirenz, etravirine and rilpivirine) have been approved by US Food and Drug Administration (FDA) for clinical use. The NNRTIs bind with a specific 'pocket' site of HIV-1 RT (allosteric site) that is closely associated with the NRTI binding site. Due to mutations of the amino acid residues surrounding the NNRTI-binding site, NNRTIs are notorious for rapidly eliciting resistance. Though, the emergence of resistant HIV strains can be circumvented if the NNRTIs are used either alone or in combination with NRTIs (AZT, 3TC, ddI, ddC, TVD or d4T) and PIs (Indinavir, nelfinavir, saquinavir, ritonavir and lopinavir etc.) as shown by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-cells. Here we are going to discuss recent advances in structure activity relationship studies on nevirapine, delavirdine, efavirenz, etravirine, rilpivirine and 4-thiazolidinones (privileged scaffold) HIV-1 NNRTIs.

  13. Introducing Spectral Structure Activity Relationship (S-SAR Analysis. Application to Ecotoxicology

    Directory of Open Access Journals (Sweden)

    Ana-Maria Lacrămă

    2007-05-01

    Full Text Available A novel quantitative structure-activity (property relationship model, namelySpectral-SAR, is presented in an exclusive algebraic way replacing the old-fashionedmulti-regression one. The actual S-SAR method interprets structural descriptors as vectorsin a generic data space that is further mapped into a full orthogonal space by means of theGram-Schmidt algorithm. Then, by coordinated transformation between the data andorthogonal spaces, the S-SAR equation is given under simple determinant form for anychemical-biological interactions under study. While proving to give the same analyticalequation and correlation results with standard multivariate statistics, the actual S-SARframe allows the introduction of the spectral norm as a valid substitute for the correlationfactor, while also having the advantage to design the various related SAR models throughthe introduced “minimal spectral path” rule. An application is given performing a completeS-SAR analysis upon the Tetrahymena pyriformis ciliate species employing its reportedeco-toxicity activities among relevant classes of xenobiotics. By representing the spectralnorm of the endpoint models against the concerned structural coordinates, the obtainedS-SAR endpoints hierarchy scheme opens the perspective to further design the eco-toxicological test batteries with organisms from different species.

  14. Structure-Activity Relationships of the Bioactive Thiazinoquinone Marine Natural Products Thiaplidiaquinones A and B

    Directory of Open Access Journals (Sweden)

    Jacquie L. Harper

    2015-08-01

    Full Text Available In an effort to more accurately define the mechanism of cell death and to establish structure-activity relationship requirements for the marine meroterpenoid alkaloids thiaplidiaquinones A and B, we have evaluated not only the natural products but also dioxothiazine regioisomers and two precursor quinones in a range of bioassays. While the natural products were found to be weak inducers of ROS in Jurkat cells, the dioxothiazine regioisomer of thiaplidiaquinone A and a synthetic precursor to thiaplidiaquinone B were found to be moderately potent inducers. Intriguingly, and in contrast to previous reports, the mechanism of Jurkat cell death (necrosis vs. apoptosis was found to be dependent upon the positioning of one of the geranyl sidechains in the compounds with thiaplidiaquinone A and its dioxothiazine regioisomer causing death dominantly by necrosis, while thiaplidiaquinone B and its dioxothiazine isomer caused cell death via apoptosis. The dioxothiazine regioisomer of thiaplidiaquinone A exhibited more potent in vitro antiproliferative activity against human tumor cells, with NCI sub-panel selectivity towards melanoma cell lines. The non-natural dioxothiazine regioisomers were also more active in antiplasmodial and anti-farnesyltransferase assays than their natural product counterparts. The results highlight the important role that natural product total synthesis can play in not only helping understand the structural basis of biological activity of natural products, but also the discovery of new bioactive scaffolds.

  15. Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439).

    Science.gov (United States)

    Dong, Yuxiang; Wang, Xiaofang; Kamaraj, Sriraghavan; Bulbule, Vivek J; Chiu, Francis C K; Chollet, Jacques; Dhanasekaran, Manickam; Hein, Christopher D; Papastogiannidis, Petros; Morizzi, Julia; Shackleford, David M; Barker, Helena; Ryan, Eileen; Scheurer, Christian; Tang, Yuanqing; Zhao, Qingjie; Zhou, Lin; White, Karen L; Urwyler, Heinrich; Charman, William N; Matile, Hugues; Wittlin, Sergio; Charman, Susan A; Vennerstrom, Jonathan L

    2017-01-18

    Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.

  16. Prediction of Toxicity of Phenols and Anilines to Algae by Quantitative Structure-activity Relationship

    Institute of Scientific and Technical Information of China (English)

    GUANG-HUA LU; CHAO WANG; XIAO-LING GUO

    2008-01-01

    Objective To measure the toxicity of phenol, aniline, and their derivatives to algae and to assess, model and predict the toxicity using quantitative structure-activity relationship (QSAR) method. Methods Oxygen production was used as the response endpoint for assessing the toxic effects of chemicals on algal photosynthesis. The energy of the lowest unoccupied molecular orbital (ELUMO) and the energy of the highest occupied molecular orbital (E) Were obtained from the ChemOffice 2004 program using the quantum chemical method MOPAC, and the frontier orbital energy gap (ΔE) was obtained. Results The compounds exhibited a reasonably wide range of algal toxicity. The most toxic compound was α-naphthol, whereas the least toxic one was aniline. A two-descriptor model was derived from the algal toxicity and structural parameters:logl/EC50=0.268logKow-1.006ΔE+11.769 (n=20,r2=0.946). This model was stable and satisfactory for predicting toxicity. Conclusion Phenol aniline, and their derivatives axe polar narcotics. Their toxicity is greater than estimated by hydrophobicity only, and addition of the frontier orbital energy gap ΔE can significantly improve the prediction of logKow-dependont models.

  17. Structure-activity relationship study of spider polyamine toxins as inhibitors of ionotropic glutamate receptors.

    Science.gov (United States)

    Xiong, Xiao-Feng; Poulsen, Mette H; Hussein, Rama A; Nørager, Niels G; Strømgaard, Kristian

    2014-12-01

    The spider polyamine toxins Joro spider toxin-3 (JSTX-3) and Nephila polyamine toxins-1 and -8 (NPTX-1 and NPTX-8) are isolated from the venom of the orb-weaver spider Nephila clavata (Joro spider). They share a high degree of structural resemblance, their aromatic head groups being the only difference, and were recently found to be very potent open-channel blockers of ionotropic glutamate (iGlu) receptors. In this study we designed and synthesized a collection of 24 analogues of these toxins using a recently developed solid-phase synthetic methodology. Systematic variation in two regions of the toxins and subsequent evaluation of biological activity at AMPA and NMDA subtypes of iGlu receptors provided succinct information on structure-activity relationships. In particular, one set of analogues were found to display exquisite selectivity and potency for AMPA receptors relative to the natural products. Thus, this systematic SAR study has provided new pharmacological tools for studies of iGlu receptors.

  18. Structure-activity relationship of sulfated hetero/galactofucan polysaccharides on dopaminergic neuron.

    Science.gov (United States)

    Wang, Jing; Liu, Huaide; Jin, Weihua; Zhang, Hong; Zhang, Quanbin

    2016-01-01

    Parkinson's disease (PD) is associated with progressive loss of dopaminergic neurons and more-widespread neuronal changes that cause complex symptoms. The aim of this study was to investigate the structure-activity relationship of sulfated hetero-polysaccharides (DF1) and sulfated galactofucan polysaccharides (DF2) on dopaminergic neuron in vivo and in vitro. Treatment with samples significantly ameliorated the depletion of both DA and TH-, Bcl-2- and Bax-positive neurons in MPTP-induced PD mice, DF1 showed the highest activity. The in vitro results found that DF1 and DF2 could reverse the decreased mitochondrial activity and the increased LDL release induced by MPP(+) (Pneuronal injury caused by MPP(+). Furthermore, the administration of samples effectively decreased lipid peroxidation and increased the level/activities of GSH, GSH-PX, MDA and CAT in MPTP mice. Thus, the neuron protective effect may be mediated, in part, through antioxidant activity and the prevention of cell apoptosis. The chemical composition of DF1, DF2 and DF differed markedly, the DF1 fraction had the most complex chemical composition and showed the highest neuron protective activity. These results suggest that diverse monosaccharides and uronic acid might contribute to neuron protective activity.

  19. Structure-Activity Relationships in Salinomycin: Cytotoxicity and Phenotype Selectivity of Semi-synthetic Derivatives.

    Science.gov (United States)

    Borgström, Björn; Huang, Xiaoli; Hegardt, Cecilia; Oredsson, Stina; Strand, Daniel

    2017-02-10

    The ionophore salinomycin has attracted attention for its exceptional ability to selectively reduce the proportion of cells with stem-like properties in cancer cell populations of varying origin. Targeting the tumorigenicity of such cells is of interest as they are implicated in recurrence, metastasis, and drug resistance. Structural derivatives of salinomycin are thus sought after, both as tools for probing the molecular mechanism(s) underlying the observed phenotype effects, and for improving selectivity and activity against cancer stem cells. Synthetic strategies for modification of each of the directly accessible functional groups of salinomycin are presented and the resulting library of analogues was investigated to establish structure-activity relationships, both with respect to cytotoxicity and phenotype selectivity in breast cancer cells. 20-O-Acylated derivatives stand out by exhibiting both improved selectivity and activity. Mechanistically, the importance of the ionophore properties of salinomycin is highlighted by a significant loss of activity by modifications directly interfering with either of the two primary ion coordinating motifs in salinomycin, the C11 ketone and the C1 carboxylate.

  20. Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships

    Directory of Open Access Journals (Sweden)

    Siew Lee Cheong

    2011-01-01

    Full Text Available In the past few decades, medicinal chemistry research towards potent and selective antagonists of human adenosine receptors (namely, A1, A2A, A2B, and A3 has been evolving rapidly. These antagonists are deemed therapeutically beneficial in several pathological conditions including neurological and renal disorders, cancer, inflammation, and glaucoma. Up to this point, many classes of compounds have been successfully synthesized and identified as potent human adenosine receptor antagonists. In this paper, an overview of the structure-activity relationship (SAR profiles of promising nonxanthine pyrazolo derivatives is reported and discussed. We have emphasized the SAR for some representative structures such as pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines; pyrazolo-[3,4-c] or -[4,3-c]quinolines; pyrazolo-[4,3-d]pyrimidinones; pyrazolo-[3,4-d]pyrimidines and pyrazolo-[1,5-a]pyridines. This overview not only clarifies the structural requirements deemed essential for affinity towards individual adenosine receptor subtypes, but it also sheds light on the rational design and optimization of existing structural templates to allow us to conceive new, more potent adenosine receptor antagonists.

  1. Predicting Flash Point of Organosilicon Compounds Using Quantitative Structure Activity Relationship Approach

    Directory of Open Access Journals (Sweden)

    Chen-Peng Chen

    2014-01-01

    Full Text Available The flash point (FP of a compound is the primary property used in the assessment of fire hazards for flammable liquids and is amongst the crucial information that people handling flammable liquids must possess as far as industrial safety is concerned. In this work, the FPs of 236 organosilicon compounds were collected and used to construct a quantitative structure activity relationship (QSAR model for predicting their FPs. The CODESSA PRO software was adopted to calculate the required molecular descriptors, and 350 molecular descriptors were developed for each compound. A modified stepwise regression algorithm was applied to choose descriptors that were highly correlated with the FP of organosilicon compounds. The proposed model was a linear regression model consisting of six descriptors. This 6-descriptor model gave an R2 value of 0.9174, QLOO2 value of 0.9106, and Q2 value of 0.8989. The average fitting error and the average predictive error were found to be of 10.34 K and 11.22 K, respectively, and the average fitting error in percentage and the average predictive error in percentage were found to be of 3.30 and 3.60%, respectively. Compared with the known reproducibility of FP measurement using standard test method, these predicted results were of a satisfactory precision.

  2. Immunostimulation by synthetic lipopeptide based vaccine candidates: structure-activity relationships.

    Directory of Open Access Journals (Sweden)

    Mehfuz eZaman

    2013-10-01

    Full Text Available Peptide based vaccines offer several advantages over conventional whole organism or protein approaches by offering improved purity and specificity in inducing immune response. However, peptides alone are generally non-immunogenic. Concerns remain about the toxicity of adjuvants which are critical for immunogenicity of synthetic peptides. The use of lipopeptides in peptide vaccines is currently under intensive investigation because potent immune responses can be generated without the use of adjuvant (thus are self-adjuvanting. Several lipopeptides derived from microbial origin, and their synthetic versions or simpler fatty acid moieties impart this self-adjuvanting activity by signalling via Toll-like receptor 2 (TLR2. Engagement of this innate immune receptor on antigen-presenting cell leads to the initiation and development of potent immune responses. Therefore optimization of lipopeptides to enhance TLR2-mediated activation is a promising strategy for vaccine development. Considerable structure-activity relationships that determine TLR2 binding and consequent stimulation of innate immune responses have been investigated for a range of lipopeptides. In this review we address the development of lipopeptide vaccines, mechanism of TLR2 recognition, and immune activation. An overview is provided of the best studied lipopeptide vaccine systems.

  3. Structure-activity relationships of flavonoids as potential inhibitors of glycogen phosphorylase.

    Science.gov (United States)

    Kato, Atsushi; Nasu, Norio; Takebayashi, Kenji; Adachi, Isao; Minami, Yasuhiro; Sanae, Fujiko; Asano, Naoki; Watson, Alison A; Nash, Robert J

    2008-06-25

    Flavonoids are ubiquitous components in vegetables, fruits, tea, and wine. Therefore, they are often consumed in large quantities in our daily diet. Several flavonoids have been shown to have potential as antidiabetic agents. In the present study, we focused on inhibition of glycogen phosphorylase (GP) by flavonoids. 6-Hydroxyluteolin, hypolaetin, and quercetagetin were identified as good inhibitors of dephosphorylated GP (GPb), with IC 50 values of 11.6, 15.7, and 9.7 microM, respectively. Furthermore, a structure-activity relationship study revealed that the presence of the 3' and 4' OH groups in the B-ring and double bonds between C2 and C3 in flavones and flavonols are important factors for enzyme recognition and binding. Quercetagetin inhibited GPb in a noncompetitive manner, with a K i value of 3.5 microM. Multiple inhibition studies by Dixon plots suggested that quercetagetin binds to the allosteric site. In primary cultured rat hepatocytes, quercetagetin and quercetin suppressed glucagon-stimulated glycogenolysis, with IC 50 values of 66.2 and 68.7 microM, respectively. These results suggested that as a group of novel GP inhibitors, flavonoids have potential to contribute to the protection or improvement of control of diabetes type II.

  4. The uridine diphosphate glucuronosyltransferases: quantitative structure-activity relationships for hydroxyl polychlorinated biphenyl substrates

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Degao [Dalian University of Technology, Department of Environmental Science and Technology, Dalian (China)

    2005-10-01

    Quantitative structure-activity relationships (QSARs), which relate the glucuronidation of hydroxyl polychlorinated biphenyls (OH-PCBs) - catalyzed by the uridine diphosphate glucuronosyltransferases (UGTs) - to their physicochemical properties and molecular structural parameters, can be used to predict the rate constants and interpret the mechanism of glucuronidation. In this study, QSARs have been developed that use 23 semi-empirical calculated quantum chemical descriptors to predict the logarithms of the constants 1/K{sub m} and V{sub max}, related to enzyme kinetics. A partial least squares regression method was used to select the optimal set of descriptors to minimize the multicollinearity between the descriptors, as well as to maximize the cross-validated coefficient (Q{sup 2} {sub cum}) values. The key descriptors affecting log(1/K{sub m}) were E{sub lumo}- E{sub homo} (the energy gap between the lowest unoccupied molecular orbital and the highest occupied molecular orbital) and q{sub C}{sup -} (the largest negative net atomic charge on a carbon atom), while the key descriptors affecting log V{sub max} were the polarizability {alpha}, the Connolly solvent-excluded volume (CSEV), and logP (the logarithm of the partition coefficient for octanol/water). From the results obtained it can be concluded that hydrophobic and electronic aspects of OH-PCBs are important in the glucuronidation of OH-PCBs. (orig.)

  5. Anti-proliferative activities of terpenoids isolated from Alisma orientalis and their structure-activity relationships.

    Science.gov (United States)

    Xu, Wen; Li, Ting; Qiu, Jian-Fang; Wu, Shui-Sheng; Huang, Ming-Qing; Lin, Li-Gen; Zhang, Qing-Wen; Chen, Xiu-Ping; Lu, Jin-Jian

    2015-01-01

    This study aimed to isolate terpenoids from Alisma orientalis (Sam.) Juzep. and elucidate their antiproliferative activities, as well as structure-activity relationships. Fourteen protostane-type triterpenoids were isolated from the rhizome of A. orientalis. Among these triterpenoids, alisol A (1), alisol A 24-acetate (2), alisol B (3), alisol B 23-acetate (4), and alisol G (8) presented inhibitory effects on cancer cell lines tested. Compounds 3 and 4 showed the highest potential; IC50 values for HepG2, MDA-MB-231, and MCF-7 cells were 16.28, 14.47, and 6.66 μM for 3 and 18.01, 15.97, and 13.56 μM for 4, respectively. Based on these results, we concluded that the degree of C-16 oxidation and the double bond between C-13 and C-17 may be significant in anti-proliferative activities. Further study showed that 3 and 4 effectively induced apoptosis, as confirmed by flow cytometry. Increased intracellular calcium concentration and endoplasmic reticulum stress were detected after treatment with 4 in HepG2 cells. Although compounds 1 and 2 induced minimal apoptosis, they evidently delayed the G2/M phase in HepG2 cells. Further study showed that 1-4 also enhanced LC3II expression, indicating autophagy is occured.

  6. The Structure-Activity Relationship of Pterostilbene Against Candida albicans Biofilms

    Directory of Open Access Journals (Sweden)

    Dan-Dan Hu

    2017-02-01

    Full Text Available Candida albicans biofilms contribute to invasive infections and dramatic drug resistance, and anti-biofilm agents are urgently needed in the clinic. Pterostilbene (PTE is a natural plant product with potentials to be developed as an anti-biofilm agent. In this study, we evaluated the structure-activity relationship (SAR of PTE analogues against C. albicans biofilms. XTT (Sodium 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl-2H-tetrazolium-5-carboxanilide inner salt reduction assay was used to evaluate the activity of the analogues against C. albicans biofilms. Knowing that hyphal formation is essential for C. albicans biofilms, anti-hyphal assay was further carried out. By comparing a series of compounds tested in this study, we found that compounds with para-hydroxy (–OH in partition A exhibited better activity than those with other substituents in the para position, and the double bond in partition B and meta-dimethoxy (–OCH3 in partition C both contributed to the best activity. Consistent results were obtained by anti-hyphal assay. Collectively, para-hydroxy (–OH, double bond and meta-dimethoxy (–OCH3 are all needed for the best activity of PTE against C. albicans biofilms.

  7. Targeted Mutations of Bacillus anthracis Dihydrofolate Reductase Condense Complex Structure-Activity Relationships

    Energy Technology Data Exchange (ETDEWEB)

    J Beierlein; N Karri; A Anderson

    2011-12-31

    Several antifolates, including trimethoprim (TMP) and a series of propargyl-linked analogues, bind dihydrofolate reductase from Bacillus anthracis (BaDHFR) with lower affinity than is typical in other bacterial species. To guide lead optimization for BaDHFR, we explored a new approach to determine structure-activity relationships whereby the enzyme is altered and the analogues remain constant, essentially reversing the standard experimental design. Active site mutants of the enzyme, Ba(F96I)DHFR and Ba(Y102F)DHFR, were created and evaluated with enzyme inhibition assays and crystal structures. The affinities of the antifolates increase up to 60-fold with the Y102F mutant, suggesting that interactions with Tyr 102 are critical for affinity. Crystal structures of the enzymes bound to TMP and propargyl-linked inhibitors reveal the basis of TMP resistance and illuminate the influence of Tyr 102 on the lipophilic linker between the pyrimidine and aryl rings. Two new inhibitors test and validate these conclusions and show the value of the technique for providing new directions during lead optimization.

  8. Derivatives of Ergot-alkaloids: Molecular structure, physical properties, and structure-activity relationships

    Science.gov (United States)

    Ivanova, Bojidarka B.; Spiteller, Michael

    2012-09-01

    A comprehensive screening of fifteen functionalized Ergot-alkaloids, containing bulk aliphatic cyclic substituents at D-ring of the ergoline molecular skeleton was performed, studying their structure-active relationships and model interactions with α2A-adreno-, serotonin (5HT2A) and dopamine D3 (D3A) receptors. The accounted high affinity to the receptors binding loops and unusual bonding situations, joined with the molecular flexibility of the substituents and the presence of proton accepting/donating functional groups in the studied alkaloids, may contribute to further understanding the mechanisms of biological activity in vivo and in predicting their therapeutic potential in central nervous system (CNS), including those related the Schizophrenia. Since the presented correlation between the molecular structure and properties, was based on the comprehensively theoretical computational and experimental physical study on the successfully isolated derivatives, through using routine synthetic pathways in a relatively high yields, marked these derivatives as 'treasure' for further experimental and theoretical studied in areas such as: (a) pharmacological and clinical testing; (b) molecular-drugs design of novel psychoactive substances; (c) development of the analytical protocols for determination of Ergot-alkaloids through a functionalization of the ergoline-skeleton, and more.

  9. Investigation and prediction of protein precipitation by polyethylene glycol using quantitative structure-activity relationship models.

    Science.gov (United States)

    Hämmerling, Frank; Ladd Effio, Christopher; Andris, Sebastian; Kittelmann, Jörg; Hubbuch, Jürgen

    2017-01-10

    Precipitation of proteins is considered to be an effective purification method for proteins and has proven its potential to replace costly chromatography processes. Besides salts and polyelectrolytes, polymers, such as polyethylene glycol (PEG), are commonly used for precipitation applications under mild conditions. Process development, however, for protein precipitation steps still is based mainly on heuristic approaches and high-throughput experimentation due to a lack of understanding of the underlying mechanisms. In this work we apply quantitative structure-activity relationships (QSARs) to model two parameters, the discontinuity point m* and the β-value, that describe the complete precipitation curve of a protein under defined conditions. The generated QSAR models are sensitive to the protein type, pH, and ionic strength. It was found that the discontinuity point m* is mainly dependent on protein molecular structure properties and electrostatic surface properties, whereas the β-value is influenced by the variance in electrostatics and hydrophobicity on the protein surface. The models for m* and the β-value exhibit a good correlation between observed and predicted data with a coefficient of determination of R(2)≥0.90 and, hence, are able to accurately predict precipitation curves for proteins. The predictive capabilities were demonstrated for a set of combinations of protein type, pH, and ionic strength not included in the generation of the models and good agreement between predicted and experimental data was achieved.

  10. Blood-brain barrier permeability mechanisms in view of quantitative structure-activity relationships (QSAR).

    Science.gov (United States)

    Bujak, Renata; Struck-Lewicka, Wiktoria; Kaliszan, Michał; Kaliszan, Roman; Markuszewski, Michał J

    2015-04-10

    The goal of the present paper was to develop a quantitative structure-activity relationship (QSAR) method using a simple statistical approach, such as multiple linear regression (MLR) for predicting the blood-brain barrier (BBB) permeability of chemical compounds. The "best" MLR models, comprised logP and either molecular mass (M) or isolated atomic energy (E(isol)), tested on a structurally diverse set of 66 compounds, is characterized the by correlation coefficients (R) around 0.8. The obtained models were validated using leave-one-out (LOO) cross-validation technique and the correlation coefficient of leave-one-out- R(LOO)(2) (Q(2)) was at least 0.6. Analysis of a case from legal medicine demonstrated informative value of our QSAR model. To best authors' knowledge the present study is a first application of the developed QSAR models of BBB permeability to case from the legal medicine. Our data indicate that molecular energy-related descriptors, in combination with the well-known descriptors of lipophilicity may have a supportive value in predicting blood-brain distribution, which is of utmost importance in drug development and toxicological studies.

  11. Automated Structure-Activity Relationship Mining: Connecting Chemical Structure to Biological Profiles.

    Science.gov (United States)

    Wawer, Mathias J; Jaramillo, David E; Dančík, Vlado; Fass, Daniel M; Haggarty, Stephen J; Shamji, Alykhan F; Wagner, Bridget K; Schreiber, Stuart L; Clemons, Paul A

    2014-06-01

    Understanding the structure-activity relationships (SARs) of small molecules is important for developing probes and novel therapeutic agents in chemical biology and drug discovery. Increasingly, multiplexed small-molecule profiling assays allow simultaneous measurement of many biological response parameters for the same compound (e.g., expression levels for many genes or binding constants against many proteins). Although such methods promise to capture SARs with high granularity, few computational methods are available to support SAR analyses of high-dimensional compound activity profiles. Many of these methods are not generally applicable or reduce the activity space to scalar summary statistics before establishing SARs. In this article, we present a versatile computational method that automatically extracts interpretable SAR rules from high-dimensional profiling data. The rules connect chemical structural features of compounds to patterns in their biological activity profiles. We applied our method to data from novel cell-based gene-expression and imaging assays collected on more than 30,000 small molecules. Based on the rules identified for this data set, we prioritized groups of compounds for further study, including a novel set of putative histone deacetylase inhibitors.

  12. Antiproliferative Pt(IV) complexes: synthesis, biological activity, and quantitative structure-activity relationship modeling.

    Science.gov (United States)

    Gramatica, Paola; Papa, Ester; Luini, Mara; Monti, Elena; Gariboldi, Marzia B; Ravera, Mauro; Gabano, Elisabetta; Gaviglio, Luca; Osella, Domenico

    2010-09-01

    Several Pt(IV) complexes of the general formula [Pt(L)2(L')2(L'')2] [axial ligands L are Cl-, RCOO-, or OH-; equatorial ligands L' are two am(m)ine or one diamine; and equatorial ligands L'' are Cl- or glycolato] were rationally designed and synthesized in the attempt to develop a predictive quantitative structure-activity relationship (QSAR) model. Numerous theoretical molecular descriptors were used alongside physicochemical data (i.e., reduction peak potential, Ep, and partition coefficient, log Po/w) to obtain a validated QSAR between in vitro cytotoxicity (half maximal inhibitory concentrations, IC50, on A2780 ovarian and HCT116 colon carcinoma cell lines) and some features of Pt(IV) complexes. In the resulting best models, a lipophilic descriptor (log Po/w or the number of secondary sp3 carbon atoms) plus an electronic descriptor (Ep, the number of oxygen atoms, or the topological polar surface area expressed as the N,O polar contribution) is necessary for modeling, supporting the general finding that the biological behavior of Pt(IV) complexes can be rationalized on the basis of their cellular uptake, the Pt(IV)-->Pt(II) reduction, and the structure of the corresponding Pt(II) metabolites. Novel compounds were synthesized on the basis of their predicted cytotoxicity in the preliminary QSAR model, and were experimentally tested. A final QSAR model, based solely on theoretical molecular descriptors to ensure its general applicability, is proposed.

  13. A Combined Quantitative Structure-Activity Relationship Research of Quinolinone Derivatives as Androgen Receptor Antagonists.

    Science.gov (United States)

    Wang, Yuwei; Bai, Fang; Cao, Hong; Li, Jiazhong; Liu, Huanxiang; Gramatica, Paola

    2015-01-01

    Antiandrogens bicalutamide, flutamide and enzalutamide etc. have been used in clinical trials to treat prostate cancer by binding to and antagonizing androgen receptor (AR). Although initially effective, the drug resistance problem will emerge eventually, which results in a high medical need for novel AR antagonist exploitation. Here in this work, to facilitate the rational design of novel AR antagonists, we studied the structure-activity relationships of a series of 2-quinolinone derivatives and investigated the structural requirements for their antiandrogenic activities. Different modeling methods, including 2D MLR, 3D CoMFA and CoMSIA, were implemented to evolve QSAR models. All these models, thoroughly validated, demonstrated satisfactory results especially for the good predictive abilities. The contour maps from 3D CoMFA and CoMSIA models provide visualized explanation of key structural characteristics relevant to the antiandrogenic activities, which is summarized to a position-specific conclusion at the end. The obtained results from this research are practically useful for rational design and screening of promising chemicals with high antiandrogenic activities.

  14. Synthesis, photodynamic activity, and quantitative structure-activity relationship modelling of a series of BODIPYs.

    Science.gov (United States)

    Caruso, Enrico; Gariboldi, Marzia; Sangion, Alessandro; Gramatica, Paola; Banfi, Stefano

    2017-02-01

    Here we report the synthesis of eleven new BODIPYs (14-24) characterized by the presence of an aromatic ring on the 8 (meso) position and of iodine atoms on the pyrrolic 2,6 positions. These molecules, together with twelve BODIPYs already reported by us (1-12), represent a large panel of BODIPYs showing different atoms or groups as substituent of the aromatic moiety. Two physico-chemical features ((1)O2 generation rate and lipophilicity), which can play a fundamental role in the outcome as photosensitizers, have been studied. The in vitro photo-induced cell-killing efficacy of 23 PSs was studied on the SKOV3 cell line treating the cells for 24h in the dark then irradiating for 2h with a green LED device (fluence 25.2J/cm(2)). The cell-killing efficacy was assessed with the MTT test and compared with that one of meso un-substituted compound (13). In order to understand the possible effect of the substituents, a predictive quantitative structure-activity relationship (QSAR) regression model, based on theoretical holistic molecular descriptors, was developed. The results clearly indicate that the presence of an aromatic ring is fundamental for an excellent photodynamic response, whereas the electronic effects and the position of the substituents on the aromatic ring do not influence the photodynamic efficacy.

  15. Synthesis and antioxidant evaluation of isochroman-derivatives of hydroxytyrosol: structure-activity relationship.

    Science.gov (United States)

    Mateos, Raquel; Madrona, Andrés; Pereira-Caro, Gema; Domínguez, Vanessa; Cert, Rosa M A; Parrado, Juan; Sarriá, Beatriz; Bravo, Laura; Espartero, José Luis

    2015-04-15

    Isochroman-derivatives of the natural olive oil phenol hydroxytyrosol (HT) have been synthesised via Oxa-Pictet-Spengler reaction in high yields. Lipophilicity and antioxidant activity were determined to establish the structure-activity relationship of isochromans compared to HT, BHT and α-tocopherol. Antioxidant capacity was tested in two different media: bulk oils, using the Rancimat test, and brain homogenates, by measuring malondialdehyde (MDA) levels as a lipoperoxidation biomarker. In addition, other antioxidant assays (FRAP, ABTS and ORAC) were carried out. Rancimat and MDA results show that antioxidant activity was related with lipophilicity, directly in brain homogenates and inversely in the oils, in agreement with the polar paradox. Free o-diphenolic groups positively determined the activity in the oils, whereas reducing and radical-scavenging activities were related to the number of free hydroxyl moieties. BHT and α-tocopherol showed lower antioxidant activity than isochromans and HT. We conclude that HT-isochromans present significant potential as bioactive compounds.

  16. Structure-activity relationship of the pro- and anticoagulant effects of Fucus vesiculosus fucoidan.

    Science.gov (United States)

    Zhang, Z; Till, S; Jiang, C; Knappe, S; Reutterer, S; Scheiflinger, F; Szabo, C M; Dockal, M

    2014-03-03

    Fucoidan is a highly complex sulfated polysaccharide commonly extracted from brown seaweed. In addition to their many biological activities, fucoidans have recently been demonstrated to inhibit or increase coagulation at different concentration ranges. Their structural features, i.e. molecular weight (Mw), Mw distribution, degree of sulfation, monosaccharide composition, and different linkages, are known to affect these activities. Therefore, structure-activity relationship (SAR) analysis of fucoidan is crucial for its potential use as a procoagulant. In this study, Fucus vesiculosus (F.v.) fucoidan was fractionated by charge and size as well as over- and desulfated to different degrees to yield preparations with various structural properties. The fractions' pro- and anticoagulant activities were assessed by calibrated automated thrombography (CAT) and activated partial thromboplastin time(aPTT) assays. Binding to and inhibition of the anticoagulant protein tissue factor pathway inhibitor (TFPI) and the ability to activate coagulation via the contact pathway were also investigated. This paper discusses the impact of charge density, size, and sugar composition on fucoidan's pro- and anticoagulant activities. Fucoidan requires a minimal charge density of 0.5 sulfates per sugar unit and a size of 70 sugar units to demonstrate desired procoagulant activities for improvement of haemostasis in factor VIII/factor IX-deficient plasma.

  17. Synthesis, Structure-Activity Relationships (SAR and in Silico Studies of Coumarin Derivatives with Antifungal Activity

    Directory of Open Access Journals (Sweden)

    José M. Barbosa-Filho

    2013-01-01

    Full Text Available The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 µg/mL. The structure-activity relationships (SAR study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and/or electron withdrawing groups (NO2 and/or acetate favor activity. These findings were confirmed using density functional theory (DFT, when calculating the LUMO density. In Principal Component Analysis (PCA, two significant principal components (PCs explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS model showed an r2 of 0.86 and q2cv of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity.

  18. Total synthesis and structure-activity relationship studies of a series of selective G protein inhibitors

    Science.gov (United States)

    Xiong, Xiao-Feng; Zhang, Hang; Underwood, Christina R.; Harpsøe, Kasper; Gardella, Thomas J.; Wöldike, Mie F.; Mannstadt, Michael; Gloriam, David E.; Bräuner-Osborne, Hans; Strømgaard, Kristian

    2016-11-01

    G proteins are key mediators of G protein-coupled receptor signalling, which facilitates a plethora of important physiological processes. The cyclic depsipeptides YM-254890 and FR900359 are the only known specific inhibitors of the Gq subfamily of G proteins; however, no synthetic route has been reported previously for these complex natural products and they are not easily isolated from natural sources. Here we report the first total synthesis of YM-254890 and FR900359, as well as of two known analogues, YM-385780 and YM-385781. The versatility of the synthetic approach also enabled the design and synthesis of ten analogues, which provided the first structure-activity relationship study for this class of compounds. Pharmacological characterization of all the compounds at Gq-, Gi- and Gs-mediated signalling provided succinct information on the structural requirements for inhibition, and demonstrated that both YM-254890 and FR900359 are highly potent inhibitors of Gq signalling, with FR900359 being the most potent. These natural products and their analogues represent unique tools for explorative studies of G protein inhibition.

  19. Quantitative structure-activity relationship and prediction of mixture toxicity of alkanols

    Institute of Scientific and Technical Information of China (English)

    WANG Bin; YU Gang; ZHANG Zulin; HU Hongying; WANG Liansheng

    2006-01-01

    Alkanols, which are narcotic compounds,were studied. The acute toxicities (15min-EG50) of 15alkanols, which have a large span of hydrophobicity,to Photobacterium phosphoreum were measured.Quantitative structure-activity relationship (QSAR)analysis of single toxicity of alkanols was conducted by using octanol-water partition coefficient (logKow).The polynomial expression was used instead of linear equation to develop QSAR model, and a QSAR model with a good predictive potential was achieved.Furthermore, the mixture toxicity of alkanols was studied. In order to predict joint toxicity of mixtures that contain very hydrophobic alkanols, the adjustment of octanol-water partition coefficient was performed, considering the influence of volume effect.And equivalent octanol-water partition coefficient was introduced. The QSAR model of mixture toxicity was developed by using equivalent mixture octanol-water partition coefficient. The result showed that even a linear model could predict mixture toxicity well by using equivalent mixture octanol-water partition coefficient.

  20. Antitumor activity of 3,4-ethylenedioxythiophene derivatives and quantitative structure-activity relationship analysis

    Science.gov (United States)

    Jukić, Marijana; Rastija, Vesna; Opačak-Bernardi, Teuta; Stolić, Ivana; Krstulović, Luka; Bajić, Miroslav; Glavaš-Obrovac, Ljubica

    2017-04-01

    The aim of this study was to evaluate nine newly synthesized amidine derivatives of 3,4- ethylenedioxythiophene (3,4-EDOT) for their cytotoxic activity against a panel of human cancer cell lines and to perform a quantitative structure-activity relationship (QSAR) analysis for the antitumor activity of a total of 27 3,4-ethylenedioxythiophene derivatives. Induction of apoptosis was investigated on the selected compounds, along with delivery options for the optimization of activity. The best obtained QSAR models include the following group of descriptors: BCUT, WHIM, 2D autocorrelations, 3D-MoRSE, GETAWAY descriptors, 2D frequency fingerprint and information indices. Obtained QSAR models should be relieved in elucidation of important physicochemical and structural requirements for this biological activity. Highly potent molecules have a symmetrical arrangement of substituents along the x axis, high frequency of distance between N and O atoms at topological distance 9, as well as between C and N atoms at topological distance 10, and more C atoms located at topological distances 6 and 3. Based on the conclusion given in the QSAR analysis, a new compound with possible great activity was proposed.

  1. 3D-quantitative structure-activity relationship study of organophosphate compounds

    Institute of Scientific and Technical Information of China (English)

    ZHAO Jinsong; WANG Bin; DAI Zhaoxia; WANG Xiaodong; KONG Lingren; WANG Liansheng

    2004-01-01

    The biological effects of most organophosphate compounds (OP) are arising by inhibition of the enzyme acetylcholinesterase (AChE). The 3D-quantitative structure-activity relationship (3D-QSAR) on the acute toxicity to housefly (Musca nobulo L.) of 35 dialkyl phenyl phosphate compounds are studied by using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods, and the reaction mechanism between the OP and the AChE are discussed. In contrast to classical QSAR methods, CoMFA and CoMSIA, especially the combination of both approaches, can give more comprehensive and accurate perspectives on the mechanism of the reaction between OP and AChE. The results show that the length of alkyl, and the electronegative of substituent on phenyl of OP have significant effects on the AChE activity, whereas, the hydrophobicity of OP has little influence. The steric and electronic properties of OP have a dominant influence on the reaction between OP and AChE.

  2. Utilization of quantitative structure-activity relationships (QSARs) in risk assessment: Alkylphenols

    Energy Technology Data Exchange (ETDEWEB)

    Beck, B.D.; Toole, A.P.; Callahan, B.G.; Siddhanti, S.K. (Gradient Corporation, Cambridge, MA (United States))

    1991-12-01

    Alkylphenols are a class of environmentally pervasive compounds, found both in natural (e.g., crude oils) and in anthropogenic (e.g., wood tar, coal gasification waste) materials. Despite the frequent environmental occurrence of these chemicals, there is a limited toxicity database on alkylphenols. The authors have therefore developed a 'toxicity equivalence approach' for alkylphenols which is based on their ability to inhibit, in a specific manner, the enzyme cyclooxygenase. Enzyme-inhibiting ability for individual alkylphenols can be estimated based on the quantitative structure-activity relationship developed by Dewhirst (1980) and is a function of the free hydroxyl group, electron-donating ring substituents, and hydrophobic aromatic ring substituents. The authors evaluated the toxicological significance of cyclooxygenase inhibition by comparison of the inhibitory capacity of alkylphenols with the inhibitory capacity of acetylsalicylic acid, or aspirin, a compound whose low-level effects are due to cyclooxygenase inhibition. Since nearly complete absorption for alkylphenols and aspirin is predicted, based on estimates of hydrophobicity and fraction of charged molecules at gastrointestinal pHs, risks from alkylphenols can be expressed directly in terms of 'milligram aspirin equivalence,' without correction for absorption differences. They recommend this method for assessing risks of mixtures of alkylphenols, especially for those compounds with no chronic toxicity data.38 references.

  3. Predicting Cell Association of Surface-Modified Nanoparticles Using Protein Corona Structure - Activity Relationships (PCSAR).

    Science.gov (United States)

    Kamath, Padmaja; Fernandez, Alberto; Giralt, Francesc; Rallo, Robert

    2015-01-01

    Nanoparticles are likely to interact in real-case application scenarios with mixtures of proteins and biomolecules that will absorb onto their surface forming the so-called protein corona. Information related to the composition of the protein corona and net cell association was collected from literature for a library of surface-modified gold and silver nanoparticles. For each protein in the corona, sequence information was extracted and used to calculate physicochemical properties and statistical descriptors. Data cleaning and preprocessing techniques including statistical analysis and feature selection methods were applied to remove highly correlated, redundant and non-significant features. A weighting technique was applied to construct specific signatures that represent the corona composition for each nanoparticle. Using this basic set of protein descriptors, a new Protein Corona Structure-Activity Relationship (PCSAR) that relates net cell association with the physicochemical descriptors of the proteins that form the corona was developed and validated. The features that resulted from the feature selection were in line with already published literature, and the computational model constructed on these features had a good accuracy (R(2)LOO=0.76 and R(2)LMO(25%)=0.72) and stability, with the advantage that the fingerprints based on physicochemical descriptors were independent of the specific proteins that form the corona.

  4. Deciphering structure-activity relationships in a series of Tat/TAR inhibitors.

    Science.gov (United States)

    Pascale, Lise; González, Alejandro López; Di Giorgio, Audrey; Gaysinski, Marc; Teixido Closa, Jordi; Tejedor, Roger Estrada; Azoulay, Stéphane; Patino, Nadia

    2016-11-01

    A series of pentameric "Polyamide Amino Acids" (PAAs) compounds derived from the same trimeric precursor have been synthesized and investigated as HIV TAR RNA ligands, in the absence and in the presence of a Tat fragment. All PAAs bind TAR with similar sub-micromolar affinities but their ability to compete efficiently with the Tat fragment strongly differs, IC50 ranging from 35 nM to >2 μM. While NMR and CD studies reveal that all PAA interact with TAR at the same site and induce globally the same RNA conformational change upon binding, a comparative thermodynamic study of PAA/TAR equilibria highlights distinct TAR binding modes for Tat competitor and non-competitor PAAs. This led us to suggest two distinct interaction modes that have been further validated by molecular modeling studies. While the binding of Tat competitor PAAs induces a contraction at the TAR bulge region, the binding of non-competitor ones widens it. This could account for the distinct PAA ability to compete with Tat fragment. Our work illustrates how comparative thermodynamic studies of a series of RNA ligands of same chemical family are of value for understanding their binding modes and for rationalizing structure-activity relationships.

  5. Synthesis, insecticidal activity, and structure-activity relationship (SAR) of anthranilic diamides analogs containing oxadiazole rings.

    Science.gov (United States)

    Li, Yuhao; Zhu, Hongjun; Chen, Kai; Liu, Rui; Khallaf, Abdalla; Zhang, Xiangning; Ni, Jueping

    2013-06-28

    A series of anthranilic diamides analogs (3–11, 16–24) containing 1,2,4- or 1,3,4-oxadiazole rings were synthesized and characterized by (1)H NMR, MS and elemental analyses. The structure of 3-bromo-N-(2-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (18, CCDC-) was determined by X-ray diffraction crystallography. The insecticidal activities against Plutella xylostella and Spodoptera exigua were evaluated. The results showed that most of title compounds displayed good larvicidal activities against P. xylostella, especially compound 3-bromo-N-(4-chloro-2-methyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (6), which displayed 71.43% activity against P. xylostella at 0.4 μg mL(-1) and 33.33% against S. exigua at 1 μg mL(-1). The structure-activity relationship showed that compounds decorated with a 1,3,4-oxadiazole were more potent than compounds decorated with a 1,2,4-oxadiazole, and different substituents attached to the oxadiazole ring also affected the insecticidal activity. This work provides some hints for further structure modification and the enhancement of insecticidal activity.

  6. Structure-activity relationships of pyrazole derivatives as potential therapeutics for immune thrombocytopenias.

    Science.gov (United States)

    Purohit, Meena K; Chakka, Sai Kumar; Scovell, Iain; Neschadim, Anton; Bello, Angelica M; Salum, Noruê; Katsman, Yulia; Bareau, Madeleine C; Branch, Donald R; Kotra, Lakshmi P

    2014-05-01

    Idiopathic or immune thrombocytopenia (ITP) is a serious clinical disorder involving the destruction of platelets by macrophages. Small molecule therapeutics are highly sought after to ease the burden on current therapies derived from human sources. Earlier, we discovered that dimers of five-membered heterocycles exhibited potential to inhibit phagocytosis of human RBCs by macrophages. Here, we reveal a structure-activity relationship of the bis-pyrazole class of molecules with -C-C-, -C-N- and -C-O- linkers, and their evaluation as inhibitors of phagocytosis of antibody-opsonized human RBCs as potential therapeutics for ITP. We have uncovered three potential candidates, 37, 47 and 50, all carrying a different linker connecting the two pyrazole moieties. Among these compounds, hydroxypyrazole derivative 50 is the most potent compound with an IC50 of 14 ± 9 μM for inhibiting the phagocytosis of antibody-opsonized human RBCs by macrophages. None of the compounds exhibited significant potential to induce apoptosis in peripheral blood mononuclear cells (PBMCs). Current study has revealed specific functional features, such as up to 2-atom spacer arm and alkyl substitution at one of the N(1) positions of the bivalent pyrazole core to be important for the inhibitory activity.

  7. Fundamental Structure-Activity Relationships of Titanium Dioxide-Based Photocatalysts

    Science.gov (United States)

    Roberts, Charles A.

    Heterogeneous photocatalysis has been identified as a means of using renewable solar energy to produce the sustainable, non-carbon fuel H 2 and a variety of useful chemical intermediates. Currently, however, heterogeneous photocatalytic reactions are too inefficient to be industrially relevant and a deeper understanding of the effect of fundamental photocatalytic material properties on photoactivity is needed to further enhance the yields of desired products. In the general field of heterogeneous catalysis, structure-activity relationships aid in the rational design of improved catalysts and this ideology was applied to photocatalytic reactions over TiO2 based photocatalysts and model supported TiO2/SiO2 catalysts in this study. The model supported TiO2/SiO2 catalysts contain well-defined TiOx nanodomain structures that vary in domain size and electronic structure and greatly facilitate the determination of structure-photoactivity relationships. These catalysts were used in reactor studies during photocatalytic water splitting and cyclohexane photo-oxidation, and were monitored for production of H2 and cyclohexanone, respectively. It was found that for both reactions the trend in photoactivity for the TiOx nanodomains proceeded as: pure TiO2 (anatase) (24 nm) > TiO2 (anatase) nanoparticles (4--11 nm) > polymeric surface TiO5 (˜1 nm) > surface isolated TiO4 (˜0.4 nm). Photoluminescence (PL) spectroscopy was employed to yield insight into how exciton generation and recombination are related to TiOx domain size and, thus, to the photoactivity of the examined reactions. Transient PL decay studies determined that the larger bulk structure found in TiO 2 (anatase) nanoparticles (NPs) acts as a reservoir for excitons exhibiting slow recombination kinetics, which have an increased opportunity to participate in photochemistry at the surface active sites. The reactions were also studied using in situ attenuated total reflectance (ATR) Fourier transform infrared

  8. Synthesis, Biological Evaluation and Structure-Activity Relationships of New Quinoxaline Derivatives as Anti-Plasmodium falciparum Agents

    Directory of Open Access Journals (Sweden)

    Ana Gil

    2014-02-01

    Full Text Available We report the synthesis and antimalarial activities of eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives, eight of which are completely novel. Compounds 1a and 2a were the most active against Plasmodium falciparum strains. Structure-activity relationships demonstrated the importance of an enone moiety linked to the quinoxaline ring.

  9. Synthesis, biological evaluation and structure-activity relationships of new quinoxaline derivatives as anti-Plasmodium falciparum agents.

    Science.gov (United States)

    Gil, Ana; Pabón, Adriana; Galiano, Silvia; Burguete, Asunción; Pérez-Silanes, Silvia; Deharo, Eric; Monge, Antonio; Aldana, Ignacio

    2014-02-18

    We report the synthesis and antimalarial activities of eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives, eight of which are completely novel. Compounds 1a and 2a were the most active against Plasmodium falciparum strains. Structure-activity relationships demonstrated the importance of an enone moiety linked to the quinoxaline ring.

  10. Benzothiophene inhibitors of MK2. Part 1: structure-activity relationships, assessments of selectivity and cellular potency.

    Science.gov (United States)

    Anderson, David R; Meyers, Marvin J; Kurumbail, Ravi G; Caspers, Nicole; Poda, Gennadiy I; Long, Scott A; Pierce, Betsy S; Mahoney, Matthew W; Mourey, Robert J

    2009-08-15

    Identification of potent benzothiophene inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK2), structure-activity relationship (SAR) studies, selectivity assessments against CDK2, cellular potency and mechanism of action are presented. Crystallographic data provide a rationale for the observed MK2 potency as well as selectivity over CDK2 for this class of inhibitors.

  11. Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: design, synthesis, structure-activity relationships, physicochemical properties and biological activity

    NARCIS (Netherlands)

    Blaazer, A.R.; Lange, J.H.M.; van der Neut, M.A.W.; Mulder, A.; den Boon, F.S.; Werkman, T.R.; Kruse, C.G.; Wadman, W.J.

    2011-01-01

    The discovery, synthesis and structure-activity relationship (SAR) of a novel series of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor ligands are reported. Based on the aminoalkylindole class of cannabinoid receptor agonists, a biphenyl moiety was introduced as novel lipophilic indole 3-acyl

  12. A quantitative structure-activity relationship for the acute toxicity of some epoxy compounds to the guppy

    NARCIS (Netherlands)

    Deneer, J.W.; Sinnige, T.L.; Seinen, W.; Hermens, J.L.M.

    1988-01-01

    The 14 day LC50 values of various epoxy compounds to the guppy (Poecilia reticulata) were determined, and investigated through the construction of a quantitative structure-activity relationship (QSAR). Both hydrophobicity and alkylating potency of the compounds are found to be necessary parameters f

  13. Synthesis, Biological Evaluation and Structure-Activity Relationships of New Quinoxaline Derivatives as Anti-Plasmodium falciparum Agents

    OpenAIRE

    Ana Gil; Adriana Pabón; Silvia Galiano; Asunción Burguete; Silvia Pérez-Silanes; Eric Deharo; Antonio Monge; Ignacio Aldana

    2014-01-01

    We report the synthesis and antimalarial activities of eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives, eight of which are completely novel. Compounds 1a and 2a were the most active against Plasmodium falciparum strains. Structure-activity relationships demonstrated the importance of an enone moiety linked to the quinoxaline ring.

  14. Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors.

    Directory of Open Access Journals (Sweden)

    Vignir Isberg

    Full Text Available Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9-11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9-11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9-11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands.

  15. Structure-activity relationship of benzophenanthridine alkaloids from Zanthoxylum rhoifolium having antimicrobial activity.

    Directory of Open Access Journals (Sweden)

    Luciana de C Tavares

    Full Text Available Zanthoxylum rhoifolium (Rutaceae is a plant alkaloid that grows in South America and has been used in Brazilian traditional medicine for the treatment of different health problems. The present study was designed to evaluate the antimicrobial activity of the steam bark crude methanol extract, fractions, and pure alkaloids of Z. rhoifolium. Its stem bark extracts exhibited a broad spectrum of antimicrobial activity, ranging from 12.5 to 100 µg/mL using bioautography method, and from 125 to 500 µg/mL in the microdilution bioassay. From the dichloromethane basic fraction, three furoquinoline alkaloids (1-3, and nine benzophenanthridine alkaloids (4-12 were isolated and the antimicrobial activity of the benzophenanthridine alkaloids is discussed in terms of structure-activity relationships. The alkaloid with the widest spectrum of activity was chelerythrine (10, followed by avicine (12 and dihydrochelerythrine (4. The minimal inhibitory concentrations of chelerythrine, of 1.50 µg/mL for all bacteria tested, and between 3.12 and 6.25 µg/mL for the yeast tested, show this compound to be a more powerful antimicrobial agent when compared with the other active alkaloids isolated from Z. rhoifolium. To verify the potential importance of the methylenedioxy group (ring A of these alkaloids, chelerythrine was selected to represent the remainder of the benzophenanthridine alkaloids isolated in this work and was subjected to a demethylation reaction giving derivative 14. Compared to chelerythrine, the derivative (14 was less active against the tested bacteria and fungi. Kinetic measurements of the bacteriolytic activities of chelerythrine against the bacteria Bacillus subtilis (Gram-positive and Escherichia coli (Gram-negative were determined by optical density based on real time assay, suggesting that its mechanism of action is not bacteriolytic. The present study did not detect hemolytic effects of chelerythrine on erythrocytes and found a protective

  16. Inhibition of angiotensin-converting enzyme activity by flavonoids: structure-activity relationship studies.

    Directory of Open Access Journals (Sweden)

    Ligia Guerrero

    Full Text Available Previous studies have demonstrated that certain flavonoids can have an inhibitory effect on angiotensin-converting enzyme (ACE activity, which plays a key role in the regulation of arterial blood pressure. In the present study, 17 flavonoids belonging to five structural subtypes were evaluated in vitro for their ability to inhibit ACE in order to establish the structural basis of their bioactivity. The ACE inhibitory (ACEI activity of these 17 flavonoids was determined by fluorimetric method at two concentrations (500 µM and 100 µM. Their inhibitory potencies ranged from 17 to 95% at 500 µM and from 0 to 57% at 100 µM. In both cases, the highest ACEI activity was obtained for luteolin. Following the determination of ACEI activity, the flavonoids with higher ACEI activity (i.e., ACEI >60% at 500 µM were selected for further IC(50 determination. The IC(50 values for luteolin, quercetin, rutin, kaempferol, rhoifolin and apigenin K were 23, 43, 64, 178, 183 and 196 µM, respectively. Our results suggest that flavonoids are an excellent source of functional antihypertensive products. Furthermore, our structure-activity relationship studies show that the combination of sub-structures on the flavonoid skeleton that increase ACEI activity is made up of the following elements: (a the catechol group in the B-ring, (b the double bond between C2 and C3 at the C-ring, and (c the cetone group in C4 at the C-ring. Protein-ligand docking studies are used to understand the molecular basis for these results.

  17. A relational learning approach to Structure-Activity Relationships in drug design toxicity studies.

    Science.gov (United States)

    Camacho, Rui; Pereira, Max; Costa, Vítor Santos; Fonseca, Nuno A; Adriano, Carlos; Simões, Carlos J V; Brito, Rui M M

    2011-09-16

    It has been recognized that the development of new therapeutic drugs is a complex and expensive process. A large number of factors affect the activity in vivo of putative candidate molecules and the propensity for causing adverse and toxic effects is recognized as one of the major hurdles behind the current "target-rich, lead-poor" scenario. Structure-Activity Relationship (SAR) studies, using relational Machine Learning (ML) algorithms, have already been shown to be very useful in the complex process of rational drug design. Despite the ML successes, human expertise is still of the utmost importance in the drug development process. An iterative process and tight integration between the models developed by ML algorithms and the know-how of medicinal chemistry experts would be a very useful symbiotic approach. In this paper we describe a software tool that achieves that goal--iLogCHEM. The tool allows the use of Relational Learners in the task of identifying molecules or molecular fragments with potential to produce toxic effects, and thus help in stream-lining drug design in silico. It also allows the expert to guide the search for useful molecules without the need to know the details of the algorithms used. The models produced by the algorithms may be visualized using a graphical interface, that is of common use amongst researchers in structural biology and medicinal chemistry. The graphical interface enables the expert to provide feedback to the learning system. The developed tool has also facilities to handle the similarity bias typical of large chemical databases. For that purpose the user can filter out similar compounds when assembling a data set. Additionally, we propose ways of providing background knowledge for Relational Learners using the results of Graph Mining algorithms.

  18. Quantitative Structure Activity Relationship and Risk Analysis of Some Pesticides in the Goat milk

    Directory of Open Access Journals (Sweden)

    Faqir Muhammad

    2013-01-01

    Full Text Available The detection and quantification of different pesticides in the goat milk samples collected from different localities of Faisalabad, Pakistan was performed by HPLC using solid phase microextraction. The analysis showed that about 50% milk samples were contaminated with pesticides. The mean+/-SEM levels (ppm of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.34+/-0.007, 0.063+/-0.002, 0.034+/-0.002 and 0.092+/-0.002, respectively; whereas, methyl parathion was not detected in any of the analyzed samples. Quantitative structure activity relationship (QSAR models were suggested to predict the residues of unknown pesticides in the goat milk using their known physicochemical characteristics including molecular weight (MW, melting point (MP, and log octanol to water partition coefficient (Ko/w in relation to the characteristics such as pH, % fat, specific gravity and refractive index of goat milk. The analysis revealed good correlation coefficient (R2 = 0.985 for goat QSAR model. The coefficients for Ko/w and refractive index for the studied pesticides were higher in goat milk. This suggests that these are better determinants for pesticide residue prediction in the milk of these animals. Based upon the determined pesticide residues and their provisional tolerable daily intakes, risk analysis was also conducted which showed that daily intake levels of pesticide residues including cyhalothrin, chlorpyrifos and cypermethrin in present study are 2.68, 5.19 and 2.71 times higher, respectively in the goat milk. This intake of pesticide contaminated milk might pose health hazards to humans in this locality.

  19. Structure activity relationship of dendrimer microbicides with dual action antiviral activity.

    Directory of Open Access Journals (Sweden)

    David Tyssen

    Full Text Available BACKGROUND: Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published. METHODS AND FINDINGS: Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115 and fourth generation (SPL7013 DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4 and CCR5-using (R5 HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina. CONCLUSIONS: Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is

  20. Benzimidazole-Based Quinazolines: In Vitro Evaluation, Quantitative Structure-Activity Relationship, and Molecular Modeling as Aurora Kinase Inhibitors.

    Science.gov (United States)

    Sharma, Alka; Luxami, Vijay; Saxena, Sanjai; Paul, Kamaldeep

    2016-03-01

    A series of benzimidazole-based quinazoline derivatives with different substitutions of primary and secondary amines at the C2 position (1-12) were evaluated for their Aurora kinase inhibitory activities. All compounds except for 3 and 6 showed good activity against Aurora kinase inhibitors, with IC50 values in the range of 0.035-0.532 μM. The ligand efficiency (LE) of the compounds with Aurora A kinase was also determined. The structure-activity relationship and the quantitative structure-activity relationship revealed that the Aurora inhibitory activities of these derivatives primarily depend on the different substitutions of the amine present at the C2 position of the quinazoline core. Molecular docking studies in the active binding site also provided theoretical support for the experimental biological data acquired. The current study identifies a novel class of Aurora kinase inhibitors, which can further be used for the treatment of cancer.

  1. Structure-guided unravelling: Phenolic hydroxyls contribute to reduction of acrylamide using multiplex quantitative structure-activity relationship modelling.

    Science.gov (United States)

    Zhang, Yu; Huang, Mengmeng; Wang, Qiao; Cheng, Jun

    2016-05-15

    We reported a structure-activity relationship study on unravelling phenolic hydroxyls instead of alcoholic hydroxyls contribute to the reduction of acrylamide formation by flavonoids. The dose-dependent study shows a close correlation between the number of phenolic hydroxyls of flavonoids and their reduction effects. In view of positions of hydroxyls, the 3',4'(ortho)-dihydroxyls in B cycle, 3-hydroxyl or hydroxyls of 3-gallate in C cycle, and 5,7(meta)-dihydroxyls in A cycle of flavonoid structures play an important role in the reduction of acrylamide. Flavone C-glycosides are more effective at reducing the formation of acrylamide than flavone O-glycosides when sharing the same aglycone. The current multiplex quantitative structure-activity relationship (QSAR) equations effectively predict the inhibitory rates of acrylamide using selected chemometric parameters (R(2): 0.835-0.938). This pioneer study opens a broad understanding on the chemoprevention of acrylamide contaminants on a structural basis.

  2. Synthesis and structure-activity relationship of p-carborane-based non-secosteroidal vitamin D analogs.

    Science.gov (United States)

    Fujii, Shinya; Kano, Atsushi; Songkram, Chalermkiat; Masuno, Hiroyuki; Taoda, Yoshiyuki; Kawachi, Emiko; Hirano, Tomoya; Tanatani, Aya; Kagechika, Hiroyuki

    2014-02-15

    1α,25-Dihydroxyvitamin D3 [1α,25(OH)₂D₃: 1] is a specific modulator of nuclear vitamin D receptor (VDR), and novel vitamin D analogs are therapeutic candidates for multiple clinical applications. We recently developed non-secosteroidal VDR agonists bearing a p-carborane cage (a carbon-containing boron cluster) as a hydrophobic core structure. These carborane derivatives are structurally quite different from classical secosteroidal vitamin D analogs. Here, we report systematic synthesis and activity evaluation of carborane-based non-secosteroidal vitamin D analogs. The structure-activity relationships of carborane derivatives are different from those of secosteroidal vitamin D derivatives, and in particular, the length and the substituent position of the dihydroxylated side chain are rather flexible in carborane derivatives. The structure-activity relationships presented here should be helpful in development of non-secosteroidal vitamin D analogs for clinical applications.

  3. Synthesis, antimicrobial activity and advances in structure-activity relationships (SARs) of novel tri-substituted thiazole derivatives.

    Science.gov (United States)

    Reddy, Guda Mallikarjuna; Garcia, Jarem Raul; Reddy, Vemulapati Hanuman; de Andrade, Ageo Meier; Camilo, Alexandre; Pontes Ribeiro, Renan Augusto; de Lazaro, Sergio Ricardo

    2016-11-10

    Trisubstituted thiazoles were synthesized and studied for their antimicrobial activity and supported by theoretical calculations. In addition, MIC, MBC and MFC were also tested. Moreover, the present study was analyzed to scrutinize comprehensive structure-activity relationships. In fact, LUMO orbital energy and orbital orientation was reliable to explain their antibacterial and antifungal assay. Amongst the tested compounds, tri-methyl-substituted thiazole compound showed higher antimicrobial activity and low MIC value due to highest LUMO energy.

  4. Synthesis, biological evaluation and structure-activity relationships of new quinoxaline derivatives as anti-Plasmodium falciparum agents

    OpenAIRE

    Gil, Ana Gloria; Pabón, Adriana; Galiano, Silvia; Burguete, M. Isabel; Pérez-Silanes, Silvia; Deharo, Eric; Monge, Antonio; Aldana Ignacio

    2014-01-01

    We report the synthesis and antimalarial activities of eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives, eight of which are completely novel. Compounds 1a and 2a were the most active against Plasmodium falciparum strains. Structure-activity relationships demonstrated the importance of an enone moiety linked to the quinoxaline ring. © 2014 by the authors; licensee MDPI, Basel, Switzerland.

  5. Determination of the Biological Activity and Structure Activity Relationships of Drugs Based on the Highly Cytotoxic Duocarmycins and CC-1065

    OpenAIRE

    2009-01-01

    The natural antibiotics CC‑1065 and the duocarmycins are highly cytotoxic compounds which however are not suitable for cancer therapy due to their general toxicity. We have developed glycosidic prodrugs of seco-analogues of these antibiotics for a selective cancer therapy using conjugates of glycohydrolases and tumour-selective monoclonal antibodies for the liberation of the drugs from the prodrugs predominantly at the tumour site. For the determination of structure activity relationships of ...

  6. Simulated Screens of DNA Encoded Libraries: The Potential Influence of Chemical Synthesis Fidelity on Interpretation of Structure-Activity Relationships.

    Science.gov (United States)

    Satz, Alexander L

    2016-07-11

    Simulated screening of DNA encoded libraries indicates that the presence of truncated byproducts complicates the relationship between library member enrichment and equilibrium association constant (these truncates result from incomplete chemical reactions during library synthesis). Further, simulations indicate that some patterns observed in reported experimental data may result from the presence of truncated byproducts in the library mixture and not structure-activity relationships. Potential experimental methods of minimizing the presence of truncates are assessed via simulation; the relationship between enrichment and equilibrium association constant for libraries of differing purities is investigated. Data aggregation techniques are demonstrated that allow for more accurate analysis of screening results, in particular when the screened library contains significant quantities of truncates.

  7. Synthesis and structure-activity relationships of novel amino/nitro substituted 3-arylcoumarins as antibacterial agents.

    Science.gov (United States)

    Matos, Maria J; Vazquez-Rodriguez, Saleta; Santana, Lourdes; Uriarte, Eugenio; Fuentes-Edfuf, Cristina; Santos, Ysabel; Muñoz-Crego, Angeles

    2013-01-24

    A new series of amino/nitro-substituted 3-arylcoumarins were synthesized and their antibacterial activity against clinical isolates of Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) was evaluated. Some of these molecules exhibited antibacterial activity against S. aureus comparable to the standards used (oxolinic acid and ampicillin). The preliminary structure-activity relationship (SAR) study showed that the antibacterial activity against S. aureus depends on the position of the 3-arylcoumarin substitution pattern. With the aim of finding the structural features for the antibacterial activity and selectivity, in the present manuscript different positions of nitro, methyl, methoxy, amino and bromo substituents on the 3-arylcoumarin scaffold were reported.

  8. Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization.

    Science.gov (United States)

    Soares de Melo, Candice; Candice, Soares de Melo; Feng, Tzu-Shean; van der Westhuyzen, Renier; Gessner, Richard K; Street, Leslie J; Morgans, Garreth L; Warner, Digby F; Moosa, Atica; Naran, Krupa; Lawrence, Nina; Boshoff, Helena I M; Barry, Clifton E; Harris, C John; Gordon, Richard; Chibale, Kelly

    2015-11-15

    Whole-cell high-throughput screening of a diverse SoftFocus library against Mycobacterium tuberculosis (Mtb) generated a novel aminopyrazolo[1,5-a]pyrimidine hit series. The synthesis and structure activity relationship studies identified compounds with potent antimycobacterial activity. The SAR of over 140 compounds shows that the 2-pyridylmethylamine moiety at the C-7 position of the pyrazolopyrimidine scaffold was important for Mtb activity, whereas the C-3 position offered a higher degree of flexibility. The series was also profiled for in vitro cytotoxicity and microsomal metabolic stability as well as physicochemical properties. Consequently liabilities to be addressed in a future lead optimization campaign have been identified.

  9. Obscure phenomena in statistical analysis of quantitative structure-activity relationships. Part 1: Multicollinearity of physicochemical descriptors.

    Science.gov (United States)

    Mager, P P; Rothe, H

    1990-10-01

    Multicollinearity of physicochemical descriptors leads to serious consequences in quantitative structure-activity relationship (QSAR) analysis, such as incorrect estimators and test statistics of regression coefficients of the ordinary least-squares (OLS) model applied usually to QSARs. Beside the diagnosis of the known simple collinearity, principal component regression analysis (PCRA) also allows the diagnosis of various types of multicollinearity. Only if the absolute values of PCRA estimators are order statistics that decrease monotonically, the effects of multicollinearity can be circumvented. Otherwise, obscure phenomena may be observed, such as good data recognition but low predictive model power of a QSAR model.

  10. Quantitative structure-activity relationship modeling of polycyclic aromatic hydrocarbon mutagenicity by classification methods based on holistic theoretical molecular descriptors.

    Science.gov (United States)

    Gramatica, Paola; Papa, Ester; Marrocchi, Assunta; Minuti, Lucio; Taticchi, Aldo

    2007-03-01

    Various polycyclic aromatic hydrocarbons (PAHs), ubiquitous environmental pollutants, are recognized mutagens and carcinogens. A homogeneous set of mutagenicity data (TA98 and TA100,+S9) for 32 benzocyclopentaphenanthrenes/chrysenes was modeled by the quantitative structure-activity relationship classification methods k-nearest neighbor and classification and regression tree, using theoretical holistic molecular descriptors. Genetic algorithm provided the selection of the best subset of variables for modeling mutagenicity. The models were validated by leave-one-out and leave-50%-out approaches and have good performance, with sensitivity and specificity ranges of 90-100%. Mutagenicity assessment for these PAHs requires only a few theoretical descriptors of their molecular structure.

  11. Extended Functional Groups (EFG: An Efficient Set for Chemical Characterization and Structure-Activity Relationship Studies of Chemical Compounds

    Directory of Open Access Journals (Sweden)

    Elena S. Salmina

    2015-12-01

    Full Text Available The article describes a classification system termed “extended functional groups” (EFG, which are an extension of a set previously used by the CheckMol software, that covers in addition heterocyclic compound classes and periodic table groups. The functional groups are defined as SMARTS patterns and are available as part of the ToxAlerts tool (http://ochem.eu/alerts of the On-line CHEmical database and Modeling (OCHEM environment platform. The article describes the motivation and the main ideas behind this extension and demonstrates that EFG can be efficiently used to develop and interpret structure-activity relationship models.

  12. Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2

    Science.gov (United States)

    Singh, Kurnvir; Tanui, Rose; Gameiro, Armanda; Eisenberg, Gilad; Colas, Claire; Schlessinger, Avner; Grewer, Christof

    2017-01-01

    The glutamine transporter ASCT2 has been identified as a promising target to inhibit rapid growth of cancer cells. However, ASCT2 pharmacology is not well established. In this report, we performed a systematic structure activity analysis of a series of substituted benzylproline derivatives. Substitutions on the phenyl ring resulted in compounds with characteristics of ASCT2 inhibitors. Apparent binding affinity increased with increasing hydrophobicity of the side chain. In contrast, interaction of the ASCT2 binding site with specific positions on the phenyl ring was not observed. The most potent compound inhibits the ASCT2 anion conductance with a Ki of 3 μM, which is in the same range as that of more bulky and higher molecular weight inhibitors recently reported by others. The experimental results are consistent with computational analysis based on docking of the inhibitors against an ASCT2 homology model. The benzylproline scaffold provides a valuable tool for further improving binding potency of future ASCT2 inhibitors. PMID:28057420

  13. Progress and perspectives of quantitative structure-activity relationships used for ecological risk assessment of toxic organic compounds

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR), collec- tively referred to as (Q)SARs, play an important role in ecological risk assessment (ERA) of organic chemicals. (Q)SARs can fill the data gap for physical-chemical, environmental behavioral and ecotoxicological parameters of organic compounds; they can decrease experimental expenses and reduce the extent of experimental testing (especially animal testing); they can also be used to assess the uncertainty of the experimental data. With the development for several decades, (Q)SARs in envi- ronmental sciences show three features: application orientation, multidisciplinary integration, and in- telligence. Progress of (Q)SAR technology for ERA of toxic organic compounds, including endpoint selection and mathematic methods for establishing simple, transparent, easily interpretable and portable (Q)SAR models, is reviewed. The recent development on defining application domains and diagnosing outliers is summarized. Model characterization with respect to goodness-of-fit, stability and predictive power is specially presented. The purpose of the review is to promote the development of (Q)SARs orientated to ERA of organic chemicals.

  14. Progress and perspectives of quantitative structure-activity relationships used for ecological risk assessment of toxic organic compounds

    Institute of Scientific and Technical Information of China (English)

    CHEN JingWen; LI XueHua; YU HaiYing; WANG YaNan; QIAO XianLiang

    2008-01-01

    Structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR), collec-tively referred to as (Q)SARs, play an important role in ecological risk assessment (ERA) of organic chemicals. (Q)SARs can fill the data gap for physical-chemical, environmental behavioral and ecotoxicological parameters of organic compounds; they can decrease experimental expenses and reduce the extent of experimental testing (especially animal testing); they can also be used to assess the uncertainty of the experimental data. With the development for several decades, (Q)SARs in envi-ronmental sciences show three features: application orientation, multidisciplinary integration, and in-telligence. Progress of (Q)SAR technology for ERA of toxic organic compounds, including endpoint selection and mathematic methods for establishing simple, transparent, easily interpretable and portable (Q)SAR models, is reviewed. The recent development on defining application domains and diagnosing outliers is summarized. Model characterization with respect to goodness-of-fit, stability and predictive power is specially presented. The purpose of the review is to promote the development of (Q)SARs orientated to ERA of organic chemicals.

  15. Structure-activity relationships of fatty acid amide ligands in activating and desensitizing G protein-coupled receptor 119.

    Science.gov (United States)

    Kumar, Pritesh; Kumar, Akhilesh; Song, Zhao-Hui

    2014-01-15

    The purpose of the current study was to apply a high throughput assay to investigate the structure-activity relationships of fatty acid amides for activating and desensitizing G protein-coupled receptor 119, a promising therapeutic target for both type 2 diabetes and obesity. A cell-based, homogenous time resolved fluorescence (HTRF) method for measuring G protein-coupled receptor 119-mediated increase of cyclic adenosine monophosphate (cAMP) levels was validated and applied in this study. Using novel fatty acid amides and detailed potency and efficacy analyses, we have demonstrated that degree of saturation in acyl chain and charged head groups of fatty acid amides have profound effects on the ability of these compounds to activate G protein-coupled receptor 119. In addition, we have demonstrated for the first time that pretreatments with G protein-coupled receptor 119 agonists desensitize the receptor and the degrees of desensitization caused by fatty acid amides correlate well with their structure-activity relationships in activating the receptor.

  16. Review on Structure-Activity Relationships among Sweeteners%甜味剂构性关系研究进展

    Institute of Scientific and Technical Information of China (English)

    樊可可; 欧阳平凯; 吴锡军

    1999-01-01

      本文对国内外甜味剂构性关系研究进行了较全面的综述。重点阐述了甜味剂构效理论的发展及其对各种类型甜味分子结构甜味关系的解释,并提出了该研究领域内面临的问题和最新发展趋势。%  Researches in structure-activity relationships among sweeteners were reviewed systematically in this paper. Emphasis was given to those hypothesises and their explanations for structure-sweet taste relationships of various sweeteners. The current problems and latest development trend in this field were also referred.

  17. Quantitative Structure-Activity Relationships in the Lithium and Sodium Affinities of n-Alkyl Fluorides

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    B3LYP/6-31+g (d, p) method was used to calculate the lithium and sodium affinities of n-alkyl fluoride. These affinities were found to obey the Holmes relationship, i.e. they correlate linearly with the quotient n/(n+1), where n is the number of carbon atoms in the alkyl chain. From the correlation the limiting values of lithium and sodium affinities for very long alkyl chain were predicted to be -153.3 kJ/mol and -108.4 kJ/mol, respectively.

  18. Structure-activity relationship for the reactivators of acetylcholinesterase inhibited by nerve agent VX.

    Science.gov (United States)

    Kuca, Kamil; Musilek, Kamil; Jun, Daniel; Karasova, Jana; Soukup, Ondrej; Pejchal, Jaroslav; Hrabinova, Martina

    2013-08-01

    Nerve agents such as sarin, VX and tabun are organophosphorus compounds able to inhibit an enzyme acetylcholinesterase (AChE). AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication with these agents. None from the known AChE reactivators is able to reactivate AChE inhibited by all kinds of nerve agents. In this work, reactivation potency of seventeen structurally different AChE reactivators was tested in vitro and subsequently, relationship between their chemical structure and biological activity was outlined. VX was chosen as appropriate member of the nerve agent family.

  19. Structure-activity relationship of memapsin 2: implications on physiological functions and Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Xiaoman Li; Lin Hong; Kathleen Coughlan; Liang Wang; Liu Cao; Jordan Tang

    2013-01-01

    Memapsin 2 (BACE1,β-secretase),a membrane aspartic protease,functions in the cleavage of the type Ⅰ transmembrane protein,β-amyloid precursor protein (APP),leading to the production of amyloid β (Aβ) in the brain.Since Aβ is closely associated with the pathogenesis of Alzheimer's disease,understanding the biological function,particularly the catalytic activities of memapsin 2,would assist in a better understanding of the disease and the development of its inhibitors.The transmembrane and cytosolic domains of memapsin 2 function in cellular transport and localization,which are important regulatory mechanisms for its activity.The catalytic ectodomain contains a long substrate cleft that is responsible for substrate recognition,specificity,and peptide bond hydrolysis.The substrate cleft accommodates 11 residues of the substrate in separate binding subsites.Besides APP,a number of membrane proteins have been reported to be substrates of memapsin 2.The elucidation for the specificity of these subsites and the amino acid sequences surrounding the memapsin 2 cleavage site in these proteins has led to the establishment of a predictive model that can quantitatively estimate the efficiency of cleavage for any potential substrates.Such tools may be employed for future studies of memapsin 2 about its biological function.Herein,we review the current knowledge on the structure-function relationship of memapsin 2 and its relationship in the biological function.

  20. Antioxidant properties of phenolic Schiff bases: structure-activity relationship and mechanism of action.

    Science.gov (United States)

    Anouar, El Hassane; Raweh, Salwa; Bayach, Imene; Taha, Muhammad; Baharudin, Mohd Syukri; Di Meo, Florent; Hasan, Mizaton Hazizul; Adam, Aishah; Ismail, Nor Hadiani; Weber, Jean-Frédéric F; Trouillas, Patrick

    2013-11-01

    Phenolic Schiff bases are known for their diverse biological activities and ability to scavenge free radicals. To elucidate (1) the structure-antioxidant activity relationship of a series of thirty synthetic derivatives of 2-methoxybezohydrazide phenolic Schiff bases and (2) to determine the major mechanism involved in free radical scavenging, we used density functional theory calculations (B3P86/6-31+(d,p)) within polarizable continuum model. The results showed the importance of the bond dissociation enthalpies (BDEs) related to the first and second (BDEd) hydrogen atom transfer (intrinsic parameters) for rationalizing the antioxidant activity. In addition to the number of OH groups, the presence of a bromine substituent plays an interesting role in modulating the antioxidant activity. Theoretical thermodynamic and kinetic studies demonstrated that the free radical scavenging by these Schiff bases mainly proceeds through proton-coupled electron transfer rather than sequential proton loss electron transfer, the latter mechanism being only feasible at relatively high pH.

  1. Quantitative structure activity relationships of some pyridine derivatives as corrosion inhibitors of steel in acidic medium.

    Science.gov (United States)

    El Ashry, El Sayed H; El Nemr, Ahmed; Ragab, Safaa

    2012-03-01

    Quantum chemical calculations using the density functional theory (B3LYP/6-31G DFT) and semi-empirical AM1 methods were performed on ten pyridine derivatives used as corrosion inhibitors for mild steel in acidic medium to determine the relationship between molecular structure and their inhibition efficiencies. Quantum chemical parameters such as total negative charge (TNC) on the molecule, energy of highest occupied molecular orbital (E (HOMO)), energy of lowest unoccupied molecular orbital (E (LUMO)) and dipole moment (μ) as well as linear solvation energy terms, molecular volume (Vi) and dipolar-polarization (π) were correlated to corrosion inhibition efficiency of ten pyridine derivatives. A possible correlation between corrosion inhibition efficiencies and structural properties was searched to reduce the number of compounds to be selected for testing from a library of compounds. It was found that theoretical data support the experimental results. The results were used to predict the corrosion inhibition of 24 related pyridine derivatives.

  2. Study of structure-activity relationship in Aurein 1.2 analogs.

    Science.gov (United States)

    Soufian, Safieh; Hassani, Leila

    2011-07-15

    Two new analogs of Aurein 1.2 antimicrobial peptide were synthesized and the antimicrobial activities were investigated. The results showed that the activity of G1R/F3W analog was higher than the native peptide and the F3W analog. Circular dichroism studies also showed that the secondary structure of the F3W was concentration-dependent, whereas, there was no such relationship seen in the case of G1R/F3W analog. It has been proposed that G1R/F3W activity was based on a single mechanism (snorkeling), while Aurein 1.2 and F3W utilized the snorkeling mechanism at low concentrations (0-0.01 mM) and the carpet mechanism at higher concentrations (0.01-0.1 mM). This study suggests that one pay attention to the concentration of biomolecules in peptide-based drug design.

  3. Molecular Descriptors Family on Structure Activity Relationships 6. Octanol-Water Partition Coefficient of Polychlorinated Biphenyls

    Directory of Open Access Journals (Sweden)

    Lorentz JÄNTSCHI

    2006-01-01

    Full Text Available Octanol-water partition coefficient of two hundred and six polychlorinated biphenyls was model by the use of an original method based on complex information obtained from compounds structure. The regression analysis shows that best results are obtained in four-varied model (r2 = 0.9168. The prediction ability of the model was studied through leave-one-out analysis (r2cv(loo = 0.9093 and in training and test sets analysis. Modeling the octanol-water partition coefficient of polychlorinated biphenyls by integration of complex structural information provide a stable and performing four-varied model, allowing us to make remarks about relationship between structure of polychlorinated biphenyls and associated octanol-water partition coefficients.

  4. Quantitative structure-activity relationship study on the biodegradation of acid dyestuffs

    Institute of Scientific and Technical Information of China (English)

    LI Yin; XI Dan-li

    2007-01-01

    Quantitative structure-biodegradability relationships (QSBRs) were established to develop predictive models and mechanistic explanations for acid dyestuffs as well as biological activities. With a total of four descriptors, molecular weight (MW), energies of the highest occupied molecular orbital (EHOMO), the lowest unoccupied molecular orbital (ELUMO), and the excited state (EES), calculated using quantum chemical semi-empirical methodology, a series of models were analyzed between the dye biodegradability and each descriptor. Results showed that EHOMO and MW were the dominant parameters controlling the biodegradability of acid dyes. A statistically robust QSBR model was developed for all studied dyes, with the combined application of EHOMO and MW. The calculated biodegradations fitted well with the experimental data monitored in a facultative-aerobic process, indicative of the reliable prediction and mechanistic character of the developed model.

  5. Structure-activity relationships of lanostane-type triterpenoids from Ganoderma lingzhi as α-glucosidase inhibitors.

    Science.gov (United States)

    Fatmawati, Sri; Kondo, Ryuichiro; Shimizu, Kuniyoshi

    2013-11-01

    A series of lanostane-type triterpenoids, identified as ganoderma alcohols and ganoderma acids, were isolated from the fruiting body of Ganoderma lingzhi. Some of these compounds were confirmed as active inhibitors of the in vitro human recombinant aldose reductase. This paper aims to explain the structural requirement for α-glucosidase inhibition. Our structure-activity studies of ganoderma alcohols showed that the OH substituent at C-3 and the double-bond moiety at C-24 and C-25 are necessary to increase α-glucosidase inhibitory activity. The structure-activity relationships of ganoderma acids revealed that the OH substituent at C-11 is an important feature and that the carboxylic group in the side chain is essential for the recognition of α-glucosidase inhibitory activity. Moreover, the double-bond moiety at C-20 and C-22 in the side chain and the OH substituent at C-3 of ganoderma acids improve α-glucosidase inhibitory activity. These results provide an approach with which to consider the structural requirements of lanostane-type triterpenoids from G. lingzhi. An understanding of these requirements is considered necessary in order to improve a new type of α-glucosidase inhibitor.

  6. Hologram quantitative structure activity relationship, docking, and molecular dynamics studies of inhibitors for CXCR4.

    Science.gov (United States)

    Zhang, Chongqian; Du, Chunmiao; Feng, Zhiwei; Zhu, Jingyu; Li, Youyong

    2015-02-01

    CXCR4 plays a crucial role as a co-receptor with CCR5 for HIV-1 anchoring to mammalian cell membrane and is implicated in cancer metastasis and inflammation. In the current work, we study the relationship of structure and activity of AMD11070 derivatives and other inhibitors of CXCR4 using HQSAR, docking and molecular dynamics (MD) simulations. We obtain an HQSAR model (q(2) = 0.779), and the HQSAR result illustrates that AMD11070 shows a high antiretroviral activity. As HQSAR only provides 2D information, we perform docking and MD to study the interaction of It1t, AMD3100, and AMD3465 with CXCR4. Our results illustrate that the binding are affected by two crucial residues Asp97 and Glu288. The butyl amine moiety of AMD11070 contributes to its high antiretroviral activity. Without a butyl amine moiety, (2,7a-Dihydro-1H-benzoimidazol-2-ylmethyl)-methyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (compound 5a) shows low antiretroviral activity. Our results provide structural details about the interactions between the inhibitors and CXCR4, which are useful for rational drug design of CXCR4.

  7. Holographic quantitative structure-activity relationship for prediction of the toxicity of polybrominated diphenyl ether congeners

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Polybrominated diphenyl ether congeners (PBDEs) might activate the AhR (aromatic hydrocarbon receptor) signal transduction,and thus might have an adverse effect on the health of humans and wildlife. Because of the limited experimental data,it is important and necessary to develop structure-based models for prediction of the toxicity of the compounds. In this study,a new molecular structure representation,molecular hologram,was employed to investigate the quantitative relationship between toxicity and molecular structures for 18 PBDEs. The model with the significant correlation and robustness (r2 = 0.991,q2LOO = 0.917) was developed. To verify the robustness and prediction capacity of the derived model,14 PBDEs were randomly selected from the database as the training set,while the rest were used as the test set. The results generated under the same modeling conditions as the optimal model are as follows:r2 = 0.988,q2LOO = 0.598,r2pred = 0.955,and RMSE (root-mean-square of errors) = 0.155,suggesting the excellent ability of the derived model to predict the toxicity of PBDEs. Furthermore,the structural features and molecular mechanism related to the toxicity of PBDEs were explored using HQSAR color coding.

  8. Quantitative Structure-activity Relationships for Anaerobic Biodegradation of Substituted Azobenzenes

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xiao-yi; ZHU Huai-wu; LUO Shi-xia; WANG Zheng-wu; XIAO Han

    2004-01-01

    The degradation rates of the azo-bonds of a series of substituted azobenzenes caused by anaerobic sludge digestion were determined by measuring the biggest change of the absorption peak area of the UV-Vis spectra of the anaerobic sludge system before and after degradation. The electronic structure of the molecules was calculated by using the quantum chemistry semiempirical method AM1. The research on the correlation between the biodegradability of the azo-bond and the molecular structure descriptors has led to the following results. (1) There is an obvious relationship between the degradation rate D and the difference Δqπ in π-charge density of the azo-bond. (2) The different substituents in the molecules result in a wave pattern of π-charge distribution and the increasing of the flowability of π-electron. A good flowability of the π-charge favors the reduction between electron contributing azo groups. (3) The effect of the substituents on the π-electron system depends on the electromerization of the substituents in combination with the conjugated systems.

  9. Synthesis, structure-activity relationship analysis and kinetics study of reductive derivatives of flavonoids as Helicobacter pylori urease inhibitors.

    Science.gov (United States)

    Xiao, Zhu-Ping; Peng, Zhi-Yun; Dong, Jing-Jun; He, Juan; Ouyang, Hui; Feng, Yu-Ting; Lu, Chun-Lei; Lin, Wan-Qiang; Wang, Jin-Xiang; Xiang, Yin-Ping; Zhu, Hai-Liang

    2013-05-01

    In a continuing study for discovering urease inhibitors based on flavonoids, nineteen reductive derivatives of flavonoids were synthesized and evaluated against Helicobacter pylori urease. Analysis of structure-activity relationship disclosed that 4-deoxy analogues are more potent than other reductive products. Out of them, 4',7,8-trihydroxyl-2-isoflavene (13) was found to be the most active with IC50 of 0.85 μM, being over 20-fold more potent than the commercial available urease inhibitor, acetohydroxamic acid (AHA). Kinetics study revealed that 13 is a competitive inhibitor of H. pylori urease with a Ki value of 0.641 μM, which is well matched with the results of molecular docking. Biological evaluation and mechanism study of 13 suggest that it is a good candidate for discovering novel anti-gastritis and anti-gastric ulcer agent.

  10. [A new SVRDF 3D-descriptor of amino acids and its application to peptide quantitative structure activity relationship].

    Science.gov (United States)

    Tong, Jian-Bo; Zhang, Sheng-Wan; Cheng, Su-Li; Li, Gai-Xian

    2007-01-01

    To establish a new amino acid structure descriptor that can be applied to polypeptide quantitative structure activity relationship (QSAR) studies, a new descriptor, SVRDF, was derived from a principal components analysis of a matrix of 150 radial distribution function index of amino acids. The scale was then applied in three panels of peptide QSAR that were molded by partial least squares regression. The obtained models with the correlation coefficients (R2(cum)), cross-validation correlation coefficients (Q2(cum)) were 0.766 and 0.724 for 48 bitter tasting dipeptides; 0.941 and 0.811 for 21 oxytocin analogues; 0.996 and 0.919 for 20 thromboplastin inhibitors. Satisfactory results showed that information related to biological activity can be systemically expressed by SVRDF scales, which may be an useful structural expression methodology for the study of peptides QSAR.

  11. Synthesis, biological activity and structure-activity relationship of 4,5-dimethoxybenzene derivatives inhibitor of rhinovirus 14 infection.

    Science.gov (United States)

    Roche, Manon; Lacroix, Céline; Khoumeri, Omar; Franco, David; Neyts, Johan; Terme, Thierry; Leyssen, Pieter; Vanelle, Patrice

    2014-04-09

    Human rhinoviruses are a common cause of respiratory infections, and thus constitute an important target for medicinal chemistry. Still, no drug has been approved for clinical use. We report herein the discovery of dibenzenic derivatives with potent and specific in vitro anti-rhinoviral 14 activity. A total of 99 structural analogues were synthesized by an original synthesis method, i.e. through one organic agent Tetrakis(DimethylAmino)Ethylene (TDAE) and a structure-activity relationship was established. It was shown that 4,5-dimethoxy scaffold and the presence of a C-4 substituted aromatic moiety were necessary to the in vitro activity of these original agents. However, modifications on liker were not convincing. The benzonitrile derivative 23 was identified as the most potent and selective inhibitor of rhinovirus replication in these series (EC₅₀ of 2 ± 0.5 μM, CC₅₀ of 184 μM, selectivity index of 92).

  12. Multistep continuous-flow synthesis in medicinal chemistry: discovery and preliminary structure-activity relationships of CCR8 ligands.

    Science.gov (United States)

    Petersen, Trine P; Mirsharghi, Sahar; Rummel, Pia C; Thiele, Stefanie; Rosenkilde, Mette M; Ritzén, Andreas; Ulven, Trond

    2013-07-08

    A three-step continuous-flow synthesis system and its application to the assembly of a new series of chemokine receptor ligands directly from commercial building blocks is reported. No scavenger columns or solvent switches are necessary to recover the desired test compounds, which were obtained in overall yields of 49-94%. The system is modular and flexible, and the individual steps of the sequence can be interchanged with similar outcome, extending the scope of the chemistry. Biological evaluation confirmed activity on the chemokine CCR8 receptor and provided initial structure-activity-relationship (SAR) information for this new ligand series, with the most potent member displaying full agonist activity with single-digit nanomolar potency. To the best of our knowledge, this represents the first published example of efficient use of multistep flow synthesis combined with biological testing and SAR studies in medicinal chemistry.

  13. Synthesis and structure-active relationship of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline anticonvulsants.

    Science.gov (United States)

    Gitto, Rosaria; De Luca, Laura; Ferro, Stefania; Agnello, Stefano; Russo, Emilio; De Sarro, Giovanbattista; Chimirri, Alba

    2010-12-01

    We have previously disclosed that some 6,7-dimethoxyisoquinoline derivatives are able to produce anticonvulsant effects in different animal models of epilepsy. Following these studies this paper describes the synthesis of a small series of new 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines strictly related to previously reported analogues. This novel series of isoquinolines was designed on the basis of well defined structure-active relationship (SAR) information already acquired for this class of anticonvulsant agents. The pharmacological effects of the new synthesized compounds were evaluated against audiogenic seizures in Dilute Brown non-Agouti (DBA/2) mice. The preliminary pharmacological screening led to the identification of a new active molecule the 2-acetyl-1-(4'-methylphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (6d) that displayed significant anticonvulsant activity. Computational studies helped to rationalize these obtained pharmacological results.

  14. Synthesis and Structure-Activity Relationships of Novel Amino/Nitro Substituted 3-Arylcoumarins as Antibacterial Agents

    Directory of Open Access Journals (Sweden)

    Ysabel Santos

    2013-01-01

    Full Text Available A new series of amino/nitro-substituted 3-arylcoumarins were synthesized and their antibacterial activity against clinical isolates of Staphylococcus aureus (Gram-positive and Escherichia coli (Gram-negative was evaluated. Some of these molecules exhibited antibacterial activity against S. aureus comparable to the standards used (oxolinic acid and ampicillin. The preliminary structure-activity relationship (SAR study showed that the antibacterial activity against S. aureus depends on the position of the 3-arylcoumarin substitution pattern. With the aim of finding the structural features for the antibacterial activity and selectivity, in the present manuscript different positions of nitro, methyl, methoxy, amino and bromo substituents on the 3-arylcoumarin scaffold were reported.

  15. Screening of 397 chemicals and development of a quantitative structure-activity relationship model for androgen receptor antagonism

    DEFF Research Database (Denmark)

    Vinggaard, Annemarie; Niemelä, Jay Russell; Wedebye, Eva Bay;

    2008-01-01

    We have screened 397 chemicals for human androgen receptor (AR) antagonism by a sensitive reporter gene assay to generate data for the development of a quantitative structure-activity relationship (QSAR) model. A total of 523 chemicals comprising data on 292 chemicals from our laboratory and data...... by the synthetic androgen R1881. The MultiCASE expert system was used to construct a QSAR model for AR antagonizing potential. A "5 Times, 2-Fold 50% Cross Validation" of the model showed a sensitivity of 64%, a specificity of 84%, and a concordance of 76%. Data for 102 chemicals were generated for an external...... validation of the model resulting in a sensitivity of 57%, a specificity of 98%, and a concordance of 92% of the model. The model was run on a set of 176103 chemicals, and 47% were within the domain of the model. Approximately 8% of chemicals was predicted active for AR antagonism. We conclude...

  16. New imidazoquinoxaline derivatives: Synthesis, biological evaluation on melanoma, effect on tubulin polymerization and structure-activity relationships.

    Science.gov (United States)

    Zghaib, Zahraa; Guichou, Jean-François; Vappiani, Johanna; Bec, Nicole; Hadj-Kaddour, Kamel; Vincent, Laure-Anaïs; Paniagua-Gayraud, Stéphanie; Larroque, Christian; Moarbess, Georges; Cuq, Pierre; Kassab, Issam; Deleuze-Masquéfa, Carine; Diab-Assaf, Mona; Bonnet, Pierre-Antoine

    2016-06-01

    Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC50 in the range of 0.077-122μM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure-activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin.

  17. A Structure-activity Relationship(SAR)Study of Fluoroquinolones with Biological Activity against Anti-S.pneumoniae

    Institute of Scientific and Technical Information of China (English)

    LI Xiao-Hong; ZHANG Rui-Zhou; CHENG Xin-Lu; YANG Xiang-Dong

    2006-01-01

    Structure-activity relationship techniques were employed to classify fluoroquino- lones against S.pneumoniae. Density functional theory (DFT) was used to calculate a set of mo- lecular descriptors (properties) for eighteen fluoroquinolones. The descriptors were further analyzed using the principal component analysis (PCA), hierarchical cluster analysis (HCA) and K-nearest neighbor (KNN) chemometeric method. The PCA and HCA methods are quite efficient to classify the eighteen compounds into two groups (active and inactive) according to their degrees of anti- S.pneumoniae activity. The classified result is consistent with the clinic experimental result. The PCA shows that the variables Q3 (net charge on atom 3), QA (net charge on ring A), QB (net charge on ring B), VOL (molecular volume) and A (surface area) are found to be responsible for the sepa- ration between compounds with higher and lower anti-S.pneumoniae.

  18. Phomentrioloxin, a fungal phytotoxin with potential herbicidal activity, and its derivatives: a structure-activity relationship study.

    Science.gov (United States)

    Cimmino, Alessio; Andolfi, Anna; Zonno, Maria Chiara; Boari, Angela; Troise, Ciro; Motta, Andrea; Vurro, Maurizio; Ash, Gavin; Evidente, Antonio

    2013-10-09

    Phomentrioloxin is a phytotoxic geranylcyclohexenetriol produced in liquid culture by Phomopsis sp. (teleomorph: Diaporthe gulyae), a potential mycoherbicide proposed for the control of the annual weed Carthamus lanatus. In this study, seven derivatives obtained by chemical modifications of the toxin were assayed for phytotoxic, antimicrobial, and zootoxic activities, and the structure-activity relationships were examined. Each compound was tested on nonhost weedy and agrarian plants, fungi, Gram+ and Gram- bacteria, and on brine shrimp larvae. The results provide insights into an investigation of the structural requirements for activity. The hydroxy groups at C-2 and C-4 appeared to be important features for the phytotoxicity, as well as an unchanged cyclohexentriol ring. A role seemed also to be played by the unsaturations of the geranyl side chain. These findings could be useful for understanding the mechanisms of action of new natural products, for identifying the active sites, and possibly in devising new herbicides of natural origin.

  19. Discovery and Structure-Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions.

    Science.gov (United States)

    Murza, Alexandre; Sainsily, Xavier; Coquerel, David; Côté, Jérôme; Marx, Patricia; Besserer-Offroy, Élie; Longpré, Jean-Michel; Lainé, Jean; Reversade, Bruno; Salvail, Dany; Leduc, Richard; Dumaine, Robert; Lesur, Olivier; Auger-Messier, Mannix; Sarret, Philippe; Marsault, Éric

    2016-04-14

    ELABELA (ELA) was recently discovered as a novel endogenous ligand of the apelin receptor (APJ), a G protein-coupled receptor. ELA signaling was demonstrated to be crucial for normal heart and vasculature development during embryogenesis. We delineate here ELA's structure-activity relationships and report the identification of analogue 3 (ELA(19-32)), a fragment of ELA that binds to APJ, activates the Gαi1 and β-arrestin-2 signaling pathways, and induces receptor internalization similarly to its parent endogenous peptide. An alanine scan performed on 3 revealed that the C-terminal residues are critical for binding to APJ and signaling. Finally, using isolated-perfused hearts and in vivo hemodynamic and echocardiographic measurements, we demonstrate that ELA and 3 both reduce arterial pressure and exert positive inotropic effects on the heart. Altogether, these results present ELA and 3 as potential therapeutic options in managing cardiovascular diseases.

  20. Synthesis and structure-activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain.

    Science.gov (United States)

    Espíndola, José Wanderlan Pontes; Cardoso, Marcos Veríssimo de Oliveira; Filho, Gevanio Bezerra de Oliveira; Oliveira E Silva, Dayane Albuquerque; Moreira, Diogo Rodrigo Magalhaes; Bastos, Tanira Matutino; Simone, Carlos Alberto de; Soares, Milena Botelho Pereira; Villela, Filipe Silva; Ferreira, Rafaela Salgado; Castro, Maria Carolina Accioly Brelaz de; Pereira, Valéria Rego Alves; Murta, Silvane Maria Fonseca; Sales Junior, Policarpo Ademar; Romanha, Alvaro José; Leite, Ana Cristina Lima

    2015-08-28

    The discovery of new antiparasitic compounds against Trypanosoma cruzi, the etiological agent of Chagas disease, is necessary. Novel aryloxy/aryl thiosemicarbazone-based conformationally constrained analogs of thiosemicarbazones (1) and (2) were developed as potential inhibitors of the T. cruzi protease cruzain, using a rigidification strategy of the iminic bond of (1) and (2). A structure-activity relationship analysis was performed in substituents attached in both aryl and aryloxy rings. This study indicated that apolar substituents or halogen atom substitution at the aryl position improved cruzain inhibition and antiparasitic activity in comparison to unsubstituted thiosemicarbazone. Two of these compounds displayed potent inhibitory antiparasitic activity by inhibiting cruzain and consequently were able to reduce the parasite burden in infected cells and cause parasite cell death through necrosis. In conclusion, we demonstrated that conformational restriction is a valuable strategy in the development of antiparasitic thiosemicarbazones.

  1. A quantitative structure-activity relationship study of anti-HIV activity of substituted HEPT using nonlinear models.

    Science.gov (United States)

    Noorizadeh, Hadi; Sajjadifar, Sami; Farmany, Abbas

    2013-01-01

    We performed studies on extended series of 79 HEPT ligands (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine), inhibitors of HIV reverse-transcriptase with anti-HIV biological activity, using quantitative structure-activity relationship (QSAR) methods that imply analysis of correlations and representation of models. A suitable set of molecular descriptors was calculated, and the genetic algorithm was employed to select those descriptors which resulted in the best-fit models. The kernel partial least square and Levenberg-Marquardt artificial neural network were utilized to construct the nonlinear QSAR models. The proposed methods will be of great significance in this research, and would be expected to apply to other similar research fields.

  2. Estimating the persistence of organic contaminants in indirect potable reuse systems using quantitative structure activity relationship (QSAR).

    Science.gov (United States)

    Lim, Seung Joo; Fox, Peter

    2012-09-01

    Predictions from the quantitative structure activity relationship (QSAR) model EPI Suite were modified to estimate the persistence of organic contaminants in indirect potable reuse systems. The modified prediction included the effects of sorption, biodegradation, and oxidation that may occur during sub-surface transport. A retardation factor was used to simulate the mobility of adsorbed compounds during sub-surface transport to a recovery well. A set of compounds with measured persistent properties during sub-surface transport was used to validate the results of the modifications to the predictions of EPI Suite. A comparison of the predicted values and measured values was done and the residual sum of the squares showed the importance of including oxidation and sorption. Sorption was the most important factor to include in predicting the fates of organic chemicals in the sub-surface environment.

  3. Design, synthesis, and structure-activity relationship studies of novel thioether pleuromutilin derivatives as potent antibacterial agents.

    Science.gov (United States)

    Ling, Chenyu; Fu, Liqiang; Gao, Suo; Chu, Wenjing; Wang, Hui; Huang, Yanqin; Chen, Xiaoyan; Yang, Yushe

    2014-06-12

    A series of novel thioether pleuromutilin derivatives incorporating various heteroaromatic substituents into the C14 side chain have been reported. Structure-activity relationship (SAR) studies resulted in compounds 52 and 55 with the most potent in vitro antibacterial activity among the series (MIC = 0.031-0.063 μg/mL). Further optimization to overcome the poor water solubility of compound 55 resulted in compounds 87, 91, 109, and 110 possessing good in vitro antibacterial activity with increased hydrophilicity. Compound 114, the water-soluble phosphate prodrug of compound 52, was also prepared and evaluated. Among the derivatives, compound 110 showed moderate pharmacokinetic profiles and good in vivo efficacy in both MSSA and MRSA systemic infection models. Compound 110 was further evaluated in CYP450 inhibition assay and displayed intermediate in vitro inhibition of CYP3A4.

  4. Chromanyl-isoxazolidines as Antibacterial agents: Synthesis, Biological Evaluation, Quantitative Structure Activity Relationship, and Molecular Docking Studies.

    Science.gov (United States)

    Singh, Gagandeep; Sharma, Anuradha; Kaur, Harpreet; Ishar, Mohan Paul S

    2016-02-01

    Regio- and stereoselective 1,3-dipolar cycloadditions of C-(chrom-4-one-3-yl)-N-phenylnitrones (N) with different mono-substituted, disubstituted, and cyclic dipolarophiles were carried out to obtain substituted N-phenyl-3'-(chrom-4-one-3-yl)-isoxazolidines (1-40). All the synthesized compounds were assayed for their in vitro antibacterial activity and display significant inhibitory potential; in particular, compound 32 exhibited good inhibitory activity against Salmonella typhymurium-1 & Salmonella typhymurium-2 with minimum inhibitory concentration value of 1.56 μg/mL and also showed good potential against methicillin-resistant Staphylococcus aureus with minimum inhibitory concentration 3.12 μg/mL. Quantitative structure activity relationship investigations with stepwise multiple linear regression analysis and docking simulation studies have been performed for validation of the observed antibacterial potential of the investigated compounds for determination of the most important parameters regulating antibacterial activities.

  5. AN IN VITRO STUDY OF THE STRUCTURE-ACTIVITY RELATIONSHIPS OF SULFATED POLYSACCHARIDE FROM BROWN ALGAE TO ITS ANTIOXIDANT EFFECT

    Institute of Scientific and Technical Information of China (English)

    JIN FENG HU; MEI YU GENG; JUN TIAN ZHANG; HAN DONG JIANG

    2001-01-01

    In this paper, the structure-activity relationships of chemically modified uronic acid polymer fragments from brown algae with regard to their antioxidant effects on H2O2-damaged lymphocyte were studied. The results indicated that the most potent antioxidant activity was obtained from the sulfated polysaccharide with ratio of mannuronate blocks (M-blocks) to guluronate blocks (G-blocks) of 3 to 1 and carboxyl residue unesterified. The sulfated G-blocks with esterified carboxyl residue also prevented lymphocyte from injury. However, the sulfated G-blocks bearing unesterified carboxyl residue hardly exerted antioxidant activity. These findings suggested that both M-blocks and esterified carboxyl residue were determinant structures in preventing lymphocyte from being oxidized by H2O2, indicating that the existence of M-blocks was more important in scavenging free radicals.

  6. Holographic quantitative structure-activity relationship for prediction acute toxicity of benzene derivatives to the guppy(poecilia reticulata)

    Institute of Scientific and Technical Information of China (English)

    HUANG Hong; WANG Xiao-dong; DAI Xuan-li; YU Ya-juan; WANG Lian-sheng

    2004-01-01

    Holographic quantitative structure-activity relationship(HQSAR) is an emerging QSAR technique with the combined application of molecular hologram, which encoded the frequency of occurrence of various molecular fragment types, and the subsequent partial least squares(PLS) regression analysis. In this paper, the acute toxicity data to the guppy(poecilia reticulata) for a series of 56 substituted benzenes, phenols, aromatic amines and nitro-aromatics were subjected and this resulted in a model with a high predictive ability. The influence of fragment size and fragment distinction parameters on the quality of HQSAR model was investigated. The robustness and predictive ability of the model were also validated by leave-one-out (LOO) cross-validation procedure and external testing data set.

  7. Discovery of novel glitazones incorporated with phenylalanine and tyrosine: synthesis, antidiabetic activity and structure-activity relationships.

    Science.gov (United States)

    Prashantha Kumar, B R; Baig, Nasir R; Sudhir, Sai; Kar, Koyal; Kiranmai, M; Pankaj, M; Joghee, Nanjan M

    2012-12-01

    We report a series of new glitazones incorporated with phenylalanine and tyrosine. All the compounds were tested for their in vitro glucose uptake activity using rat-hemidiaphragm, both in presence and absence of insulin. Six of the most active compounds from the in vitro screening were taken forward for their in vivo triglyceride and glucose lowering activity against dexamethazone induced hyperlipidemia and insulin resistance in Wistar rats. The liver samples of rats that received the most active compounds, 23 and 24, in the in vivo studies, were subjected to histopathological examination to assess their short term hepatotoxicity. The investigations on the in vitro glucose uptake, in vivo triglyceride and glucose lowering activity are described here along with the quantitative structure-activity relationships.

  8. Semisynthesis and quantitative structure-activity relationship (QSAR) study of some cholesterol-based hydrazone derivatives as insecticidal agents.

    Science.gov (United States)

    Yang, Chun; Shao, Yonghua; Zhi, Xiaoyan; Huan, Qu; Yu, Xiang; Yao, Xiaojun; Xu, Hui

    2013-09-01

    In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, four series of novel cholesterol-based hydrazone derivatives were synthesized, and their insecticidal activity was tested against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1mg/mL. All the derivatives showed the better insecticidal activity than their precursor cholesterol. Quantitative structure-activity relationship (QSAR) model demonstrated that six descriptors such as RDF085v, Mor06u, Mor11u, Dv, HATS0v and H-046, are likely to influence the insecticidal activity of these compounds. Among them, two important ones are the Mor06u and RDF085v.

  9. Acyl sulfonamide anti-proliferatives: benzene substituent structure-activity relationships for a novel class of antitumor agents.

    Science.gov (United States)

    Lobb, Karen L; Hipskind, Philip A; Aikins, James A; Alvarez, Enrique; Cheung, Yiu-Yin; Considine, Eileen L; De Dios, Alfonso; Durst, Gregory L; Ferritto, Rafael; Grossman, Cora Sue; Giera, Deborah D; Hollister, Beth A; Huang, Zhongping; Iversen, Philip W; Law, Kevin L; Li, Tiechao; Lin, Ho-Shen; Lopez, Beatriz; Lopez, Jose E; Cabrejas, Luisa M Martin; McCann, Denis J; Molero, Victoriano; Reilly, John E; Richett, Michael E; Shih, Chuan; Teicher, Beverly; Wikel, James H; White, Wesley T; Mader, Mary M

    2004-10-21

    Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.

  10. Thermodynamics of engineered gold binding peptides: establishing the structure-activity relationships.

    Science.gov (United States)

    Seker, Urartu Ozgur Safak; Wilson, Brandon; Kulp, John L; Evans, John S; Tamerler, Candan; Sarikaya, Mehmet

    2014-07-14

    Adsorption behavior of a gold binding peptide was experimentally studied to achieve kinetics and thermodynamics parameters toward understanding of the binding of an engineered peptide onto a solid metal surface. The gold-binding peptide, GBP1, was originally selected using a cell surface display library and contains 14 amino acid residues. In this work, single- and three-repeats of GBP1 were used to assess the effects of two parameters: molecular architecture versus secondary structure on adsorption on to gold substrate. The adsorption measurements were carried out using surface plasmon resonance (SPR) spectroscopy at temperatures ranging from 10 to 55 °C. At all temperatures, two different regimes of peptide adsorption were observed, which, based on the model, correspond to two sets of thermodynamics values. The values of enthalpy, ΔH(ads), and entropy, ΔS(ads), in these two regimes were determined using the van't Hoff approach and Gibbs-Helmholtz relationship. In general, the values of enthalpy for both peptides are negative indicating GBP1 binding to gold is an exothermic phenomenon and that the binding of three repeat gold binding peptide (3l-GBP1) is almost 5 times tighter than that for the single repeat (l-GBP1). More intriguing result is that the entropy of adsorption for the 3l-GBP1 is negative (-43.4 ± 8.5 cal/(mol K)), while that for the l-GBP1 is positive (10.90 ± 1.3 cal/(mol K)). Among a number of factors that synergistically contribute to the decrease of entropy, long-range ordered self-assembly of the 3l-GBP1 on gold surface is the most effective, probably through both peptide-solid and peptide-peptide intermolecular interactions. Additional adsorption experiments were conducted in the presence of 2,2,2-trifluoroethanol (TFE) to determine how the conformational structures of the biomolecules responded to the environmental perturbation. We found that the peptides differ in their conformational responses to the change in solution conditions; while

  11. SARANEA: a freely available program to mine structure-activity and structure-selectivity relationship information in compound data sets.

    Science.gov (United States)

    Lounkine, Eugen; Wawer, Mathias; Wassermann, Anne Mai; Bajorath, Jürgen

    2010-01-01

    We introduce SARANEA, an open-source Java application for interactive exploration of structure-activity relationship (SAR) and structure-selectivity relationship (SSR) information in compound sets of any source. SARANEA integrates various SAR and SSR analysis functions and utilizes a network-like similarity graph data structure for visualization. The program enables the systematic detection of activity and selectivity cliffs and corresponding key compounds across multiple targets. Advanced SAR analysis functions implemented in SARANEA include, among others, layered chemical neighborhood graphs, cliff indices, selectivity trees, editing functions for molecular networks and pathways, bioactivity summaries of key compounds, and markers for bioactive compounds having potential side effects. We report the application of SARANEA to identify SAR and SSR determinants in different sets of serine protease inhibitors. It is found that key compounds can influence SARs and SSRs in rather different ways. Such compounds and their SAR/SSR characteristics can be systematically identified and explored using SARANEA. The program and source code are made freely available under the GNU General Public License.

  12. Brand Nostalgia and Consumers Relationships to Luxury Brands: A Continuous and Categorical Moderated Mediation Approach

    OpenAIRE

    Kessous, Aurélie; Magnoni, Fanny; Valette-Florence, Pierre

    2016-01-01

    International audience; This study investigates the role of nostalgia in the consumer-brand relationships in the luxury sector. Results indicate that the nostalgic luxury car brands (vs. futuristic luxury car brands) lead to stronger consumer-brand relationships. Moreover, brand nostalgia has a direct positive effect on brand attachment and separation distress. Brand attachment is also a partial mediator between brand nostalgia and separation distress. In addition, the influence of two modera...

  13. 核磁共振技术在构效关系研究中的应用%Progress on Structure-Activity Relationship by NMR Methods

    Institute of Scientific and Technical Information of China (English)

    王明安

    2000-01-01

      In this paper, two kinds of NMR methods which were used in structure-activity relationship research were introduced. They were structure-activity relationship by 13C NMR and 2D 15N/1H HSQC spectrum.%  介绍了核磁共振技术在构效关系研究中的应用,包括:1)13C NMR在构效关系研究中的应用;2) SAR by NMR 新方法的应用,重点介绍第二种方法。

  14. Molecular docking, kinetics study, and structure-activity relationship analysis of quercetin and its analogous as Helicobacter pylori urease inhibitors.

    Science.gov (United States)

    Xiao, Zhu-Ping; Wang, Xu-Dong; Peng, Zhi-Yun; Huang, Shen; Yang, Pan; Li, Qing-Shan; Zhou, Li-Hu; Hu, Xiao-Jun; Wu, Li-Jun; Zhou, Yin; Zhu, Hai-Liang

    2012-10-24

    It was disclosed in our group for the first time that the flavonoids in Lonicera japonica Thunb. are related to its therapy for gastric ulcer. Based on this finding, 20 flavonoids were selected for Helicobacter pylori urease inhibitory activity evaluation, and quercetin showed excellent potency with IC(50) of 11.2 ± 0.9 μM. Structure-activity relationship analysis revealed that removal of the 5-, 3-, or 3'-OH in quercetin led to a sharp decrease in activity. Thus, 3- and 5-OH as well as 3',4'-dihydroxyl groups are believed to be the key structural characteristics for active compounds, which was supported by the molecular docking study. Meanwhile, the results obtained from molecular docking and enzymatic kinetics research strongly suggested that quercetin is a noncompetitive urease inhibitor, indicating that quercetin may be able to tolerate extensive structural modification irrespective of the shape of the active site cavity and could be used as a lead candidate for the development of novel urease inhibitors.

  15. Predicting quantitative structure-activity relationship of substituted 17α-acetoxyprogesterones by molecular hybridization electronegativity-distance vector

    Institute of Scientific and Technical Information of China (English)

    SUN Li-li; LAN Yu-kun; ZHOU Li-ping; YU Yu; LI Zhi-liang

    2007-01-01

    A set of novel structural descriptors (molecular hybridization electronegativity-distance vector, VMEDh) was put forward, and the quantitative structure-activity relationship (QSAR) of a series of 17α-Acetoxyprogesterones (Aps) was investigated. Taking into account the effect of various hybridized orbits on atomic electronegativities, we developed the structure descriptors with amended electronegativities to build a QSAR model. The 10-parameter model based on VMEDh yields a correlation coefficient R=0.972 and standard deviation SD=0.262, which are more desirable than those of the previous molecular electonegativity-distance vector (MEDV-4) (R=0.969, SD=0.275). By stepwise multiple linear regression, several parameters are selected to construct optimal models. The 7-parameter model based on VMEDh has R=0.960 and SD=0.276; its correlation coefficient (RCV) and standard deviation (SDCV) for leave-one-out procedure crossvalidation are respectively RCV=0.890 and SDCV=0.445. The 6-parameter MEDV-4 model has R=0.946, SD=0.304, RCV=0.903 and SDCV=0.406. It is demonstrated that VMEDh has desirable estimation performance and good predictive capability for this series of chemical compounds.

  16. Structural Characterization and Evaluation of the Antioxidant Activity of Phenolic Compounds from Astragalus taipaishanensis and Their Structure-Activity Relationship

    Science.gov (United States)

    Pu, Wenjun; Wang, Dongmei; Zhou, Dan

    2015-09-01

    Eight phenolic compounds were isolated using bio-guided isolation and purified from the roots of Astragalus taipaishanensis Y. C. Ho et S. B. Ho (A. taipaishanensis) for the first time. Their structures were elucidated by ESI-MS, HR-ESI-MS, 1D-NMR and 2D-NMR as 7,2‧-dihydroxy-3‧,4‧-dimethoxy isoflavan (1), formononetin (2), isoliquiritigenin (3), quercetin (4), kaempferol (5), ononin (6), p-hydroxybenzoic acid (7) and vanillic acid (8). Six flavonoids (compounds 1-6) exhibited stronger antioxidant activities (determined by DPPH, ABTS, FRAP and lipid peroxidation inhibition assays) than those of BHA and TBHQ and also demonstrated noticeable protective effects (particularly quercetin and kaempferol) on Escherichia coli under oxidative stress. Additionally, the chemical constituents compared with those of Astragalus membranaceus and the structure-activity relationship of the isolated compounds were both analyzed. The results clearly demonstrated that A. taipaishanensis has the potential to be selected as an alternative medicinal and food plant that can be utilized in health food products, functional tea and pharmaceutical products.

  17. Quantitative structure-activity relationship studies of [(biphenyloxy)propyl]isoxazole derivatives. Inhibitors of human rhinovirus 2 replication.

    Science.gov (United States)

    Kuz'min, Victor E; Artemenko, Anatoly G; Muratov, Eugene N; Volineckaya, Ingrid L; Makarov, Vadim A; Riabova, Olga B; Wutzler, Peter; Schmidtke, Michaela

    2007-08-23

    The 50% cytotoxic concentration (CC50) in HeLa cells, the 50% inhibitory concentration (IC50) against human rhinovirus 2 (HRV-2), and the selectivity index (SI = CC50/IC50) of [(biphenyloxy)propyl]isoxazole derivatives were used to develop quantitative structure-activity relationships (QSAR) based on simplex representation of molecular structure. Statistic characteristics for partial least-squares models are quite satisfactory (R2 = 0.838 - 0.918; Q2 = 0.695 - 0.87) for prediction of CC50, IC50, and SI values and permit the virtual screening and molecular design of new compounds with strong anti-HRV-2 activity. The quality of prognosis for designed compounds was additionally estimated by analysis of domain applicability for each QSAR model. A hypothesis to the effect that terminal benzene substituents must have negative electrostatic potential and definite length (approximately 5.5-5.6 A) to possess strong antiviral activity has been suggested. The quality of developed analysis, i.e., high level of antiviral action of three new designed compounds, has been confirmed experimentally.

  18. Development of quantitative structure activity relationship (QSAR) model for disinfection byproduct (DBP) research: A review of methods and resources.

    Science.gov (United States)

    Chen, Baiyang; Zhang, Tian; Bond, Tom; Gan, Yiqun

    2015-12-15

    Quantitative structure-activity relationship (QSAR) models are tools for linking chemical activities with molecular structures and compositions. Due to the concern about the proliferating number of disinfection byproducts (DBPs) in water and the associated financial and technical burden, researchers have recently begun to develop QSAR models to investigate the toxicity, formation, property, and removal of DBPs. However, there are no standard procedures or best practices regarding how to develop QSAR models, which potentially limit their wide acceptance. In order to facilitate more frequent use of QSAR models in future DBP research, this article reviews the processes required for QSAR model development, summarizes recent trends in QSAR-DBP studies, and shares some important resources for QSAR development (e.g., free databases and QSAR programs). The paper follows the four steps of QSAR model development, i.e., data collection, descriptor filtration, algorithm selection, and model validation; and finishes by highlighting several research needs. Because QSAR models may have an important role in progressing our understanding of DBP issues, it is hoped that this paper will encourage their future use for this application.

  19. Structure-activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators.

    Science.gov (United States)

    Nguyen, Thuy; German, Nadezhda; Decker, Ann M; Li, Jun-Xu; Wiley, Jenny L; Thomas, Brian F; Kenakin, Terry P; Zhang, Yanan

    2015-05-01

    A series of substituted 1H-indole-2-carboxamides structurally related to compounds Org27569 (1), Org29647 (2) and Org27759 (3) were synthesized and evaluated for CB1 allosteric modulating activity in calcium mobilization assays. Structure-activity relationship studies showed that the modulation potency of this series at the CB1 receptor was enhanced by the presence of a diethylamino group at the 4-position of the phenyl ring, a chloro or fluoro group at the C5 position and short alkyl groups at the C3 position on the indole ring. The most potent compound (45) had an IC₅₀ value of 79 nM which is ∼2.5 and 10 fold more potent than the parent compounds 3 and 1, respectively. These compounds appeared to be negative allosteric modulators at the CB1 receptor and dose-dependently reduced the Emax of agonist CP55,940. These analogs may provide the basis for further optimization and use of CB1 allosteric modulators.

  20. Analysis of positions and substituents on genotoxicity of fluoroquinolones with quantitative structure-activity relationship and 3D Pharmacophore model.

    Science.gov (United States)

    Fengxian, Chen; Reti, Hai

    2017-02-01

    The genotoxicity values of 21 quinolones were studied to establish a quantitative structure-activity relationship model and 3D Pharmacophore model separately for screening essential positions and substituents that contribute to genotoxicity of fluoroquinolones (FQs). A full factor experimental design was performed to analyze the specific main effect and second-order interaction effect of different positions and substituents on genotoxicity, forming a reasonable modification scheme which was validated on typical FQ with genotoxicity and efficacy data. Four positions (1, 5, 7, 8) were screened finally to form the full factorial experimental design which contained 72 congeners in total, illustrating that: the dominant effect of 5 and 7-positions on genotoxicity of FQs is main effect; meanwhile the effect of 1 and 8-positions is a second-order interaction effect; two adjacent positions always have stronger second-order interaction effect and lower genotoxicity; the obtained modification scheme had been validated on typical FQ congeners with the modified compound has a lower genotoxicity, higher synthesis feasibilities and efficacy.

  1. Two- and Three-Dimensional Quantitative Structure-Activity Relationships Studies on a Series of Liver X Receptor Ligands

    Science.gov (United States)

    Honório, Káthia M; Salum, Lívia B; Garratt, Richard C; Polikarpov, Igor; Andricopulo, Adriano D

    2008-01-01

    Liver X receptor (LXR) is an attractive drug target for the development of novel therapeutic agents for the treatment of dyslipidaemia and cholestasis. In the present work, comparative molecular field analysis (CoMFA) and hologram quantitative structure-activity relationship (HQSAR) studies were conducted on a series of potent LXR ligands. Significant correlation coefficients (CoMFA, r2 = 0.98 and q2 = 0.69; HQSAR, r2 = 0.99 and q2 = 0.85) were obtained, indicating the potential of the models for untested compounds. The models were then used to predict the potency of an external test set, and the predicted values obtained from the 2D and 3D models were in good agreement with the experimental results. The final QSAR models, along with the information obtained from 3D steric and electrostatic contour maps and 2D contribution maps should be useful for the design of novel LXR ligands having improved potency. PMID:19696872

  2. Structure-activity relationships for a class of selective inhibitors of the major cysteine protease from Trypanosoma cruzi.

    Science.gov (United States)

    Guido, Rafael V C; Trossini, Gustavo H G; Castilho, Marcelo S; Oliva, Glaucius; Ferreira, Elizabeth I; Andricopulo, Adriano D

    2008-12-01

    Chagas' disease is a parasitic infection widely distributed throughout Latin America, with devastating consequences in terms of human morbidity and mortality. Cruzain, the major cysteine protease from Trypanosoma cruzi, is an attractive target for antitrypanosomal chemotherapy. In the present work, classical two-dimensional quantitative structure-activity relationships (2D QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 45 thiosemicarbazone and semicarbazone derivatives as inhibitors of T. cruzi cruzain. Significant statistical models (HQSAR, q(2) = 0.75 and r(2) = 0.96; classical QSAR, q(2) = 0.72 and r(2) = 0.83) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 10 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, r(2)(pred) = 0.95; classical QSAR, r(2)(pred) = 0.91), indicating the existence of complementary between the two ligand-based drug design techniques.

  3. Defining RNA motif-aminoglycoside interactions via two-dimensional combinatorial screening and structure-activity relationships through sequencing.

    Science.gov (United States)

    Velagapudi, Sai Pradeep; Disney, Matthew D

    2013-10-15

    RNA is an extremely important target for the development of chemical probes of function or small molecule therapeutics. Aminoglycosides are the most well studied class of small molecules to target RNA. However, the RNA motifs outside of the bacterial rRNA A-site that are likely to be bound by these compounds in biological systems is largely unknown. If such information were known, it could allow for aminoglycosides to be exploited to target other RNAs and, in addition, could provide invaluable insights into potential bystander targets of these clinically used drugs. We utilized two-dimensional combinatorial screening (2DCS), a library-versus-library screening approach, to select the motifs displayed in a 3×3 nucleotide internal loop library and in a 6-nucleotide hairpin library that bind with high affinity and selectivity to six aminoglycoside derivatives. The selected RNA motifs were then analyzed using structure-activity relationships through sequencing (StARTS), a statistical approach that defines the privileged RNA motif space that binds a small molecule. StARTS allowed for the facile annotation of the selected RNA motif-aminoglycoside interactions in terms of affinity and selectivity. The interactions selected by 2DCS generally have nanomolar affinities, which is higher affinity than the binding of aminoglycosides to a mimic of their therapeutic target, the bacterial rRNA A-site.

  4. Synthetic cannabinoids: In silico prediction of the cannabinoid receptor 1 affinity by a quantitative structure-activity relationship model.

    Science.gov (United States)

    Paulke, Alexander; Proschak, Ewgenij; Sommer, Kai; Achenbach, Janosch; Wunder, Cora; Toennes, Stefan W

    2016-03-14

    The number of new synthetic psychoactive compounds increase steadily. Among the group of these psychoactive compounds, the synthetic cannabinoids (SCBs) are most popular and serve as a substitute of herbal cannabis. More than 600 of these substances already exist. For some SCBs the in vitro cannabinoid receptor 1 (CB1) affinity is known, but for the majority it is unknown. A quantitative structure-activity relationship (QSAR) model was developed, which allows the determination of the SCBs affinity to CB1 (expressed as binding constant (Ki)) without reference substances. The chemically advance template search descriptor was used for vector representation of the compound structures. The similarity between two molecules was calculated using the Feature-Pair Distribution Similarity. The Ki values were calculated using the Inverse Distance Weighting method. The prediction model was validated using a cross validation procedure. The predicted Ki values of some new SCBs were in a range between 20 (considerably higher affinity to CB1 than THC) to 468 (considerably lower affinity to CB1 than THC). The present QSAR model can serve as a simple, fast and cheap tool to get a first hint of the biological activity of new synthetic cannabinoids or of other new psychoactive compounds.

  5. Antileishmanial Activity and Structure-Activity Relationship of Triazolic Compounds Derived from the Neolignans Grandisin, Veraguensin, and Machilin G

    Directory of Open Access Journals (Sweden)

    Eduarda C. Costa

    2016-06-01

    Full Text Available Sixteen 1,4-diaryl-1,2,3-triazole compounds 4–19 derived from the tetrahydrofuran neolignans veraguensin 1, grandisin 2, and machilin G 3 were tested against Leishmania (Leishmania amazonensis intracellular amastigotes. Triazole compounds 4–19 were synthetized via Click Chemistry strategy by 1,3-dipolar cycloaddition between terminal acetylenes and aryl azides containing methoxy and methylenedioxy groups as substituents. Our results suggest that most derivatives were active against intracellular amastigotes, with IC50 values ranging from 4.4 to 32.7 µM. The index of molecular hydrophobicity (ClogP ranged from 2.8 to 3.4, reflecting a lipophilicity/hydrosolubility rate suitable for transport across membranes, which may have resulted in the potent antileishmanial activity observed. Regarding structure-activity relationship (SAR, compounds 14 and 19, containing a trimethoxy group, were the most active (IC50 values of 5.6 and 4.4 µM, respectively, with low cytotoxicity on mammalian cells (SI = 14.1 and 10.6. These compounds induced nitric oxide production by the host macrophage cells, which could be suggested as the mechanism involved in the intracellular killing of parasites. These results would be useful for the planning of new derivatives with higher antileishmanial activities.

  6. Similarity boosted quantitative structure-activity relationship--a systematic study of enhancing structural descriptors by molecular similarity.

    Science.gov (United States)

    Girschick, Tobias; Almeida, Pedro R; Kramer, Stefan; Stålring, Jonna

    2013-05-24

    The concept of molecular similarity is one of the most central in the fields of predictive toxicology and quantitative structure-activity relationship (QSAR) research. Many toxicological responses result from a multimechanistic process and, consequently, structural diversity among the active compounds is likely. Combining this knowledge, we introduce similarity boosted QSAR modeling, where we calculate molecular descriptors using similarities with respect to representative reference compounds to aid a statistical learning algorithm in distinguishing between different structural classes. We present three approaches for the selection of reference compounds, one by literature search and two by clustering. Our experimental evaluation on seven publicly available data sets shows that the similarity descriptors used on their own perform quite well compared to structural descriptors. We show that the combination of similarity and structural descriptors enhances the performance and that a simple stacking approach is able to use the complementary information encoded by the different descriptor sets to further improve predictive results. All software necessary for our experiments is available within the cheminformatics software framework AZOrange.

  7. A Quantitative Structure Activity Relationship for acute oral toxicity of pesticides on rats: Validation, domain of application and prediction.

    Science.gov (United States)

    Hamadache, Mabrouk; Benkortbi, Othmane; Hanini, Salah; Amrane, Abdeltif; Khaouane, Latifa; Si Moussa, Cherif

    2016-02-13

    Quantitative Structure Activity Relationship (QSAR) models are expected to play an important role in the risk assessment of chemicals on humans and the environment. In this study, we developed a validated QSAR model to predict acute oral toxicity of 329 pesticides to rats because a few QSAR models have been devoted to predict the Lethal Dose 50 (LD50) of pesticides on rats. This QSAR model is based on 17 molecular descriptors, and is robust, externally predictive and characterized by a good applicability domain. The best results were obtained with a 17/9/1 Artificial Neural Network model trained with the Quasi Newton back propagation (BFGS) algorithm. The prediction accuracy for the external validation set was estimated by the Q(2)ext and the root mean square error (RMS) which are equal to 0.948 and 0.201, respectively. 98.6% of external validation set is correctly predicted and the present model proved to be superior to models previously published. Accordingly, the model developed in this study provides excellent predictions and can be used to predict the acute oral toxicity of pesticides, particularly for those that have not been tested as well as new pesticides.

  8. Structure-Activity Relationships of Antimicrobial Gallic Acid Derivatives from Pomegranate and Acacia Fruit Extracts against Potato Bacterial Wilt Pathogen.

    Science.gov (United States)

    Farag, Mohamed A; Al-Mahdy, Dalia A; Salah El Dine, Riham; Fahmy, Sherifa; Yassin, Aymen; Porzel, Andrea; Brandt, Wolfgang

    2015-06-01

    Bacterial wilts of potato, tomato, pepper, and or eggplant caused by Ralstonia solanacearum are among the most serious plant diseases worldwide. In this study, the issue of developing bactericidal agents from natural sources against R. solanacearum derived from plant extracts was addressed. Extracts prepared from 25 plant species with antiseptic relevance in Egyptian folk medicine were screened for their antimicrobial properties against the potato pathogen R. solancearum by using the disc-zone inhibition assay and microtitre plate dilution method. Plants exhibiting notable antimicrobial activities against the tested pathogen include extracts from Acacia arabica and Punica granatum. Bioactivity-guided fractionation of A. arabica and P. granatum resulted in the isolation of bioactive compounds 3,5-dihydroxy-4-methoxybenzoic acid and gallic acid, in addition to epicatechin. All isolates displayed significant antimicrobial activities against R. solanacearum (MIC values 0.5-9 mg/ml), with 3,5-dihydroxy-4-methoxybenzoic acid being the most effective one with a MIC value of 0.47 mg/ml. We further performed a structure-activity relationship (SAR) study for the inhibition of R. solanacearum growth by ten natural, structurally related benzoic acids.

  9. Applying quantitative structure-activity relationship (QSAR) methodology for modeling postmortem redistribution of benzodiazepines and tricyclic antidepressants.

    Science.gov (United States)

    Giaginis, Constantinos; Tsantili-Kakoulidou, Anna; Theocharis, Stamatios

    2014-06-01

    Postmortem redistribution (PMR) constitutes a multifaceted process, which complicates the interpretation of drug concentrations by forensic toxicologists. The present study aimed to apply quantitative structure-activity relationship (QSAR) analysis for modeling PMR data of structurally related drugs, 10 benzodiazepines and 10 tricyclic antidepressants. For benzodiazepines, an adequate QSAR model was obtained (R(2) = 0.98, Q(2) = 0.88, RMSEE = 0.12), in which energy, ionization and molecular size exerted significant impact. For tricyclic antidepressants, an adequate QSAR model with slightly inferior statistics (R(2) = 0.95, Q(2) = 0.87, RMSEE = 0.29) was established after exclusion of maprotiline, in which energy parameters, basicity character and lipophilicity exerted significant contribution. Thus, QSAR analysis could be used as a complementary tool to provide an informative illustration of the contributing molecular, physicochemical and structural properties in PMR process. However, the complexity, non-static and time-dependent nature of PMR endpoints raises serious concerns whether QSAR methodology could predict the degree of redistribution, highlighting the need for animal-derived PMR data.

  10. Quantitative structure-activity relationship modelling of oral acute toxicity and cytotoxic activity of fragrance materials in rodents.

    Science.gov (United States)

    Papa, E; Luini, M; Gramatica, P

    2009-10-01

    Fragrance materials are used as ingredients in many consumer and personal care products. The wide and daily use of these substances, as well as their mainly uncontrolled discharge through domestic sewage, make fragrance materials both potential indoor and outdoor air pollutants which are also connected to possible toxic effects on humans (asthma, allergies, headaches). Unfortunately, little is known about the environmental fate and toxicity of these substances. However, the use of alternative, predictive approaches, such as quantitative structure-activity relationships (QSARs), can help in filling the data gap and in the characterization of the environmental and toxicological profile of these substances. In the proposed study, ordinary least squares regression-based QSAR models were developed for three toxicological endpoints: mouse oral LD(50), inhibition of NADH-oxidase (EC(50) NADH-Ox) and the effect on mitochondrial membrane potential (EC(50) DeltaPsim). Theoretical molecular descriptors were calculated by using DRAGON software, and the best QSAR models were developed according to the principles defined by the Organization for Economic Co-operation and Development.

  11. In vitro antileukemia, antibacterial and antifungal activities of some 3d metal complexes: chemical synthesis and structure - activity relationships.

    Science.gov (United States)

    Gulea, Aurelian; Poirier, Donald; Roy, Jenny; Stavila, Vitalie; Bulimestru, Ion; Tapcov, Victor; Birca, Maria; Popovschi, Lilia

    2008-12-01

    The present paper describes the synthesis, characterization and in vitro biological evaluation screening of different classes (ammoniacates, dioximates, carboxylates, semi- and thiosemicarbazidates) of Co(II), Co(III), Cu(II), Ni(II), Mn(II), Zn(II) and Fe(III) complexes. Schiff bases were obtained from the reaction of some salicyl aldehydes with, respectively, furoylhydrazine, benzoylhydrazine, semicarbazide, thiosemicarbazide and S-methylthiosemicarbazide to give tridentate ligands containing ONO, ONS or ONN as donor atoms. The synthetic metal complexes are of various geometrical and electronic structures, thermodynamic and thermal stabilities, and magnetic and conductance properties. All complexes, except those of Cu, are octahedral. Some Cu, Co and Mn compounds have a dimeric or a polymeric structure. The composition and structure of complexes were analysed by elemental analysis, IR and (1)H NMR and (13)C NMR spectroscopies, and magnetochemical, thermoanalytical and molar conductance measurements. All ligands and metal complexes were tested as inhibitors of human leukemia (HL-60) cells growth, and the most potent, the Cu(II) complexes, have been also tested for their in vitro antibacterial and antifungal activities. Structure-activity relationships were carried out.

  12. Terpenes: Natural Products for Controlling Insects of Importance to Human Health—A Structure-Activity Relationship Study

    Directory of Open Access Journals (Sweden)

    José S. Dambolena

    2016-01-01

    Full Text Available Many insects affect food production and human health, and in an attempt to control these insects the use of synthetic insecticides has become widespread. However, this has resulted in the development of resistance in these organisms, human diseases, contamination of food, and pollution of the environment. Plants natural products and essential oil components such as terpenes and phenylpropenes have been shown to have a significant potential for insect control. However, the molecular properties related to their insecticidal activity are not well understood. The purpose of this review is to provide an overview of the toxicity of terpene compounds against three insects of importance to human health: lice, cockroaches, and Triatominae bugs and to evaluate which molecular descriptors are important in the bioactivity of terpenes. For the insects studied, quantitative structure-activity relationship (QSAR studies were performed in order to predict the insecticidal activity of terpene compounds. The obtained QSAR models indicated that the activity of these compounds depends on their ability to reach the targets and to interact with them. The QSAR analysis can be used to predict the bioactivities of other structurally related molecules. Our findings may provide an important contribution in the search for new compounds with insecticidal activity.

  13. Isolation of lignans from Schisandra chinensis with anti-proliferative activity in human colorectal carcinoma: Structure-activity relationships.

    Science.gov (United States)

    Gnabre, John; Unlu, Irem; Chang, Tso-Cheng; Lisseck, Paul; Bourne, Bryan; Scolnik, Ryan; Jacobsen, Neil E; Bates, Robert; Huang, Ru Chih

    2010-10-15

    Separate benzocyclooctadiene lignans were isolated from the berries of Schisandra chinensis in milligram quantities on analytical reverse phase (RP) HPLC by an automated repeat-injection method and shown to have anti-proliferative activity against human colorectal cancer cells. Structures of the compounds were determined by a combination of NMR and mass spectrometry. Stereospecific NMR assignments for gomisin-N and deoxyschisandrin, gave more complete and accurate data than previously reported, based on 600MHz 2D HSQC, DQF-COSY and HMBC data. Comparison of coupling constants and HMBC crosspeak intensities with calculated and X-ray crystal structures confirmed their stereochemistry and conformation. Analysis of structure-activity relationships revealed the importance of key structural determinants. The S-biphenyl configuration of gomisin N, the most active lignan, correlated with increased anti-proliferative activity, while the presence of a hydroxyl group at the C7 position reduced or abolished this activity. Increased activity was also observed when a methylenedioxy group was present between C12 and C13. The percent yield of the most active compounds relative to the starting plant materials was 0.0156% for deoxyschisandrin and 0.0173% for gomisin N. The results of these studies indicate that automated repeat-injection method of analytical HPLC may provide a superior alternative to the standard semi-preparative HPLC techniques for separation of complex mixtures.

  14. A quantitative structure-activity relationship to predict efficacy of granular activated carbon adsorption to control emerging contaminants.

    Science.gov (United States)

    Kennicutt, A R; Morkowchuk, L; Krein, M; Breneman, C M; Kilduff, J E

    2016-08-01

    A quantitative structure-activity relationship was developed to predict the efficacy of carbon adsorption as a control technology for endocrine-disrupting compounds, pharmaceuticals, and components of personal care products, as a tool for water quality professionals to protect public health. Here, we expand previous work to investigate a broad spectrum of molecular descriptors including subdivided surface areas, adjacency and distance matrix descriptors, electrostatic partial charges, potential energy descriptors, conformation-dependent charge descriptors, and Transferable Atom Equivalent (TAE) descriptors that characterize the regional electronic properties of molecules. We compare the efficacy of linear (Partial Least Squares) and non-linear (Support Vector Machine) machine learning methods to describe a broad chemical space and produce a user-friendly model. We employ cross-validation, y-scrambling, and external validation for quality control. The recommended Support Vector Machine model trained on 95 compounds having 23 descriptors offered a good balance between good performance statistics, low error, and low probability of over-fitting while describing a wide range of chemical features. The cross-validated model using a log-uptake (qe) response calculated at an aqueous equilibrium concentration (Ce) of 1 μM described the training dataset with an r(2) of 0.932, had a cross-validated r(2) of 0.833, and an average residual of 0.14 log units.

  15. Novel hinge-binding motifs for Janus kinase 3 inhibitors: a comprehensive structure-activity relationship study on tofacitinib bioisosteres.

    Science.gov (United States)

    Gehringer, Matthias; Forster, Michael; Pfaffenrot, Ellen; Bauer, Silke M; Laufer, Stefan A

    2014-11-01

    The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7H-pyrrolo[2,3-d]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure-activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models.

  16. Biologically relevant chemical space navigator: from patent and structure-activity relationship analysis to library acquisition and design.

    Science.gov (United States)

    Rabal, Obdulia; Oyarzabal, Julen

    2012-12-21

    A new and versatile visualization tool, based on a descriptor accounting for ligand-receptor interactions (LiRIf), is introduced for guiding medicinal chemists in analyzing the R-groups from a congeneric series. Analysis is performed in a reference-independent scenario where the whole biologically relevant chemical space (BRCS) is represented. Using a real project-based data set, we show the impact of this tool on four key navigation strategies for the drug discovery process. First, this navigator analyzes competitors' patents, including a comparison of patents coverage and the identification of the most frequent fragments. Second, the tool analyzes the structure-activity relationship (SAR) leading to the representation of reference-independent activity landscapes that enable the identification not only of critical ligand-receptor interactions (LRI) and substructural features but also of activity cliffs. Third, this navigator enables comparison of libraries, thus selecting commercially available molecules that complement unexplored spaces or areas of interest. Finally, this tool also enables the design of new analogues, which is based on reaction types and the exploration purpose (focused or diverse), selecting the most appropriate reagents.

  17. Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling

    Energy Technology Data Exchange (ETDEWEB)

    Kumar G.; Swaminathan S.; Kumaran, D.; Ahmed, S. A.

    2012-05-01

    Clostridium botulinum neurotoxins are classified as Category A bioterrorism agents by the Centers for Disease Control and Prevention (CDC). The seven serotypes (A-G) of the botulinum neurotoxin, the causative agent of the disease botulism, block neurotransmitter release by specifically cleaving one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and induce flaccid paralysis. Using a structure-based drug-design approach, a number of peptide inhibitors were designed and their inhibitory activity against botulinum serotype A (BoNT/A) protease was determined. The most potent peptide, RRGF, inhibited BoNT/A protease with an IC{sub 50} of 0.9 {micro}M and a K{sub i} of 358 nM. High-resolution crystal structures of various peptide inhibitors in complex with the BoNT/A protease domain were also determined. Based on the inhibitory activities and the atomic interactions deduced from the cocrystal structures, the structure-activity relationship was analyzed and a pharmacophore model was developed. Unlike the currently available models, this pharmacophore model is based on a number of enzyme-inhibitor peptide cocrystal structures and improved the existing models significantly, incorporating new features.

  18. Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase.

    Science.gov (United States)

    Kim, In-Hae; Park, Yong-Kyu; Nishiwaki, Hisashi; Hammock, Bruce D; Nishi, Kosuke

    2015-11-15

    Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase (sEH) were investigated. First, a series of alkyl or aryl groups were substituted on the carbon alpha to the phosphonate function in amide compounds to see whether substituted phosphonates can act as a secondary pharmacophore. A tert-butyl group (16) on the alpha carbon was found to yield most potent inhibition on the target enzyme. A 4-50-fold drop in inhibition was induced by other substituents such as aryls, substituted aryls, cycloalkyls, and alkyls. Then, the modification of the O-substituents on the phosphonate function revealed that diethyl groups (16 and 23) were preferable for inhibition to other longer alkyls or substituted alkyls. In amide compounds with the optimized diethylphosphonate moiety and an alkyl substitution such as adamantane (16), tetrahydronaphthalene (31), or adamantanemethane (36), highly potent inhibitions were gained. In addition, the resulting potent amide-phosphonate compounds had reasonable water solubility, suggesting that substituted phosphonates in amide inhibitors are effective for both inhibition potency on the human sEH and water solubility as a secondary pharmacophore.

  19. Structure-activity relationship of a recombinant hybrid Manganese superoxide dismutase of Staphylococcus saprophyticus/S. equorum.

    Science.gov (United States)

    Retnoningrum, Debbie S; Arumsari, Sekar; Artarini, Anita; Ismaya, Wangsa T

    2017-05-01

    Recombinant hybrid Manganese superoxide dismutase from Staphyloccus saphropyticus/S. equorum (rMnSODSeq) exhibits stability at high temperatures. The enzyme occurs as a dimer that dissociates around 52°C prior to unfolding of the monomer around 64°C, demonstrating contribution of the dimeric form to stability. Here, structure - activity relationship of rMnSODSeq was evaluated on the basis of its activity and stability in the presence of inhibitors, NaCl, denaturants, detergents, reducing agents, and at different pH values. The activity was evaluated at both 37°C and 52°C, which the latter is the temperature for dissociation of the dimer. Dimer to monomer transition coincided with significant decrease in residual activity at 52°C. However, the activity assay results at 52°C and 37°C suggest spontaneous re-association of the monomer into dimer. Intriguingly, various new species with melting temperature (TM) values other than those of the dimer or monomer were observed. These species displayed medium to comparable level of residual activities to the native at 37°C. This report suggests that dimer to monomer transition may be not the only explanation for activity loss or decrease.

  20. Isolation of Insecticidal Constituent from Ruta graveolens and Structure-Activity Relationship Studies against Stored-Food Pests (Coleoptera).

    Science.gov (United States)

    Jeon, Ju-Hyun; Lee, Sang-Guei; Lee, Hoi-Seon

    2015-08-01

    Isolates from essential oil extracted from the flowers and leaves of Ruta graveolens and commercial phenolic analogs were evaluated using fumigant and contact toxicity bioassays against adults of the stored-food pests Sitophilus zeamais, Sitophilus oryzae, and Lasioderma serricorne. The insecticidal activity of these compounds was then compared with that of the synthetic insecticide dichlorvos. To investigate the structure-activity relationships, the activity of 2-isopropyl-5-methylphenol and its analogs was examined against these stored-food pests. Based on the 50% lethal dose, the most toxic compound against S. zeamais was 3-isopropylephenol, followed by 2-isopropylphenol, 4-isopropylphenol, 5-isopropyl-2-methylphenol, 2-isopropyl-5-methylphenol, 3-methylphenol, and 2-methylphenol. Similar results were observed with phenolic compounds against S. oryzae. However, when 2-isopropyl-5-methylphenol isolated from R. graveolens oil and its structurally related analogs were used against L. serricorne, little or no insecticidal activity was found regardless of bioassay. These results indicate that introducing and changing the positions of functional groups in the phenol skeleton have an important effect on insecticidal activity of these compounds against stored-food pests.

  1. Biofunctional constituent isolated from Citrullus colocynthis fruits and structure-activity relationships of its analogues show acaricidal and insecticidal efficacy.

    Science.gov (United States)

    Jeon, Ju-Hyun; Lee, Hoi-Seon

    2014-08-27

    The acaricidal and insecticidal potential of the active constituent isolated from Citrullus colocynthis fruits and its structurally related analogues was evaluated by performing leaf disk, contact toxicity, and fumigant toxicity bioassays against Tetranychus urticae, Sitophilus oryzae, and Sitophilus zeamais adults. The active constituent of C. colocynthis fruits was isolated by chromatographic techniques and was identified as 4-methylquinoline on the basis of spectroscopic analyses. To investigate the structure-activity relationships, 4-methylquinoline and its structural analogues were tested against mites and two insect pests. On the basis of the LC50 values, 7,8-benzoquinoline was the most effective against T. urticae. Quinoline, 8-hydroxyquinoline, 2-methylquinoline, 4-methylquinoline, 6-methylquinoline, 8-methylquinoline, and 7,8-benzoquinoline showed high insecticidal activities against S. oryzae and S. zeamais regardless of the application method. These results indicate that introduction of a functional group into the quinoline skeleton and changing the position of the group have an important influence on the acaricidal and insecticidal activities. Furthermore, 4-methylquinoline isolated from C. colocynthis fruits, along with its structural analogues, could be effective natural pesticides for managing spider mites and stored grain weevils.

  2. Design, synthesis and insight into the structure-activity relationship of 1,3-disubstituted indazoles as novel HIF-1 inhibitors.

    Science.gov (United States)

    An, Hongchan; Kim, Nam-Jung; Jung, Jong-Wha; Jang, Hannah; Park, Jong-Wan; Suh, Young-Ger

    2011-11-01

    Design, synthesis and insight into the structure-activity relationship (SAR) of 1,3-disubstituted indazoles as novel HIF-1 inhibitors are described. In particular, the substituted furan moiety on indazole skeleton as well as its substitution pattern turns out crucial for the high HIF-1 inhibition.

  3. The discovery and structure-activity relationships of pyrano[3,4-b]indole based inhibitors of hepatitis C virus NS5B polymerase.

    Science.gov (United States)

    LaPorte, Matthew G; Draper, Tandy L; Miller, Lori E; Blackledge, Charles W; Leister, Lara K; Amparo, Eugene; Hussey, Alison R; Young, Dorothy C; Chunduru, Srinivas K; Benetatos, Christopher A; Rhodes, Gerry; Gopalsamy, Ariamala; Herbertz, Torsten; Burns, Christopher J; Condon, Stephen M

    2010-05-01

    We describe the structure-activity relationship of the C1-group of pyrano[3,4-b]indole based inhibitors of HCV NS5B polymerase. Further exploration of the allosteric binding site led to the discovery of the significantly more potent compound 12.

  4. Design and structure-activity relationships of potent and selective inhibitors of undecaprenyl pyrophosphate synthase (UPPS): tetramic, tetronic acids and dihydropyridin-2-ones.

    Science.gov (United States)

    Peukert, Stefan; Sun, Yingchuan; Zhang, Rui; Hurley, Brian; Sabio, Mike; Shen, Xiaoyu; Gray, Christen; Dzink-Fox, JoAnn; Tao, Jianshi; Cebula, Regina; Wattanasin, Sompong

    2008-03-15

    Based on a pharmacophore hypothesis substituted tetramic and tetronic acid 3-carboxamides as well as dihydropyridin-2-one-3-carboxamides were investigated as inhibitors of undecaprenyl pyrophosphate synthase (UPPS) for use as novel antimicrobial agents. Synthesis and structure-activity relationship patterns for this class of compounds are discussed. Selectivity data and antibacterial activities for selected compounds are provided.

  5. Molecular docking and 3D-quantitative structure activity relationship analyses of peptidyl vinyl sulfones: Plasmodium Falciparum cysteine proteases inhibitors

    Science.gov (United States)

    Teixeira, Cátia; Gomes, José R. B.; Couesnon, Thierry; Gomes, Paula

    2011-08-01

    Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (39 molecules) of peptidyl vinyl sulfone derivatives as potential Plasmodium Falciparum cysteine proteases inhibitors. Two different methods of alignment were employed: (i) a receptor-docked alignment derived from the structure-based docking algorithm GOLD and (ii) a ligand-based alignment using the structure of one of the ligands derived from a crystal structure from the PDB databank. The best predictions were obtained for the receptor-docked alignment with a CoMFA standard model ( q 2 = 0.696 and r 2 = 0.980) and with CoMSIA combined electrostatic, and hydrophobic fields ( q 2 = 0.711 and r 2 = 0.992). Both models were validated by a test set of nine compounds and gave satisfactory predictive r 2 pred values of 0.76 and 0.74, respectively. CoMFA and CoMSIA contour maps were used to identify critical regions where any change in the steric, electrostatic, and hydrophobic fields may affect the inhibitory activity, and to highlight the key structural features required for biological activity. Moreover, the results obtained from 3D-QSAR analyses were superimposed on the Plasmodium Falciparum cysteine proteases active site and the main interactions were studied. The present work provides extremely useful guidelines for future structural modifications of this class of compounds towards the development of superior antimalarials.

  6. Structure-activity relationship of dihydroxy-4-methylcoumarins as powerful antioxidants: correlation between experimental & theoretical data and synergistic effect.

    Science.gov (United States)

    Kancheva, Vessela D; Saso, Luciano; Boranova, Petya V; Khan, Abdullah; Saroj, Manju K; Pandey, Mukesh K; Malhotra, Shashwat; Nechev, Jordan Z; Sharma, Sunil K; Prasad, Ashok K; Georgieva, Maya B; Joseph, Carleta; DePass, Anthony L; Rastogi, Ramesh C; Parmar, Virinder S

    2010-09-01

    The chain-breaking antioxidant activities of eight coumarins [7-hydroxy-4-methylcoumarin (1), 5,7-dihydroxy-4-methylcoumarin (2), 6,7-dihydroxy-4-methylcoumarin (3), 6,7-dihydroxycoumarin (4), 7,8-dihydroxy-4-methylcoumarin (5), ethyl 2-(7,8-dihydroxy-4-methylcoumar-3-yl)-acetate (6), 7,8-diacetoxy-4-methylcoumarin (7) and ethyl 2-(7,8-diacetoxy-4-methylcoumar-3-yl)-acetate (8)] during bulk lipid autoxidation at 37 degrees C and 80 degrees C in concentrations of 0.01-1.0 mM and their radical scavenging activities at 25 degrees C using TLC-DPPH test have been studied and compared. It has been found that the o-dihydroxycoumarins 3-6 demonstrated excellent activity as antioxidants and radical scavengers, much better than the m-dihydroxy analogue 2 and the monohydroxycoumarin 1. The substitution at the C-3 position did not have any effect either on the chain-breaking antioxidant activity or on the radical scavenging activity of the 7,8-dihydroxy- and 7,8-diacetoxy-4-methylcoumarins 6 and 8. The comparison with DL-alpha-tocopherol (TOH), caffeic acid (CA) and p-coumaric acid (p-CumA) showed that antioxidant efficiency decreases in the following sequence: TOH>CA>3>4>6>5>2>1=7=8=p-CumA. Theoretical calculations and the "Lipinski's Rule of Five" were used for explaining the structure-activity relationships and pharmacokinetic behavior. A higher TGSO oxidation stability was observed in the presence of equimolar (1:1) binary mixtures of coumarins with TOH (1+TOH, 3+TOH and 5+TOH). However, the synergism (14%) was observed only for the binary mixture of 5 + TOH.

  7. Structure activity relationship of uridine 5′-diphosphate analogues at the human P2Y6 receptor

    Science.gov (United States)

    Besada, Pedro; Shin, Dae Hong; Costanzi, Stefano; Ko, Hyojin; Mathé, Christophe; Gagneron, Julien; Gosselin, Gilles; Maddileti, Savitri; Harden, T. Kendall; Jacobsona, Kenneth A.

    2012-01-01

    The structure activity relationships and molecular modeling of the uracil nucleotide-activated P2Y6 receptor have been studied. A series of UDP analogues bearing substitutions of the ribose moiety, the uracil ring, and the diphosphate group was synthesized and assayed for activity at the human P2Y6 receptor. The uracil ring was modified at the 4-position, with the synthesis of 4-substituted-thiouridine-5′-diphosphate analogues, as well as at positions 3 and 5. The effect of modifications at the level of the phosphate chain was studied by preparing a cyclic 3′,5′-diphosphate analogue, a 3′-diphosphate analogue and several dinucleotide diphosphates. 5-Iodo-UDP 32 (EC50 0.15 μM) was equipotent to UDP, while substitutions of the 2′-hydroxyl (amino, azido) greatly reduce potency. 2- and 4-Thio analogues, 20 and 21, respectively, were also relatively potent in comparison to UDP. However, most other modifications greatly reduced potency. Molecular modeling indicates that the β-phosphate of 5′-UDP and analogs is essential for the establishment of electrostatic interactions with two of the three conserved cationic residues of the receptor. Among 4-thioether derivatives, a 4-ethylthio analogue 23 displayed an EC50 of 0.28 μM, indicative of favorable interactions predicted for a small 4-alkylthio moiety with the aromatic ring of Y33 in TM1. The activity of analogue 19 in which the ribose was substituted with a 2-oxabicyclohexane ring in a rigid (S) conformation (P= 126°, 1′-exo) was consistent with molecular modeling. These results provide a better understanding of molecular recognition at the P2Y6 receptor and will be helpful in designing selective and potent P2Y6 receptor ligands PMID:16942026

  8. Predicting the Structure-Activity Relationship of Hydroxyapatite-Binding Peptides by Enhanced-Sampling Molecular Simulation.

    Science.gov (United States)

    Zhao, Weilong; Xu, Zhijun; Cui, Qiang; Sahai, Nita

    2016-07-12

    Understanding the molecular structural and energetic basis of the interactions between peptides and inorganic surfaces is critical to their applications in tissue engineering and biomimetic material synthesis. Despite recent experimental progresses in the identification and functionalization of hydroxyapatite (HAP)-binding peptides, the molecular mechanisms of their interactions with HAP surfaces are yet to be explored. In particular, the traditional method of molecular dynamics (MD) simulation suffers from insufficient sampling at the peptide-inorganic interface that renders the molecular-level observation dubious. Here we demonstrate that an integrated approach combining bioinformatics, MD, and metadynamics provides a powerful tool for investigating the structure-activity relationship of HAP-binding peptides. Four low charge density peptides, previously identified by phage display, have been considered. As revealed by bioinformatics and MD, the binding conformation of the peptides is controlled by both the sequence and the amino acid composition. It was found that formation of hydrogen bonds between lysine residue and phosphate ions on the surface dictates the binding of positively charged peptide to HAP. The binding affinities of the peptides to the surface are estimated by free energy calculation using parallel-tempering metadynamics, and the results compare favorably to measurements reported in previous experimental studies. The calculation suggests that the charge density of the peptide primarily controls the binding affinity to the surface, while the backbone secondary structure that may restrain side chain orientation toward the surface plays a minor role. We also report that the application of enhanced-sampling metadynamics effects a major advantage over the steered MD method by significantly improving the reliability of binding free energy calculation. In general, our novel integration of diverse sampling techniques should contribute to the rational

  9. Synthesis and quantitative structure activity relationship (QSAR) of arylidene (benzimidazol-1-yl)acetohydrazones as potential antibacterial agents.

    Science.gov (United States)

    El-Kilany, Yeldez; Nahas, Nariman M; Al-Ghamdi, Mariam A; Badawy, Mohamed E I; El Ashry, El Sayed H

    2015-01-01

    Ethyl (benzimidazol-1-yl)acetate was subjected to hydrazinolysis with hydrazine hydrate to give (benzimidazol-1-yl)acetohydrazide. The latter was reacted with various aromatic aldehydes to give the respective arylidene (1H-benzimidazol-1-yl)acetohydrazones. Solutions of the prepared hydrazones were found to contain two geometric isomers. Similarly (2-methyl-benzimidazol-1-yl)acetohydrazide was reacted with various aldehydes to give the corresponding hydrazones. The antibacterial activity was evaluated in vitro by minimum inhibitory concentration (MIC) against Agrobacterium tumefaciens (A. tumefaciens), Erwinia carotovora (E. carotovora), Corynebacterium fascians (C. fascians) and Pseudomonas solanacearum (P. solanacearum). MIC result demonstrated that salicylaldehyde(1H-benzimidazol-1-yl)acetohydrazone (4) was the most active compound (MIC = 20, 35, 25 and 30 mg/L against A. tumefaciens, C. fascians, E. carotovora and P. solanacearum, respectively). Quantitative structure activity relationship (QSAR) investigation using Hansch analysis was applied to find out the correlation between antibacterial activity and physicochemical properties. Various physicochemical descriptors and experimentally determined MIC values for different microorganisms were used as independent and dependent variables, respectively. pMICs of the compounds exhibited good correlation (r = 0.983, 0.914, 0.960 and 0.958 for A. tumefaciens, C. fascians, E. carotovora and P. solanacearum, respectively) with the prediction made by the model. QSAR study revealed that the hydrophobic parameter (ClogP), the aqueous solubility (LogS), calculated molar refractivity, topological polar surface area and hydrogen bond acceptor were found to have overall significant correlation with antibacterial activity. The statistical results of training set, correlation coefficient (r and r (2)), the ratio between regression and residual variances (f, Fisher's statistic), the standard error of estimates and

  10. Development of acute toxicity quantitative structure activity relationships (QSAR) and their use in linear alkylbenzene sulfonate species sensitivity distributions.

    Science.gov (United States)

    Belanger, Scott E; Brill, Jessica L; Rawlings, Jane M; Price, Brad B

    2016-07-01

    Linear Alkylbenzene Sulfonate (LAS) is high tonnage and widely dispersed anionic surfactant used by the consumer products sector. A range of homologous structures are used in laundry applications that differ primarily on the length of the hydrophobic alkyl chain. This research summarizes the development of a set of acute toxicity QSARs (Quantitative Structure Activity Relationships) for fathead minnows (Pimephales promelas) and daphnids (Daphnia magna, Ceriodaphnia dubia) using accepted test guideline approaches. A series of studies on pure chain length LAS from C10 to C14 were used to develop the QSARs and the robustness of the QSARs was tested by evaluation of two technical mixtures of differing compositions. All QSARs were high quality (R(2) were 0.965-0.997, p < 0.0001). Toxicity normalization employing QSARs is used to interpret a broader array of tests on LAS chain length materials to a diverse group of test organisms with the objective of developing Species Sensitivity Distributions (SSDs) for various chain lengths of interest. Mixtures include environmental distributions measured from exposure monitoring surveys of wastewater effluents, various commercial mixtures, or specific chain lengths. SSD 5th percentile hazardous concentrations (HC5s) ranged from 0.129 to 0.254 mg/L for wastewater effluents containing an average of 11.26-12 alkyl carbons. The SSDs are considered highly robust given the breadth of species (n = 19), use of most sensitive endpoints from true chronic studies and the quality of the underlying statistical properties of the SSD itself. The data continue to indicate a low hazard to the environment relative to expected environmental concentrations.

  11. The antimicrobial efficacy and structure activity relationship of novel carbohydrate fatty acid derivatives against Listeria spp. and food spoilage microorganisms.

    Science.gov (United States)

    Nobmann, Patricia; Smith, Aoife; Dunne, Julie; Henehan, Gary; Bourke, Paula

    2009-01-15

    Novel mono-substituted carbohydrate fatty acid (CFA) esters and ethers were investigated for their antibacterial activity against a range of pathogenic and spoilage bacteria focussing on Listeria monocytogenes. Carbohydrate derivatives with structural differences enable comparative studies on the structure/activity relationship for antimicrobial efficacy and mechanism of action. The antimicrobial efficacy of the synthesized compounds was compared with commercially available compounds such as monolaurin and monocaprylin, as well as the pure free fatty acids, lauric acid and caprylic acid, which have proven antimicrobial activity. Compound efficacy was compared using an absorbance based broth microdilution assay to determine the minimum inhibitory concentration (MIC), increase in lag phase and decrease in maximum growth rate. Among the carbohydrate derivatives synthesized, lauric ether of methyl alpha-d-glucopyranoside and lauric ester of methyl alpha-d-mannopyranoside showed the highest growth-inhibitory effect with MIC values of 0.04 mM, comparable to monolaurin. CFA derivatives were generally more active against Gram positive bacteria than Gram negative bacteria. The analysis of both ester and ether fatty acid derivatives of the same carbohydrate, in tandem with alpha and beta configuration of the carbohydrate moiety suggest that the carbohydrate moiety is involved in the antimicrobial activity of the fatty acid derivatives and that the nature of the bond also has a significant effect on efficacy, which requires further investigation. This class of CFA derivatives has great potential for developing antibacterial agents relevant to the food industry, particularly for control of Listeria or other Gram-positive pathogens.

  12. Synthesis and quantitative structure-activity relationship (QSAR) study of novel isoxazoline and oxime derivatives of podophyllotoxin as insecticidal agents.

    Science.gov (United States)

    Wang, Yi; Shao, Yonghua; Wang, Yangyang; Fan, Lingling; Yu, Xiang; Zhi, Xiaoyan; Yang, Chun; Qu, Huan; Yao, Xiaojun; Xu, Hui

    2012-08-29

    In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, 33 isoxazoline and oxime derivatives of podophyllotoxin modified in the C and D rings were synthesized and their structures were characterized by Proton nuclear magnetic resonance ((1)H NMR), high-resolution mass spectrometry (HRMS), electrospray ionization-mass spectrometry (ESI-MS), optical rotation, melting point (mp), and infrared (IR) spectroscopy. The stereochemical configurations of compounds 5e, 5f, and 9f were unambiguously determined by X-ray crystallography. Their insecticidal activity was evaluated against the pre-third-instar larvae of northern armyworm, Mythimna separata (Walker), in vivo. Compounds 5e, 9c, 11g, and 11h especially exhibited more promising insecticidal activity than toosendanin, a commercial botanical insecticide extracted from Melia azedarach . A genetic algorithm combined with multiple linear regression (GA-MLR) calculation is performed by the MOBY DIGS package. Five selected descriptors are as follows: one two-dimensional (2D) autocorrelation descriptor (GATS4e), one edge adjacency indice (EEig06x), one RDF descriptor (RDF080v), one three-dimensional (3D) MoRSE descriptor (Mor09v), and one atom-centered fragment (H-052) descriptor. Quantitative structure-activity relationship studies demonstrated that the insecticidal activity of these compounds was mainly influenced by many factors, such as electronic distribution, steric factors, etc. For this model, the standard deviation error in prediction (SDEP) is 0.0592, the correlation coefficient (R(2)) is 0.861, and the leave-one-out cross-validation correlation coefficient (Q(2)loo) is 0.797.

  13. Structure-activity relationships of nonisomerizable derivatives of tamoxifen: importance of hydroxyl group and side chain positioning for biological activity.

    Science.gov (United States)

    Murphy, C S; Parker, C J; McCague, R; Jordan, V C

    1991-03-01

    The antiestrogen tamoxifen [(Z)-1(p-beta-dimethylaminoethoxy-phenyl)-1,2-diphenylbut-1-ene] is an effective anticancer agent against estrogen receptor (ER)-positive breast cancer. The alkylaminoethane side chain is essential for antiestrogenic activity, but the potency of the antiestrogen can be increased by para hydroxylation of the phenyl ring on carbon 1 of but-1-ene. This compound, 4-hydroxytamoxifen, is a metabolite of tamoxifen and has a very high binding affinity for ER [J. Endocrinol. 75:305-316 (1977)] because the hydroxyl is located in the equivalent position as the 3-phenolic hydroxyl of 17 beta-estradiol. In this study, we have examined the relationship between the relative positions of the hydroxyl and the alkyl-aminoethane side chain and the pharmacological activity of the ligand. A fixed seven-membered ring derivative of the triphenylethylene was used to prevent isomerization. All compounds were tested, with and without 17 beta-estradiol, for their effects on the growth of estrogen-responsive T47D and MCF-7 human breast cancer cells in vitro. The growth of MDA-MB-231 ER-negative breast cancer cells was not affected by any of the compounds tested, at a concentration (1 microM) that had a profound estrogenic or antiestrogenic action in ER-positive cell lines. The relative binding affinity of the compounds was determined using rat uterine ER and was found to be consistent with the observed potencies in vitro. The compounds found to be antiestrogens in vitro were antiestrogenic against estradiol (0.08 micrograms daily) in the 3-day immature rat uterine weight test. All compounds were partial agonists in vivo. In general, the estrogenic and antiestrogenic results obtained in vivo were consistent with the potency estimates obtained with the breast cancer cells in vitro. The results of this extensive structure-activity relationship study demonstrate that the substitution for 4-hydroxytamoxifen appears to be optimal to produce a potent antiestrogen; all

  14. Structure-activity relationships in cytotoxic Au(I)/Au(III) complexes derived from 2-(2'-pyridyl)benzimidazole.

    Science.gov (United States)

    Maiore, Laura; Aragoni, Maria Carla; Deiana, Carlo; Cinellu, Maria Agostina; Isaia, Francesco; Lippolis, Vito; Pintus, Anna; Serratrice, Maria; Arca, Massimiliano

    2014-04-21

    Gold(I) and gold(III) complexes derived from 2-(2'-pyridyl)benzimidazole (pbiH) were proven to be a promising class of in vitro antitumor agents against A2780 human ovarian cancer cells. In this paper, a comparative electrochemical, UV-vis absorption, and emission spectroscopic investigation is reported on pbiH, the two mononuclear Au(III) complexes [(pbi)AuX2] (X = Cl (1), AcO (2)), the four mononuclear Au(I) derivatives [(pbiH)AuCl] (3), [(pbiH)Au(PPh3)]PF6 ((4(+))(PF6(-))), [(pbi)Au(PPh3)] (5), and [(pbi)Au(TPA)] (6), the three mixed-valence Au(III)/Au(I) complexes [(μ-pbi)Au2Cl3] (7), [(Ph3P)Au(μ-pbi)AuX2]PF6 (X = Cl ((8(+))(PF6(-))), AcO ((9(+))(PF6(-)))), and the binuclear Au(I)-Au(I) compound [(μ-pbi)Au2(PPh3)2]PF6 ((10(+))(PF6(-))). All complexes feature irreversible reduction processes related to the Au(III)/Au(I) or Au(I)/Au(0) processes and peculiar luminescent emission at about 360-370 nm in CH2Cl2, with quantum yields that are remarkably lower ((0.7-14.5) × 10(-2)) in comparison to that determined for the free pbiH ligand (31.5 × 10(-2)) in the same solvent. The spectroscopic and electrochemical properties of all complexes were interpreted on the grounds of time-dependent PBE0/DFT calculations carried out both in the gas phase and in CH2Cl2 implicitly considered within the IEF-PCM SCRF approach. The electronic structure of the complexes, and in particular the energy and composition of the Kohn-Sham LUMOs, can be related to the antiproliferative properties against the A2780 ovarian carcinoma cell line, providing sound quantitative structure-activity relationships and shedding a light on the role played by the global charge and nature of ancillary ligands in the effectiveness of Au-based antitumor drugs.

  15. The influence of R and S configurations of a series of amphetamine derivatives on quantitative structure-activity relationship models

    Energy Technology Data Exchange (ETDEWEB)

    Fresqui, Maira A.C., E-mail: maira@iqsc.usp.br [Institute of Chemistry of Sao Carlos, University of Sao Paulo, Av. Trabalhador Sao-carlense, 400, POB 780, 13560-970 Sao Carlos, SP (Brazil); Ferreira, Marcia M.C., E-mail: marcia@iqm.unicamp.br [Institute of Chemistry, University of Campinas - UNICAMP, POB 6154, 13083-970 Campinas, SP (Brazil); Trsic, Milan, E-mail: cra612@gmail.com [Institute of Chemistry of Sao Carlos, University of Sao Paulo, Av. Trabalhador Sao-carlense, 400, POB 780, 13560-970 Sao Carlos, SP (Brazil)

    2013-01-08

    Highlights: Black-Right-Pointing-Pointer The QSAR model is not dependent of ligand conformation. Black-Right-Pointing-Pointer Amphetamines were analyzed by quantum chemical, steric and hydrophobic descriptors. Black-Right-Pointing-Pointer CHELPG atomic charges on the benzene ring are one of the most important descriptors. Black-Right-Pointing-Pointer The PLS models built were extensively validated. Black-Right-Pointing-Pointer Manual docking supports the QSAR results by pi-pi stacking interactions. - Abstract: Chiral molecules need special attention in drug design. In this sense, the R and S configurations of a series of thirty-four amphetamines were evaluated by quantitative structure-activity relationship (QSAR). This class of compounds has antidepressant, anti-Parkinson and anti-Alzheimer effects against the enzyme monoamine oxidase A (MAO A). A set of thirty-eight descriptors, including electronic, steric and hydrophobic ones, were calculated. Variable selection was performed through the correlation coefficients followed by the ordered predictor selection (OPS) algorithm. Six descriptors (CHELPG atomic charges C3, C4 and C5, electrophilicity, molecular surface area and log P) were selected for both configurations and a satisfactory model was obtained by PLS regression with three latent variables with R{sup 2} = 0.73 and Q{sup 2} = 0.60, with external predictability Q{sup 2} = 0.68, and R{sup 2} = 0.76 and Q{sup 2} = 0.67 with external predictability Q{sup 2} = 0.50, for R and S configurations, respectively. To confirm the robustness of each model, leave-N-out cross validation (LNO) was carried out and the y-randomization test was used to check if these models present chance correlation. Moreover, both automated or a manual molecular docking indicate that the reaction of ligands with the enzyme occurs via pi-pi stacking interaction with Tyr407, inclined face-to-face interaction with Tyr444, while aromatic hydrogen-hydrogen interactions with Tyr197 are preferable

  16. In Silico Quantitative Structure-Activity Relationship Studies on P-gp Modulators of Tetrahydroisoquinoline-Ethyl-Phenylamine Series

    Directory of Open Access Journals (Sweden)

    Kothandan Gugan

    2011-01-01

    Full Text Available Abstract Background Multidrug resistance (MDR is a major obstacle in cancer chemotherapy. The drug efflux by a transport protein is the main reason for MDR. In humans, MDR mainly occurs when the ATP-binding cassette (ABC family of proteins is overexpressed simultaneously. P-glycoprotein (P-gp is most commonly associated with human MDR; it utilizes energy from adenosine triphosphate (ATP to transport a number of substrates out of cells against concentration gradients. By the active transport of substrates against concentration gradients, intracellular concentrations of substrates are decreased. This leads to the cause of failure in cancer chemotherapy. Results Herein, we report Topomer CoMFA (Comparative Molecular Field Analysis and HQSAR (Hologram Quantitative Structure Activity Relationship models for third generation MDR modulators. The Topomer CoMFA model showed good correlation between the actual and predicted values for training set molecules. The developed model showed cross validated correlation coefficient (q2 = 0.536 and non-cross validated correlation coefficient (r2 = 0.975 with eight components. The best HQSAR model (q2 = 0.777, r2 = 0.956 with 5-8 atom counts was used to predict the activity of test set compounds. Both models were validated using test set compounds, and gave a good predictive values of 0.604 and 0.730. Conclusions The contour map near R1 indicates that substitution of a bulkier and polar group to the ortho position of the benzene ring enhances the inhibitory effect. This explains why compounds with a nitro group have good inhibitory potency. Molecular fragment analyses shed light on some essential structural and topological features of third generation MDR modulators. Fragments analysis showed that the presence of tertiary nitrogen, a central phenyl ring and an aromatic dimethoxy group contributed to the inhibitory effect. Based on contour map information and fragment information, five new molecules with variable R1

  17. Modeling chemical interaction profiles: II. Molecular docking, spectral data-activity relationship, and structure-activity relationship models for potent and weak inhibitors of cytochrome P450 CYP3A4 isozyme.

    Science.gov (United States)

    Tie, Yunfeng; McPhail, Brooks; Hong, Huixiao; Pearce, Bruce A; Schnackenberg, Laura K; Ge, Weigong; Buzatu, Dan A; Wilkes, Jon G; Fuscoe, James C; Tong, Weida; Fowler, Bruce A; Beger, Richard D; Demchuk, Eugene

    2012-03-15

    Polypharmacy increasingly has become a topic of public health concern, particularly as the U.S. population ages. Drug labels often contain insufficient information to enable the clinician to safely use multiple drugs. Because many of the drugs are bio-transformed by cytochrome P450 (CYP) enzymes, inhibition of CYP activity has long been associated with potentially adverse health effects. In an attempt to reduce the uncertainty pertaining to CYP-mediated drug-drug/chemical interactions, an interagency collaborative group developed a consensus approach to prioritizing information concerning CYP inhibition. The consensus involved computational molecular docking, spectral data-activity relationship (SDAR), and structure-activity relationship (SAR) models that addressed the clinical potency of CYP inhibition. The models were built upon chemicals that were categorized as either potent or weak inhibitors of the CYP3A4 isozyme. The categorization was carried out using information from clinical trials because currently available in vitro high-throughput screening data were not fully representative of the in vivo potency of inhibition. During categorization it was found that compounds, which break the Lipinski rule of five by molecular weight, were about twice more likely to be inhibitors of CYP3A4 compared to those, which obey the rule. Similarly, among inhibitors that break the rule, potent inhibitors were 2-3 times more frequent. The molecular docking classification relied on logistic regression, by which the docking scores from different docking algorithms, CYP3A4 three-dimensional structures, and binding sites on them were combined in a unified probabilistic model. The SDAR models employed a multiple linear regression approach applied to binned 1D ¹³C-NMR and 1D ¹⁵N-NMR spectral descriptors. Structure-based and physical-chemical descriptors were used as the basis for developing SAR models by the decision forest method. Thirty-three potent inhibitors and 88 weak

  18. Modeling Chemical Interaction Profiles: II. Molecular Docking, Spectral Data-Activity Relationship, and Structure-Activity Relationship Models for Potent and Weak Inhibitors of Cytochrome P450 CYP3A4 Isozyme

    Directory of Open Access Journals (Sweden)

    Eugene Demchuk

    2012-03-01

    Full Text Available Polypharmacy increasingly has become a topic of public health concern, particularly as the U.S. population ages. Drug labels often contain insufficient information to enable the clinician to safely use multiple drugs. Because many of the drugs are bio-transformed by cytochrome P450 (CYP enzymes, inhibition of CYP activity has long been associated with potentially adverse health effects. In an attempt to reduce the uncertainty pertaining to CYP-mediated drug-drug/chemical interactions, an interagency collaborative group developed a consensus approach to prioritizing information concerning CYP inhibition. The consensus involved computational molecular docking, spectral data-activity relationship (SDAR, and structure-activity relationship (SAR models that addressed the clinical potency of CYP inhibition. The models were built upon chemicals that were categorized as either potent or weak inhibitors of the CYP3A4 isozyme. The categorization was carried out using information from clinical trials because currently available in vitro high-throughput screening data were not fully representative of the in vivo potency of inhibition. During categorization it was found that compounds, which break the Lipinski rule of five by molecular weight, were about twice more likely to be inhibitors of CYP3A4 compared to those, which obey the rule. Similarly, among inhibitors that break the rule, potent inhibitors were 2–3 times more frequent. The molecular docking classification relied on logistic regression, by which the docking scores from different docking algorithms, CYP3A4 three-dimensional structures, and binding sites on them were combined in a unified probabilistic model. The SDAR models employed a multiple linear regression approach applied to binned 1D 13C-NMR and 1D 15N-NMR spectral descriptors. Structure-based and physical-chemical descriptors were used as the basis for developing SAR models by the decision forest method. Thirty-three potent inhibitors

  19. Augmented multivariate image analysis applied to quantitative structure-activity relationship modeling of the phytotoxicities of benzoxazinone herbicides and related compounds on problematic weeds.

    Science.gov (United States)

    Freitas, Mirlaine R; Matias, Stella V B G; Macedo, Renato L G; Freitas, Matheus P; Venturin, Nelson

    2013-09-11

    Two of major weeds affecting cereal crops worldwide are Avena fatua L. (wild oat) and Lolium rigidum Gaud. (rigid ryegrass). Thus, development of new herbicides against these weeds is required; in line with this, benzoxazinones, their degradation products, and analogues have been shown to be important allelochemicals and natural herbicides. Despite earlier structure-activity studies demonstrating that hydrophobicity (log P) of aminophenoxazines correlates to phytotoxicity, our findings for a series of benzoxazinone derivatives do not show any relationship between phytotoxicity and log P nor with other two usual molecular descriptors. On the other hand, a quantitative structure-activity relationship (QSAR) analysis based on molecular graphs representing structural shape, atomic sizes, and colors to encode other atomic properties performed very accurately for the prediction of phytotoxicities of these compounds against wild oat and rigid ryegrass. Therefore, these QSAR models can be used to estimate the phytotoxicity of new congeners of benzoxazinone herbicides toward A. fatua L. and L. rigidum Gaud.

  20. Identification of Lilial as a fragrance sensitizer in a perfume by bioassay-guided chemical fractionation and structure-activity relationships

    DEFF Research Database (Denmark)

    Arnau, E G; Andersen, Klaus Ejner; Bruze, M

    2000-01-01

    Fragrance materials are among the most common causes of allergic contact dermatitis. The aim of this study was to identify in a perfume fragrance allergens not included in the fragrance mix, by use of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships...... test on the pre-sensitized patient. The chemical composition of the fractions giving a positive patch-test response and repeated open application test reactions was obtained by gas chromatography-mass spectrometry. From the compounds identified, those that contained a "structural alert...... mix. The combination of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships seems to be a valuable tool for the investigation of contact allergy to fragrance materials....

  1. Categorical and dimensional approaches in the evaluation of the relationship between attachment and personality disorders: an empirical study.

    Science.gov (United States)

    Chiesa, Marco; Cirasola, Antonella; Williams, Riccardo; Nassisi, Valentina; Fonagy, Peter

    2017-04-01

    Although several studies have highlighted the relationship between attachment states of mind and personality disorders, their findings have not been consistent, possibly due to the application of the traditional taxonomic classification model of attachment. A more recently developed dimensional classification of attachment representations, including more specific aspects of trauma-related representations, may have advantages. In this study, we compare specific associations and predictive power of the categorical attachment and dimensional models applied to 230 Adult Attachment Interview transcripts obtained from personality disordered and nonpsychiatric subjects. We also investigate the role that current levels of psychiatric distress may have in the prediction of PD. The results showed that both models predict the presence of PD, with the dimensional approach doing better in discriminating overall diagnosis of PD. However, both models are less helpful in discriminating specific PD diagnostic subtypes. Current psychiatric distress was found to be the most consistent predictor of PD capturing a large share of the variance and obscuring the role played by attachment variables. The results suggest that attachment parameters correlate with the presence of PD alone and have no specific associations with particular PD subtypes when current psychiatric distress is taken into account.

  2. Structure-Activity Relationships and Identification of Optmized CC-Chemokine Receptor CCR1, 5, and 8 Metal-Ion Chelators

    DEFF Research Database (Denmark)

    Chalikiopoulos, Alexander; Thiele, Stefanie; Malmgaard-Clausen, Mikkel;

    2013-01-01

    Chemokine receptors are involved in trafficking of leukocytes and represent targets for autoimmune conditions, inflammatory diseases, viral infections, and cancer. We recently published CCR1, CCR8, and CCR5 agonists and positive modulators based on a three metal-ion chelator series: 2,2'-bipyridine...... bipyridine (23). The structure-activity relationships contribute to small-molecule drug development, and the novel chelators constitute valuable tools for studies of structural mechanisms for chemokine receptor activation....

  3. Positive Relationship Between Individuality and Social Identity in Virtual Communities: Self-Categorization and Social Identification as Distinct Forms of Social Identity.

    Science.gov (United States)

    Guo, Tian-Chao; Li, Xuemei

    2016-11-01

    Previous studies have reported conflicting results regarding the relationship between individuality and social identity, indicating this area requires further examination. This study constructed a research model to help understand the positive role of individualized behavior and social identity in virtual communities. The results of an online survey conducted to assess our theoretical research model indicated that social identity can be expressed in two ways: self-categorization and social identification. Furthermore, we found individualized behavior was positively related to social identification, while self-categorization was directly derived from social identification.

  4. Molecular Modeling on Berberine Derivatives toward BuChE: An Integrated Study with Quantitative Structure-Activity Relationships Models, Molecular Docking, and Molecular Dynamics Simulations.

    Science.gov (United States)

    Fang, Jiansong; Pang, Xiaocong; Wu, Ping; Yan, Rong; Gao, Li; Li, Chao; Lian, Wenwen; Wang, Qi; Liu, Ai-lin; Du, Guan-hua

    2016-05-01

    A dataset of 67 berberine derivatives for the inhibition of butyrylcholinesterase (BuChE) was studied based on the combination of quantitative structure-activity relationships models, molecular docking, and molecular dynamics methods. First, a series of berberine derivatives were reported, and their inhibitory activities toward butyrylcholinesterase (BuChE) were evaluated. By 2D- quantitative structure-activity relationships studies, the best model built by partial least-square had a conventional correlation coefficient of the training set (R(2)) of 0.883, a cross-validation correlation coefficient (Qcv2) of 0.777, and a conventional correlation coefficient of the test set (Rpred2) of 0.775. The model was also confirmed by Y-randomization examination. In addition, the molecular docking and molecular dynamics simulation were performed to better elucidate the inhibitory mechanism of three typical berberine derivatives (berberine, C2, and C55) toward BuChE. The predicted binding free energy results were consistent with the experimental data and showed that the van der Waals energy term (ΔEvdw) difference played the most important role in differentiating the activity among the three inhibitors (berberine, C2, and C55). The developed quantitative structure-activity relationships models provide details on the fine relationship linking structure and activity and offer clues for structural modifications, and the molecular simulation helps to understand the inhibitory mechanism of the three typical inhibitors. In conclusion, the results of this study provide useful clues for new drug design and discovery of BuChE inhibitors from berberine derivatives.

  5. Quantitative structure-activity relationships of insecticides and plant growth regulators: comparative studies toward understanding the molecular mechanism of action.

    Science.gov (United States)

    Iwamura, H; Nishimura, K; Fujita, T

    1985-01-01

    Emphasis was put on the comparative quantitative structure-activity approaches to the exploration of action mechanisms of structurally different classes of compounds showing the same type of activity as well as those of the same type of compounds having different actions. Examples were selected from studies performed on insecticides and plant growth regulators, i.e., neurotoxic carbamates, phosphates, pyrethroids and DDT analogs, insect juvenile hormone mimics, and cytokinin agonistic and antagonistic compounds. Similarities and dissimilarities in structures required to elicit activity between compounds classes were revealed in terms of physicochemical parameters, provoking further exploration and evoking insights into the molecular mechanisms of action which may lead to the development of new structures having better qualities. PMID:3905379

  6. Longitudinal categorical data analysis

    CERN Document Server

    Sutradhar, Brajendra C

    2014-01-01

    This is the first book in longitudinal categorical data analysis with parametric correlation models developed based on dynamic relationships among repeated categorical responses. This book is a natural generalization of the longitudinal binary data analysis to the multinomial data setup with more than two categories. Thus, unlike the existing books on cross-sectional categorical data analysis using log linear models, this book uses multinomial probability models both in cross-sectional and longitudinal setups. A theoretical foundation is provided for the analysis of univariate multinomial responses, by developing models systematically for the cases with no covariates as well as categorical covariates, both in cross-sectional and longitudinal setups. In the longitudinal setup, both stationary and non-stationary covariates are considered. These models have also been extended to the bivariate multinomial setup along with suitable covariates. For the inferences, the book uses the generalized quasi-likelihood as w...

  7. Sticky Categorizations

    DEFF Research Database (Denmark)

    Lagermann, Laila Colding

    2015-01-01

    What are the possibilities and/or limitations in becoming subjects who are differenciated from earlier processes of categorizations that certain students are subjected to? This is the question explored in the analysis of this paper, based on observations of, and narratives and perspectives of two...

  8. Child categorization.

    Science.gov (United States)

    Gelman, Susan A; Meyer, Meredith

    2011-01-01

    Categorization is a process that spans all of development, beginning in earliest infancy yet changing as children's knowledge and cognitive skills develop. In this review article, we address three core issues regarding childhood categorization. First, we discuss the extent to which early categories are rooted in perceptual similarity versus knowledge-enriched theories. We argue for a composite perspective in which categories are steeped in commonsense theories from a young age but also are informed by low-level similarity and associative learning cues. Second, we examine the role of language in early categorization. We review evidence to suggest that language is a powerful means of expressing, communicating, shaping, and supporting category knowledge. Finally, we consider categories in context. We discuss sources of variability and flexibility in children's categories, as well as the ways in which children's categories are used within larger knowledge systems (e.g., to form analogies, make inferences, or construct theories). Categorization is a process that is intrinsically tied to nearly all aspects of cognition, and its study provides insight into cognitive development, broadly construed.

  9. Design, synthesis and bioactivity of novel ALS enzyme inhibitors (II)——Molecular mechanics, quantum chemistry and structure-activity relationship studies on the herbicidal heterocyclic sulfonamide

    Institute of Scientific and Technical Information of China (English)

    陆荣健; 杨华铮; 尚贞锋; 汪惟为; 潘荫明; 赵学庄

    1996-01-01

    In view of quantum pharmacology, the structure-activity relationships of different kinds of fused heterocydic sulfonamides with the same mode of action were first investigated using molecular mechanics, quantum chemistry and discriminatory analysis. It has been found that the process of the interaction of the fused heterocydic sulfonamide with ALS enzyme involves the electropositive region of the sulfonyl bridge chain and the electronegative region of the heterocydic moiety. The herbicidal activity is related to the potency of electric charge translocation of the related regions.

  10. Novel, Unifying Mechanism for Mescaline in The Central Nervous System: Electrochemistry, Catechol Redox Metabolite, Receptor, Cell Signaling and Structure Activity Relationships

    Directory of Open Access Journals (Sweden)

    Peter Kovacic

    2009-01-01

    Full Text Available A unifying mechanism for abused drugs has been proposed previously from the standpoint of electron transfer. Mescaline can be accommodated within the theoretical framework based on redox cycling by the catechol metabolite with its quinone counterpart. Electron transfer may play a role in electrical effects involving the nervous system in the brain. This approach is in accord with structure activity relationships involving mescaline, abused drugs, catecholamines and etoposide. Inefficient demethylation is in keeping with the various drug properties, such as requirement for high dosage and slow acting.

  11. Jatrophane diterpenes as P-glycoprotein inhibitors. First insights of structure-activity relationships and discovery of a new, powerful lead.

    Science.gov (United States)

    Corea, Gabriella; Fattorusso, Ernesto; Lanzotti, Virginia; Taglialatela-Scafati, Orazio; Appendino, Giovanni; Ballero, Mauro; Simon, Pierre-Noël; Dumontet, Charles; Di Pietro, Attilio

    2003-07-17

    The Mediterranean spurge Euphorbia dendroides L. afforded a series of 10 closely related jatrophane polyesters, nine of which are new, which served as a base for the establishment of structure-activity relationships within this class of P-glycoprotein inhibitors. The results, while pointing to the general role of lipophilicity for activity, also highlighted the relevance of the substitution pattern at the positions 2, 3, and 5, suggesting the involvement of this fragment in binding. The most powerful compound of the series, euphodendroidin D (4), outperformed cyclosporin by a factor of 2 to inhibit Pgp-mediated daunomycin transport.

  12. Structure-activity relationship of benzodiazepine derivatives as LXXLL peptide mimetics that inhibit the interaction of vitamin D receptor with coactivators.

    Science.gov (United States)

    Mita, Yusuke; Dodo, Kosuke; Noguchi-Yachide, Tomomi; Hashimoto, Yuichi; Ishikawa, Minoru

    2013-02-15

    Suppression of vitamin D receptor (VDR)-mediated transcription is expected to be of therapeutic value in Paget's disease of bone. It is known that interaction between VDR and coactivators is necessary for VDR transactivation, and the interaction occurs when VDR recognizes an LXXLL peptide motif of coactivators. We previously reported that benzodiazepine derivatives designed as LXXLL peptide mimetics inhibited the interaction of VDR and coactivators, and reduced VDR transcription. Here, we investigated the structure-activity relationship of 7- and 8-substituted benzodiazepine derivatives, and established that the amino group at the 8-position is critical for the inhibitory activity.

  13. Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists.

    Science.gov (United States)

    Morin, Matthew D; Wang, Ying; Jones, Brian T; Su, Lijing; Surakattula, Murali M R P; Berger, Michael; Huang, Hua; Beutler, Elliot K; Zhang, Hong; Beutler, Bruce; Boger, Dale L

    2016-05-26

    Herein, we report studies leading to the discovery of the neoseptins and a comprehensive examination of the structure-activity relationships (SARs) of this new class of small-molecule mouse Toll-like receptor 4 (mTLR4) agonists. The compounds in this class, which emerged from screening an α-helix mimetic library, stimulate the immune response, act by a well-defined mechanism (mouse TLR4 agonist), are easy to produce and structurally manipulate, exhibit exquisite SARs, are nontoxic, and elicit improved and qualitatively different responses compared to lipopolysaccharide, even though they share the same receptor.

  14. Cyclotide structure-activity relationships: qualitative and quantitative approaches linking cytotoxic and anthelmintic activity to the clustering of physicochemical forces.

    Directory of Open Access Journals (Sweden)

    Sungkyu Park

    Full Text Available Cyclotides are a family of plant-derived proteins that are characterized by a cyclic backbone and a knotted disulfide topology. Their cyclic cystine knot (CCK motif makes them exceptionally resistant to thermal, chemical, and enzymatic degradation. Cyclotides exert much of their biological activity via interactions with cell membranes. In this work, we qualitatively and quantitatively analyze the cytotoxic and anthelmintic membrane activities of cyclotides. The qualitative and quantitative models describe the potency of cyclotides using four simple physicochemical terms relevant to membrane contact. Specifically, surface areas of the cyclotides representing lipophilic and hydrogen bond donating properties were quantified and their distribution across the molecular surface was determined. The resulting quantitative structure-activity relation (QSAR models suggest that the activity of the cyclotides is proportional to their lipophilic and positively charged surface areas, provided that the distribution of these surfaces is asymmetric. In addition, we qualitatively analyzed the physicochemical differences between the various cyclotide subfamilies and their effects on the cyclotides' orientation on the membrane and membrane activity.

  15. Extending the structure-activity relationship study of marine natural ningalin B analogues as P-glycoprotein inhibitors.

    Science.gov (United States)

    Yang, Chao; Wong, Iris L K; Peng, Kai; Liu, Zhen; Wang, Peng; Jiang, Tingfu; Jiang, Tao; Chow, Larry M C; Wan, Sheng Biao

    2017-01-05

    In the present study, a total of 25 novel ningalin B analogues were synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast cancer cell line LCC6MDR. Preliminary structure-activity study shows that A ring and its two methoxy groups are important pharmacophores for P-gp inhibiting activity. Among all derivatives, 23 is the most potent P-gp modulator with EC50 of 120-165 nM in reversing paclitaxel, DOX, vinblastine and vincristine resistance. It is relatively safe to use with selective index at least greater than 606 compared to verapamil. Mechanistic study demonstrates that compound 23 reverses P-gp mediated drug resistance by inhibiting transport activity of P-gp, thereby restoring intracellular drug accumulation. In summary, our study demonstrates that ningalin B analogue 23 is a non-cytotoxic and effective P-gp chemosensitizer that can be used in the future for reversing P-gp mediated clinical cancer drug resistance.

  16. Thinking in Terms of Structure-Activity-Relationships (T-SAR: A Tool to Better Understand Nanofiltration Membranes

    Directory of Open Access Journals (Sweden)

    Stefan Stolte

    2011-07-01

    Full Text Available A frontier to be conquered in the field of membrane technology is related to the very limited scientific base for the rational and task-specific design of membranes. This is especially true for nanofiltration membranes with properties that are based on several solute-membrane interaction mechanisms. “Thinking in terms of Structure-Activity-Relationships” (T-SAR is a methodology which applies a systematic analysis of a chemical entity based on its structural formula. However, the analysis become more complex with increasing size of the molecules considered. In this study, T-SAR was combined with classical membrane characterization methods, resulting in a new methodology which allowed us not only to explain membrane characteristics, but also provides evidence for the importance of the chemical structure for separation performance. We demonstrate an application of the combined approach and its potential to discover stereochemistry, molecular interaction potentials, and reactivity of two FilmTec nanofiltration membranes (NF-90 and NF-270. Based on these results, it was possible to predict both properties and performance in the recovery of hydrophobic ionic liquids from aqueous solution.

  17. Structure activity relationship modelling of milk protein-derived peptides with dipeptidyl peptidase IV (DPP-IV) inhibitory activity.

    Science.gov (United States)

    Nongonierma, Alice B; FitzGerald, Richard J

    2016-05-01

    Quantitative structure activity type models were developed in an attempt to predict the key features of peptide sequences having dipeptidyl peptidase IV (DPP-IV) inhibitory activity. The models were then employed to help predict the potential of peptides, which are currently reported in the literature to be present in the intestinal tract of humans following milk/dairy product ingestion, to act as inhibitors of DPP-IV. Two models (z- and v-scale) for short (2-5 amino acid residues) bovine milk peptides, behaving as competitive inhibitors of DPP-IV, were developed. The z- and the v-scale models (p<0.05, R(2) of 0.829 and 0.815, respectively) were then applied to 56 milk protein-derived peptides previously reported in the literature to be found in the intestinal tract of humans which possessed a structural feature of DPP-IV inhibitory peptides (P at the N2 position). Ten of these peptides were synthetized and tested for their in vitro DPP-IV inhibitory properties. There was no agreement between the predicted and experimentally determined DPP-IV half maximal inhibitory concentrations (IC50) for the competitive peptide inhibitors. However, the ranking for DPP-IV inhibitory potency of the competitive peptide inhibitors was conserved. Furthermore, potent in vitro DPP-IV inhibitory activity was observed with two peptides, LPVPQ (IC50=43.8±8.8μM) and IPM (IC50=69.5±8.7μM). Peptides present within the gastrointestinal tract of human may have promise for the development of natural DPP-IV inhibitors for the management of serum glucose.

  18. Quantitative structure-activity relationship study of P2X7 receptor inhibitors using combination of principal component analysis and artificial intelligence methods.

    Science.gov (United States)

    Ahmadi, Mehdi; Shahlaei, Mohsen

    2015-01-01

    P2X7 antagonist activity for a set of 49 molecules of the P2X7 receptor antagonists, derivatives of purine, was modeled with the aid of chemometric and artificial intelligence techniques. The activity of these compounds was estimated by means of combination of principal component analysis (PCA), as a well-known data reduction method, genetic algorithm (GA), as a variable selection technique, and artificial neural network (ANN), as a non-linear modeling method. First, a linear regression, combined with PCA, (principal component regression) was operated to model the structure-activity relationships, and afterwards a combination of PCA and ANN algorithm was employed to accurately predict the biological activity of the P2X7 antagonist. PCA preserves as much of the information as possible contained in the original data set. Seven most important PC's to the studied activity were selected as the inputs of ANN box by an efficient variable selection method, GA. The best computational neural network model was a fully-connected, feed-forward model with 7-7-1 architecture. The developed ANN model was fully evaluated by different validation techniques, including internal and external validation, and chemical applicability domain. All validations showed that the constructed quantitative structure-activity relationship model suggested is robust and satisfactory.

  19. Identification of Lilial as a fragrance sensitizer in a perfume by bioassay-guided chemical fractionation and structure-activity relationships.

    Science.gov (United States)

    Arnau, E G; Andersen, K E; Bruze, M; Frosch, P J; Johansen, J D; Menné, T; Rastogi, S C; White, I R; Lepoittevin, J P

    2000-12-01

    Fragrance materials are among the most common causes of allergic contact dermatitis. The aim of this study was to identify in a perfume fragrance allergens not included in the fragrance mix, by use of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships (SARs). The basis for the investigation was a 45-year-old woman allergic to her own perfume. She had a negative patch test to the fragrance mix and agreed to participate in the study. Chemical fractionation of the perfume concentrate was used for repeated patch testing and/or repeated open application test on the pre-sensitized patient. The chemical composition of the fractions giving a positive patch-test response and repeated open application test reactions was obtained by gas chromatography-mass spectrometry. From the compounds identified, those that contained a "structural alert" in their chemical structure, indicating an ability to modify skin proteins and thus behave as a skin sensitizer, were tested on the patient. The patient reacted positively to the synthetic fragrance p-t-butyl-alpha-methylhydrocinnamic aldehyde (Lilial), a widely used fragrance compound not present in the fragrance mix. The combination of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships seems to be a valuable tool for the investigation of contact allergy to fragrance materials.

  20. Molecular field analysis and 3D-quantitative structure-activity relationship study (MFA 3D-QSAR) unveil novel features of bile acid recognition at TGR5.

    Science.gov (United States)

    Macchiarulo, Antonio; Gioiello, Antimo; Thomas, Charles; Massarotti, Alberto; Nuti, Roberto; Rosatelli, Emiliano; Sabbatini, Paola; Schoonjans, Kristina; Auwerx, Johan; Pellicciari, Roberto

    2008-09-01

    Bile acids regulate nongenomic actions through the activation of TGR5, a membrane receptor that is G protein-coupled to the induction of adenylate cyclase. In this work, a training set of 43 bile acid derivatives is used to develop a molecular interaction field analysis (MFA) and a 3D-quantitative structure-activity relationship study (3D-QSAR) of TGR5 agonists. The predictive ability of the resulting model is evaluated using an external set of compounds with known TGR5 activity, and six bile acid derivatives whose unknown TGR5 activity is herein assessed with in vitro luciferase assay of cAMP formation. The results show a good predictive model and indicate a statistically relevant degree of correlation between the TGR5 activity and the molecular interaction fields produced by discrete positions of the bile acid scaffold. This information is instrumental to extend on a quantitative basis the current structure-activity relationships of bile acids as TGR5 modulators and will be fruitful to design new potent and selective agonists of the receptor.

  1. Kinetic analysis of interactions of different sarin and tabun analogues with human acetylcholinesterase and oximes: is there a structure-activity relationship?

    Science.gov (United States)

    Aurbek, Nadine; Herkert, Nadja M; Koller, Marianne; Thiermann, Horst; Worek, Franz

    2010-09-06

    The repeated misuse of highly toxic organophosphorus compound (OP) based chemical warfare agents in military conflicts and terrorist attacks poses a continuous threat to the military and civilian sector. The toxic symptomatology of OP poisoning is mainly caused by inhibition of acetylcholinesterase (AChE, E.C. 3.1.1.7) resulting in generalized cholinergic crisis due to accumulation of the neurotransmitter acetylcholine (ACh) in synaptic clefts. Beside atropine as competitive antagonist of ACh at muscarinic ACh receptors oximes as reactivators of OP-inhibited AChE are a mainstay of standard antidotal treatment. However, human AChE inhibited by certain OP is rather resistant to oxime-induced reactivation. The development of more effective oxime-based reactivators may fill the gaps. To get more insight into a potential structure-activity relationship between human AChE, OPs and oximes in vitro studies were conducted to investigate interactions of different tabun and sarin analogues with human AChE and the oximes obidoxime and HI 6 by determination of various kinetic constants. Rate constants for the inhibition of human AChE by OPs, spontaneous dealkylation and reactivation as well as reactivation by obidoxime and HI 6 of OP-inhibited human AChE were determined. The recorded kinetic data did not allow a general statement concerning a structure-activity relationship between human AChE, OP and oximes.

  2. Study on the quantitative structure-activity relationship of C-10 substituted artemisinin (QHS)'s derivatives using rough set theory

    Institute of Scientific and Technical Information of China (English)

    LIU Hao; QU LingBo; GAO HongBin; WANG JinXiang; HAN LiPing; XIANG BingRen

    2008-01-01

    The structure-activity relationship study of C-10 substituted artemisinin (QHS) derivatives that are used as antimalarial was performed with the RS (rough sets) method. An RS process is a concise nonlinear process, and it has broad application foreground in the data mining of nonlinear life courses. In this work, initially the parameters of C-10 substituted QHS's derivatives were computed with the quantum chemistry method, and the information table was constructed from the parameters (condition attributes) and biological activity (decision attributes). Based on the analysis of rough set theory, the core and reduction of attributes sets were obtained. Then the decision rules were extracted and the structure-activity relationship was analyzed. As a nonlinear system, RS theory can extract the special relation in the database. It has the advantage of being nonlinear over multiple linear regression (MLR), principal component analysis (PCA), partial least square (PLS), etc., and the advantage of obtaining results with unambiguous physical meanings over artificial neuron networks (ANNs), etc. The result obtained in this study is instructive to the study of pharmacodynamics, resistance mechanism of QHS and development of QHS's derivatives.

  3. Comparison between 5,10,15,20-tetraaryl- and 5,15-diarylporphyrins as photosensitizers: synthesis, photodynamic activity, and quantitative structure-activity relationship modeling.

    Science.gov (United States)

    Banfi, Stefano; Caruso, Enrico; Buccafurni, Loredana; Murano, Roberto; Monti, Elena; Gariboldi, Marzia; Papa, Ester; Gramatica, Paola

    2006-06-01

    The synthesis of a panel of seven nonsymmetric 5,10,15,20-tetraarylporphyrins, 13 symmetric and nonsymmetric 5,15-diarylporphyrins, and one 5,15-diarylchlorin is described. In vitro photodynamic activities on HCT116 human colon adenocarcinoma cells were evaluated by standard cytotoxicity assays. A predictive quantitative structure-activity relationship (QSAR) regression model, based on theoretical holistic molecular descriptors, of a series of 34 tetrapyrrolic photosensitizers (PSs), including the 24 compounds synthesized in this work, was developed to describe the relationship between structural features and photodynamic activity. The present study demonstrates that structural features significantly influence the photodynamic activity of tetrapyrrolic derivatives: diaryl compounds were more active with respect to the tetraarylporphyrins, and among the diaryl derivatives, hydroxy-substituted compounds were more effective than the corresponding methoxy-substituted ones. Furthermore, three monoarylporphyrins, isolated as byproducts during diarylporphyrin synthesis, were considered for both photodynamic and QSAR studies; surprisingly they were found to be particularly active photosensitizers.

  4. Novel anti-tumour barringenol-like triterpenoids from the husks of Xanthoceras sorbifolia Bunge and their three dimensional quantitative structure activity relationships analysis.

    Science.gov (United States)

    Wang, Da; Su, Dan; Yu, Bin; Chen, Chuming; Cheng, Li; Li, Xianzhe; Xi, Ronggang; Gao, Huiyuan; Wang, Xiaobo

    2017-01-01

    The high edible oil content of Xanthoceras sorbifolia Bunge seeds contributes to its economic value. In this study, we analysed the barrigenol-like triterpenoids derived from X. sorbifolia husks. We also identified anti-tumour agents that could enhance the health benefits and medicinal value of X. sorbifolia. We isolated 10 barrigenol triterpenoids, including six new compounds (1-6) and four known compounds (7-10). New compounds 3 and 5 showed significant inhibitory activity against the proliferation of three human tumour cell lines, namely, HepG2, HCT-116 and U87-MG. We determined the relationship between the structures and inhibitory activity of 25 barrigenol triterpenoids and 15 penta-cyclic triterpenoids through analysis of three-dimensional quantitative structure activity relationships (3D-QSAR). The isolation of novel barrigenol derivatives with anti-tumour activity from X. sorbifolia implied that husks of this plant may be a good source of anti-tumour agents.

  5. Categorical Pullbacks

    Directory of Open Access Journals (Sweden)

    Riccardi Marco

    2015-03-01

    Full Text Available The main purpose of this article is to introduce the categorical concept of pullback in Mizar. In the first part of this article we redefine homsets, monomorphisms, epimorpshisms and isomorphisms [7] within a free-object category [1] and it is shown there that ordinal numbers can be considered as categories. Then the pullback is introduced in terms of its universal property and the Pullback Lemma is formalized [15]. In the last part of the article we formalize the pullback of functors [14] and it is also shown that it is not possible to write an equivalent definition in the context of the previous Mizar formalization of category theory [8].

  6. Use of a (Quantitative) Structure-Activity Relationship [(Q)SAR] model to predict the toxicity of naphthenic acids

    DEFF Research Database (Denmark)

    Frank, Richard; Sanderson, Hans; Kavanagh, Richard

    2010-01-01

    -Activity Relationship ((Q)SAR) model to accurately predict the toxicity of NA-like surrogates was investigated.  The USEPA’s ECOSAR model predicted the toxicity of NA-like surrogates with acceptable accuracy in comparison to observed toxicity values from Vibrio fischeri and Daphnia magna assays, indicating...... that the model has potential to serve as a prioritization tool for identifying NA structures likely to have an increased toxicity.  Investigating NAs of equal MW, the ECOSAR model predicted increased toxic potency for NAs containing fewer carbon rings.  Furthermore, NA structures with a linear grouping of carbon...

  7. Structure-activity relationship study of dibenzocyclooctadiene lignans isolated from Schisandra chinensis on lipopolysaccharide-induced microglia activation.

    Science.gov (United States)

    Hu, Di; Han, Na; Yao, Xuechun; Liu, Zhihui; Wang, Yu; Yang, Jingyu; Yin, Jun

    2014-06-01

    To explore the relationship of the dibenzocyclooctadiene lignans from Schisandra chinensis to their anti-inflammatory activities, series of dibenzocyclooctadiene lignans were isolated and assessed by testing their inhibitory effects on nitric oxide production in lipopolysaccharide-induced BV2 mouse microglia. It was found, for the first time, that dibenzocyclooctadiene lignans which have S-biphenyl and methylenedioxy groups strongly inhibited LPS-induced microglia activation. The methoxy group on the cyclooctadiene introduced more effectiveness, but the presence of an acetyl group on the cyclooctadiene or hydroxyl group on C-7 decreased the inhibitory activity.

  8. Quantitative structure activity relationship study of anticonvulsant activity of α_substituted acetamido-N-benzylacetamide derivatives

    Directory of Open Access Journals (Sweden)

    Usman Abdulfatai

    2016-12-01

    Full Text Available To develop the quantitative structure–activity relationship (QSAR for predicting the anticonvulsant activity of α_substituted acetamido-N-benzylacetamide derivatives. Density Functional Theory (B3LYP/6-31G* quantum chemical calculation method was used to find the optimized geometry of the studied molecules. Nine types of molecular descriptors were used to derive a quantitative relation between anticonvulsant activity and structural properties. The relevant molecular descriptors were selected by genetic algorithm approximation. The high value of the correlation coefficient, (R2 of 0.98, indicates that the model was satisfactory. The proposed model has good stability, robustness, and predictability on verifying with internal and external validation.

  9. Structure-activity relationship and role of oxygen in the potential antitumour activity of fluoroquinolones in human epithelial cancer cells.

    Science.gov (United States)

    Perucca, Paola; Savio, Monica; Cazzalini, Ornella; Mocchi, Roberto; Maccario, Cristina; Sommatis, Sabrina; Ferraro, Daniela; Pizzala, Roberto; Pretali, Luca; Fasani, Elisa; Albini, Angelo; Stivala, Lucia Anna

    2014-11-01

    The photobehavior of ciprofloxacin, lomefloxacin and ofloxacin fluoroquinolones was investigated using several in vitro methods to assess their cytotoxic, antiproliferative, and genotoxic potential against two human cancer cell lines. We focused our attention on the possible relationship between their chemical structure, O₂ partial pressure and photobiological activity on cancer cells. The three molecules share the main features of most fluoroquinolones, a fluorine in 6 and a piperazino group in 7, but differ at the key position 8, unsubstituted in ciprofloxacin, a fluorine in lomefloxacin and an alkoxy group in ofloxacin. Studies in solution show that ofloxacin has a low photoreactivity; lomefloxacin reacts via aryl cation, ciprofloxacin reacts but not via the cation. In our experiments, ciprofloxacin and lomefloxacin showed a high and comparable potential for photodamaging cells and DNA. Lomefloxacin appeared the most efficient molecule in hypoxia, acting mainly against tumour cell proliferation and generating DNA plasmid photocleavage. Although our results do not directly provide evidence that a carbocation is involved in photodamage induced by lomefloxacin, our data strongly support this hypothesis. This may lead to new and more efficient anti-tumour drugs involving a cation in their mechanism of action. This latter acting independently of oxygen, can target hypoxic tumour tissue.

  10. Thermal properties and nanodispersion behavior of synthesized β-sitosteryl acyl esters: a structure-activity relationship study.

    Science.gov (United States)

    Panpipat, Worawan; Dong, Mingdong; Xu, Xuebing; Guo, Zheng

    2013-10-01

    The efficiency (dose response) of cholesterol-lowering effect of phytosterols in humans depends on their chemical forms (derived or non-derived) and formulation methods in a delivery system. With a series of synthesized β-sitosteryl fatty acid esters (C2:0-C18:0 and C18:1-C18:3), this work examined their thermal properties and applications in preparation of nanodispersion with β-sitosterol as a comparison. Inspection of the melting point (Tm) and the heat of fusion (ΔH) of β-sitosteryl fatty acid esters and the chain length and unsaturation degree of fatty acyl moiety revealed a pronounced structure-property relationship. The nanodispersions prepared with β-sitosterol and β-sitosteryl saturated fatty acid (SFA) esters displayed different particle size distribution patterns (polymodal vs bimodal), mean diameter (115 nm vs less than 100 nm), and polydispersity index (PDI) (0.50 vs 0.23-0.38). β-sitosteryl unsaturated fatty acid (USFA) esters showed a distinctly different dispersion behavior to form nanoemulsions, rather than nanodispersions, with more homogeneous particle size distribution (monomodal, mean diameter 27-63 nm and PDI 0.18-0.25). The nanodispersion of β-sitosteryl medium chain SFA ester (C14:0) demonstrated a best storage stability.

  11. Lathyrol diterpenes as modulators of P-glycoprotein dependent multidrug resistance: structure-activity relationship studies on Euphorbia factor L3 derivatives.

    Science.gov (United States)

    Jiao, Wei; Wan, Zhongmin; Chen, Shuang; Lu, Runhua; Chen, Xiaozhen; Fang, Dongmei; Wang, Jiufeng; Pu, Shengcai; Huang, Xin; Gao, Haixiang; Shao, Huawu

    2015-05-14

    Five series of 37 new acylate and epoxide derivatives (3-39) of Euphorbia factor L3, a lathyrol diterpene isolated from Euphorbia lathyris, were designed by modifying the hydroxyl moiety of C-3, C-5, or C-15. Chemoreversal effects of the acylates on multidrug resistance (MDR) were evaluated in breast cancer multidrug-resistant MCF-7/ADR cells that overexpress P-glycoprotein (P-gp). Eight derivatives exhibited greater chemoreversal ability than verapamil (VRP) against adriamycin (ADR) resistance. Compounds 19 and 25 exhibited 4.8 and 4.0 times, respectively, more effective reversal ability than VRP against ADR resistance. To determine the key characteristics of Euphorbia factor L3 derivatives that contribute to MDR reversal, we conducted a structure-activity relationship study of these compounds. The simulation studies indicated different possible mechanisms and revealed the important influence of hydrophobic interactions and hydrogen bonds in the flexible cavity of P-gp.

  12. Jatrophane diterpenes as modulators of multidrug resistance. Advances of structure-activity relationships and discovery of the potent lead pepluanin A.

    Science.gov (United States)

    Corea, Gabriella; Fattorusso, Ernesto; Lanzotti, Virginia; Motti, Riccardo; Simon, Pierre-Noël; Dumontet, Charles; Di Pietro, Attilio

    2004-02-12

    From the whole plant of Euphorbia peplus L., five new diterpenes based on a jatrophane skeleton (pepluanins A-E, 1-5) were isolated, together with two known analogues (6 and 7), which served to divulge in detail the structure-activity relationships within this class of P-glycoprotein inhibitors. The results revealed the importance of substitutions on the medium-sized ring (carbons 8, 9, 14, and 15). In particular, the activity is collapsed by the presence of a free hydroxyl at C-8, while it increases with a carbonyl at C-14, an acetoxyl at C-9, and a free hydroxyl at C-15. The most potent compound of the series, pepluanin A, showed a very high activity for a jatrophane diterpene, outperforming cyclosporin A by a factor of at least 2 in the inhibition of Pgp-mediated daunomycin transport.

  13. Structure-activity relationships for euphocharacins A-L, a new series of jatrophane diterpenes, as inhibitors of cancer cell P-glycoprotein.

    Science.gov (United States)

    Corea, Gabriella; Fattorusso, Ernesto; Lanzotti, Virginia; Motti, Riccardo; Simon, Pierre-Noël; Dumontet, Charles; Di Pietro, Attilio

    2004-07-01

    The Mediterranean spurge Euphorbia characias L. afforded twelve new diterpenes based on a jatrophane skeleton named euphocharacins A-L. Their chemical structures were elucidated by extensive nuclear magnetic resonance and mass spectrometry methods. Euphocharacins A-L were tested as inhibitors of the daunomycin-efflux activity of P-glycoprotein from cancer cells. The results were used to extend the structure-activity relationship established for this class of compounds, highlighting the positive effects of propyl and benzoyl groups at positions 3 and 9, respectively, and evidencing the negative effect of a free hydroxyl group at position 2. Among the tested compounds, euphocharacins C and I showed an activity higher than cyclosporin to inhibit Pgp-mediated daunomycin transport.

  14. 2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 2. Reduction of hERG activity, observed species selectivity, and structure-activity relationships.

    Science.gov (United States)

    Slee, Deborah H; Moorjani, Manisha; Zhang, Xiaohu; Lin, Emily; Lanier, Marion C; Chen, Yongsheng; Rueter, Jaimie K; Lechner, Sandra M; Markison, Stacy; Malany, Siobhan; Joswig, Tanya; Santos, Mark; Gross, Raymond S; Williams, John P; Castro-Palomino, Julio C; Crespo, María I; Prat, Maria; Gual, Silvia; Díaz, José-Luis; Jalali, Kayvon; Sai, Yang; Zuo, Zhiyang; Yang, Chun; Wen, Jenny; O'Brien, Zhihong; Petroski, Robert; Saunders, John

    2008-03-27

    Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.

  15. Structure-activity relationships among antifungal nylon-3 polymers: identification of materials active against drug-resistant strains of Candida albicans.

    Science.gov (United States)

    Liu, Runhui; Chen, Xinyu; Falk, Shaun P; Mowery, Brendan P; Karlsson, Amy J; Weisblum, Bernard; Palecek, Sean P; Masters, Kristyn S; Gellman, Samuel H

    2014-03-19

    Fungal infections are a major challenge to human health that is heightened by pathogen resistance to current therapeutic agents. Previously, we were inspired by host-defense peptides to develop nylon-3 polymers (poly-β-peptides) that are toxic toward the fungal pathogen Candida albicans but exert little effect on mammalian cells. Based on subsequent analysis of structure-activity relationships among antifungal nylon-3 polymers, we have now identified readily prepared cationic homopolymers active against strains of C. albicans that are resistant to the antifungal drugs fluconazole and amphotericin B. These nylon-3 polymers are nonhemolytic. In addition, we have identified cationic-hydrophobic copolymers that are highly active against a second fungal pathogen, Cryptococcus neoformans, and moderately active against a third pathogen, Aspergillus fumigatus.

  16. Structure activity relationship of phenolic diterpenes from Salvia officinalis as activators of the nuclear factor E2-related factor 2 pathway.

    Science.gov (United States)

    Fischedick, Justin T; Standiford, Miranda; Johnson, Delinda A; Johnson, Jeffrey A

    2013-05-01

    Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to activate cytoprotective genes which may be useful in the treatment of neurodegenerative disease. In order to better understand the structure activity relationship of phenolic diterpenes from Salvia officinalis L., we isolated carnosic acid, carnosol, epirosmanol, rosmanol, 12-methoxy-carnosic acid, sageone, and carnosaldehyde using polyamide column, centrifugal partition chromatography, and semi-preparative high performance liquid chromatography. Isolated compounds were screened in vitro for their ability to active the Nrf2 and general cellular toxicity using mouse primary cortical cultures. All compounds except 12-methoxy-carnosic acid were able to activate the antioxidant response element. Furthermore both carnosol and carnoasldehyde were able to induce Nrf2-dependent gene expression as well as protect mouse primary cortical neuronal cultures from H(2)O(2) induced cell death.

  17. Synthesis, Antifungal Activity and Structure-Activity Relationships of Novel 3-(Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic Acid Amides

    Directory of Open Access Journals (Sweden)

    Shijie Du

    2015-05-01

    Full Text Available A series of novel 3-(difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H-indazol-1-ylphenyl-3-(difluoro-methyl-1-methyl-1H-pyrazole-4-carboxamide (9m exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH.

  18. The insulin secretory action of novel polycyclic guanidines: discovery through open innovation phenotypic screening, and exploration of structure-activity relationships.

    Science.gov (United States)

    Shaghafi, Michael B; Barrett, David G; Willard, Francis S; Overman, Larry E

    2014-02-15

    We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3-arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner.

  19. Synthesis and structure-activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists.

    Science.gov (United States)

    Moritomo, Ayako; Yamada, Hiroyoshi; Watanabe, Toshihiro; Itahana, Hirotsune; Akuzawa, Shinobu; Okada, Minoru; Ohta, Mitsuaki

    2013-12-15

    To identify potent dual 5-HT2B and 5-HT7 receptor antagonists, we synthesized a series of novel carbonyl guanidine derivatives and examined their structure-activity relationships. Among these compounds, N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (10) had a good in vitro profile, that is, potent affinity for human 5-HT2B and 5-HT7 receptor subtypes (Ki=1.8 nM and Ki=17.6 nM, respectively) and high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 10 also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered.

  20. Synthesis, quantitative structure-activity relationship and biological evaluation of 1,3,4-oxadiazole derivatives possessing diphenylamine moiety as potential anticancer agents.

    Science.gov (United States)

    Abdel Rahman, Doaa Ezzat

    2013-01-01

    Synthesis of 2,5-disubstituted-1,3,4-oxadiazole (2a-c), 3-substituted aminomethyl-5-substituted-1,3,4-oxadiazole-2(3H)-thione (4a-m) and 2-substituted thio-5-substituted-1,3,4-oxadiazole (5a, b) had been described. All the synthesized derivatives were screened for anticancer activity against HT29 and MCF7 cancer cell lines using Sulfo-Rodamine B (SRB) standard method. Most of the tested compounds exploited potent antiproliferative activity against HT29 cancer cell line rather than MCF7 cancer cell line. Compounds 2a-c, 4f and 5a exhibited potent cytotoxicity (IC(50) 1.3-2.0 µM) and selectivity against HT29 cancer cell line. Quantitative structure-activity relationship (QSAR) study was applied to find a correlation between the experimental antiproliferative activities of the newly synthesized oxadiazole derivatives with their physicochemical parameter and topological index.

  1. Using quantitative structure activity relationship models to predict an appropriate solvent system from a common solvent system family for countercurrent chromatography separation.

    Science.gov (United States)

    Marsden-Jones, Siân; Colclough, Nicola; Garrard, Ian; Sumner, Neil; Ignatova, Svetlana

    2015-06-12

    Countercurrent chromatography (CCC) is a form of liquid-liquid chromatography. It works by running one immiscible solvent (mobile phase) over another solvent (stationary phase) being held in a CCC column using centrifugal force. The concentration of compound in each phase is characterised by the partition coefficient (Kd), which is the concentration in the stationary phase divided by the concentration in the mobile phase. When Kd is between approximately 0.2 and 2, it is most likely that optimal separation will be achieved. Having the Kd in this range allows the compound enough time in the column to be separated without resulting in a broad peak and long run time. In this paper we report the development of quantitative structure activity relationship (QSAR) models to predict logKd. The QSAR models use only the molecule's 2D structure to predict the molecular property logKd.

  2. Soyasaponins Protect Against Palmitic Acid-Induced Oxidative Stress in Primary Mouse Hepatocytes:Structure-Activity Relationship

    Institute of Scientific and Technical Information of China (English)

    Guang-zhi HE; Jia-ding CHEN; Yan-hong HU; Jin-bin CHEN; Jian-lin LV; Long-ying ZHA

    2014-01-01

    Objective To investigate the relationship between the structure and activity in protection of soyasaponins against palmitic acid (PA)-induced oxidative stress in primary mouse hepatocytes.Methods The primary mouse hepatocytes were treated with 0.05 mmol/L PA in the presence or absence of soyasaponins (10μg/ml) for 16h. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), the contents of malondialdehyde (MDA), triglyceride (TG) and reactive oxygen species (ROS) were determined.Results PA treatment significantly lowered cellular SOD and GSH-Px activities (P<0.05), increased the contents of MDA and TG (P<0.05) and the production of ROS in mitochondria was elevated (P<0.05). When compared to the treatment of PA alone, the combined treatment of soyasaponins and PA significantly increased the activities of SOD and GSH-Px (P<0.05) and decreased the contents of MDA, TG and ROS (P<0.05). It was found that soyasaponin-A1 or A2 significantly increased the cellular activities of SOD and GSH-Px (P<0.05) and decreased the contents of MDA and ROS as compared with soyasapogenol-A (P<0.05). Similarly, soyasaponin-I significantly increased activities of cellular SOD and GSH-Px (P<0.05) and decreased the content of ROS as compared with soyasapogenol-B (P<0.05).Conclusion Soyasaponins possess antioxidant activity against PA-induced oxidative stress in primary mouse hepatocytes. Soyasaponin-A1, A2 and I are stronger than their corresponding soyasapogenols (soyasapogenol-A and B) in antioxidant activity, probably due to the sugar moieties presented in their chemical structures.

  3. Hologram quantitative structure-activity relationship and comparative molecular field analysis studies within a series of tricyclic phthalimide HIV-1 integrase inhibitors.

    Science.gov (United States)

    Magalhães, Uiaran de Oliveira; Souza, Alessandra Mendonça Teles de; Albuquerque, Magaly Girão; Brito, Monique Araújo de; Bello, Murilo Lamim; Cabral, Lucio Mendes; Rodrigues, Carlos Rangel

    2013-01-01

    Acquired immunodeficiency syndrome is a public health problem worldwide caused by the Human immunodeficiency virus (HIV). Treatment with antiretroviral drugs is the best option for viral suppression, reducing morbidity and mortality. However, viral resistance in HIV-1 therapy has been reported. HIV-1 integrase (IN) is an essential enzyme for effective viral replication and an attractive target for the development of new inhibitors. In the study reported here, two- and three-dimensional quantitative structure-activity relationship (2D/3D-QSAR) studies, applying hologram quantitative structure-activity relationship (HQSAR) and comparative molecular field analysis (CoMFA) methods, respectively, were performed on a series of tricyclic phthalimide HIV-1 IN inhibitors. The best HQSAR model (q (2) = 0.802, r (2) = 0.972) was obtained using atoms, bonds, and connectivity as the fragment distinction, a fragment size of 2-5 atoms, hologram length of 61 bins, and six components. The best CoMFA model (q (2) = 0.748, r (2) = 0.974) was obtained with alignment of all atoms of the tricyclic phthalimide moiety (alignment II). The HQSAR contribution map identified that the carbonyl-hydroxy-aromatic nitrogen motif made a positive contribution to the activity of the compounds. Furthermore, CoMFA contour maps suggested that bulky groups in meta and para positions in the phenyl ring would increase the biological activity of this class. The conclusions of this work may lead to a better understanding of HIV-1 IN inhibition and contribute to the design of new and more potent derivatives.

  4. Categorically Not!

    Science.gov (United States)

    Cole, K. C.

    2011-04-01

    The artist Bob Miller liked to say that the worst disease afflicting humankind is ``hardening of the categories'' - the tendency to cram subjects into boxes labeled ``science,'' ``art,'' ``politics,'' ``economics,'' ``play'' - labels that are as outdated and meaningless as divisions between the colors on a continuous spectrum. Over the past 10 years, KC Cole has been organizing free form events that tear down these artificial barriers, and with intriguing results: actors gain insights into character from a topologist; a choreographer solves engineering problems through her knowledge of motion; neuroscientists learn about intuition from filmmakers and string theorists. Categorically Not! - as the series is called - is not (merely) an attempt to ``popularize'' science by looking at it through unlikely lenses, but a real exploration into the deep connections that both illuminate and energize all fields of study. It is a ``people's'' salon, free and open to the general public. Cole will talk about how she overcomes ``hardening of the categories'' not just through events, but also in her popular magazine and newspaper articles, books, radio commentaries, and teaching at USC's Annenberg School of Communication and Journalism.

  5. A strategy for the incorporation of water molecules present in a ligand binding site into a three-dimensional quantitative structure--activity relationship analysis.

    Science.gov (United States)

    Pastor, M; Cruciani, G; Watson, K A

    1997-12-05

    Water present in a ligand binding site of a protein has been recognized to play a major role in ligand-protein interactions. To date, rational drug design techniques do not usually incorporate the effect of these water molecules into the design strategy. This work represents a new strategy for including water molecules into a three-dimensional quantitative structure-activity relationship analysis using a set of glucose analogue inhibitors of glycogen phosphorylase (GP). In this series, the structures of the ligand-enzyme complexes have been solved by X-ray crystallography, and the positions of the ligands and the water molecules at the ligand binding site are known. For the structure-activity analysis, some water molecules adjacent to the ligands were included into an assembly which encompasses both the inhibitor and the water involved in the ligand-enzyme interaction. The mobility of some water molecules at the ligand binding site of GP gives rise to differences in the ligand-water assembly which have been accounted for using a simulation study involving force-field energy calculations. The assembly of ligand plus water was used in a GRID/GOLPE analysis, and the models obtained compare favorably with equivalent models when water was excluded. Both models were analyzed in detail and compared with the crystallographic structures of the ligand-enzyme complexes in order to evaluate their ability to reproduce the experimental observations. The results demonstrate that incorporation of water molecules into the analysis improves the predictive ability of the models and makes them easier to interpret. The information obtained from interpretation of the models is in good agreement with the conclusions derived from the structural analysis of the complexes and offers valuable insights into new characteristics of the ligands which may be exploited for the design of more potent inhibitors.

  6. A systematic investigation of quaternary ammonium ions as asymmetric phase-transfer catalysts. Application of quantitative structure activity/selectivity relationships.

    Science.gov (United States)

    Denmark, Scott E; Gould, Nathan D; Wolf, Larry M

    2011-06-01

    Although the synthetic utility of asymmetric phase-transfer catalysis continues to expand, the number of proven catalyst types and design criteria remains limited. At the origin of this scarcity is a lack in understanding of how catalyst structural features affect the rate and enantioselectivity of phase transfer catalyzed reactions. Described in this paper is the development of quantitative structure-activity relationships (QSAR) and -selectivity relationships (QSSR) for the alkylation of a protected glycine imine with libraries of quaternary ammonium ion catalysts. Catalyst descriptors including ammonium ion accessibility, interfacial adsorption affinity, and partition coefficient were found to correlate meaningfully with catalyst activity. The physical nature of the descriptors was rationalized through differing contributions of the interfacial and extraction mechanisms to the reaction under study. The variation in the observed enantioselectivity was rationalized employing a comparative molecular field analysis (CoMFA) using both the steric and electrostatic fields of the catalysts. A qualitative analysis of the developed model reveals preferred regions for catalyst binding to afford both configurations of the alkylated product.

  7. Endochin optimization: structure-activity and structure-property relationship studies of 3-substituted 2-methyl-4(1H)-quinolones with antimalarial activity.

    Science.gov (United States)

    Cross, R Matthew; Monastyrskyi, Andrii; Mutka, Tina S; Burrows, Jeremy N; Kyle, Dennis E; Manetsch, Roman

    2010-10-14

    Since the 1940s endochin and analogues thereof were known to be causal prophylactic and potent erythrocytic stage agents in avian models. Preliminary screening in a current in vitro assay identified several 4(1H)-quinolones with nanomolar EC(50) against erythrocytic stages of multidrug resistant W2 and TM90-C2B isolates of Plasmodium falciparum. Follow-up structure-activity relationship (SAR) studies on 4(1H)-quinolone analogues identified several key features for biological activity. Nevertheless, structure-property relationship (SPR) studies conducted in parallel revealed that 4(1H)-quinolone analogues are limited by poor solubilities and rapid microsomal degradations. To improve the overall efficacy, multiple 4(1H)-quinolone series with varying substituents on the benzenoid quinolone ring and/or the 3-position were synthesized and tested for in vitro antimalarial activity. Several structurally diverse 6-chloro-2-methyl-7-methoxy-4(1H)-quinolones with EC(50) in the low nanomolar range against the clinically relevant isolates W2 and TM90-C2B were identified with improved physicochemical properties while maintaining little to no cross-resistance with atovaquone.

  8. Dietary Protection Against Free Radicals: A Case for Multiple Testing to Establish Structure-activity Relationships for Antioxidant Potential of Anthocyanic Plant Species

    Directory of Open Access Journals (Sweden)

    Chiara Cheng Lim

    2009-03-01

    Full Text Available DNA damage by reactive species is associated with susceptibility to chronic human degenerative disorders. Anthocyanins are naturally occurring antioxidants, that may prevent or reverse such damage. There is considerable interest in anthocyanic food plants as good dietary sources, with the potential for reducing susceptibility to chronic disease. While structure-activity relationships have provided guidelines on molecular structure in relation to free hydroxyl- radical scavenging, this may not cover the situation in food plants where the anthocyanins are part of a complex mixture, and may be part of complex structures, including anthocyanic vacuolar inclusions (AVIs. Additionally, new analytical methods have revealed new structures in previously-studied materials. We have compared the antioxidant activities of extracts from six anthocyanin-rich edible plants (red cabbage, red lettuce, blueberries, pansies, purple sweetpotato skin, purple sweetpotato flesh and Maori potato flesh using three chemical assays (DPPH, TRAP and ORAC, and the in vitro Comet assay. Extracts from the flowering plant, lisianthus, were used for comparison. The extracts showed differential effects in the chemical assays, suggesting that closely related structures have different affinities to scavenge different reactive species. Integration of anthocyanins to an AVI led to more sustained radical scavenging activity as compared with the free anthocyanin. All but the red lettuce extract could reduce endogenous DNA damage in HT-29 colon cancer cells. However, while extracts from purple sweetpotato skin and flesh, Maori potato and pansies, protected cells against subsequent challenge by hydrogen peroxide at 0oC, red cabbage extracts were pro-oxidant, while other extracts had no effect. When the peroxide challenge was at 37oC, all of the extracts appeared pro-oxidant. Maori potato extract, consistently the weakest antioxidant in all the chemical assays, was more effective in the

  9. Toxic and antifeedant activities of prenylated flavonoids isolated from Tephrosia apollinea L. against three major coleopteran pests of stored grains with reference to their structure-activity relationship.

    Science.gov (United States)

    Nenaah, Gomah E

    2014-01-01

    Four prenylated flavonoids, isoglabratephrin, (+)-glabratephrin, tephroapollin-F and lanceolatin-A, were isolated from Tephrosia apollinea L. and tested against three stored grain insects. Using the filter paper bioassay, compounds showed adulticidal activity against Sitophilus oryzae (L), Rhyzopertha dominica (F) and Tribolium castaneum (Herbst) at concentrations of 0.875, 1.75 and 3.5 mg mL(- 1). At 3.5 mg mL(- 1), tephroapollin-F was the most toxic (78.6%, 64.6% and 60.7% mortality was recorded after 10 days exposure of S. oryzae, R. dominica and T. castaneum, respectively). The F1 progeny production of insects was affected after parental exposure to flavonoids, where S. oryzae was the most susceptible. A nutritional bioassay, employing a flour disc and test concentrations of 0.65, 1.3 and 2.6 mg g(- 1), revealed a significant reduction in the relative growth rate, relative consumption rate and efficiency of conversion of ingested food by all insects. The structure-activity relationship among the tested flavonoids was discussed.

  10. Formulation development of transdermal dosage forms: quantitative structure-activity relationship model for predicting activities of terpenes that enhance drug penetration through human skin.

    Science.gov (United States)

    Kang, L; Yap, C W; Lim, P F C; Chen, Y Z; Ho, P C; Chan, Y W; Wong, G P; Chan, S Y

    2007-07-31

    Terpenes and terpenoids have been used as enhancers in transdermal formulations for facilitating penetration of drugs into human skin. Knowledge of the correlation between the human skin penetration effect (HSPE) and the physicochemical properties of these enhancers is important for facilitating the discovery and development of more enhancers. In this work, the HSPE of 49 terpenes and terpenoids were compared by the in vitro permeability coefficients of haloperidol (HP) through excised human skin. A first-order multiple linear regression (MLR) model was constructed to link the permeability coefficient of the drug to the lipophilicity, molecular weight, boiling point, the terpene type and the functional group of each enhancer. The Quantitative Structure-Activity Relationship (QSAR) model was derived from our data generated by using standardized experimental protocols, which include: HP in propylene glycol (PG) of 3 mg/ml as the donor solution containing 5% (w/v) of the respective terpene, the same composition and volume of receptor solution, similar human skin samples, in the same set of automated flow-through diffusion cells. The model provided a simple method to predict the enhancing effects of terpenes for drugs with physicochemical properties similar to HP. Our study suggested that an ideal terpene enhancer should possess at least one or combinations of the following properties: hydrophobic, in liquid form at room temperature, with an ester or aldehyde but not acid functional group, and is neither a triterpene nor tetraterpene. Possible mechanisms revealed by the QSAR model were discussed.

  11. Quantitative Structure-Activity Relationship Analysis of Xanthone Derivates as Cytotoxic Agents in Liver Cancer Cell Line HepG2

    Directory of Open Access Journals (Sweden)

    Isnatin Miladiyah

    2016-05-01

    Full Text Available The study of xanthone derivatives as cytotoxic agents in cancer is increasing. This study was conducted to explore the Quantitative Structure-Activity Relationship (QSAR of xanthones as cytotoxic agents in HepG2 cells, to find compounds with better potency. The data set were taken from the previous study, involving 26 xanthone derivates and their cytotoxic activities in Inhibitory Concentration 50% (IC50. The parameters (descriptors were obtained from quantum mechanics calculation using semiempirical AM1 method and QSAR models determined with principle component regression, with log (1/IC50 as a dependent variable and five latent variables as independent variables. From the 26 main descriptors, PCR reduced them to five latent variables (1st– 5th LV. The QSAR analysis gave the best model as follows: log (1/IC50 = 4.592 – 0.204 LV1 + 0.295 LV2 + 0.028 LV3 (n = 26, r = 0.571, SE = 0.234, Fcount/Ftable ratio = 1.165, PRESS value = 3.766. The study concluded that the descriptors contributed to anticancer activity were volume, mass, surface area, log P, dipole moment, HOMO energy, LUMO energy, and atomic net charge of some atoms. Modifications of substitution that would contribute to cytotoxic activity can be performed at phenyl ring A and C, but not at B.

  12. Substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides as antimitotics. Antiproliferative, antiangiogenic and antitumoral activity, and quantitative structure-activity relationships.

    Science.gov (United States)

    Fortin, Sébastien; Wei, Lianhu; Moreau, Emmanuel; Lacroix, Jacques; Côté, Marie-France; Petitclerc, Eric; Kotra, Lakshmi P; Gaudreault, René C

    2011-11-01

    The importance of the bridge linking the two phenyl moieties of substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) was assessed using a sulfonamide group, which is a bioisostere of sulfonate and ethenyl groups. Forty one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamide (PIB-SA) derivatives were prepared and biologically evaluated. PIB-SAs exhibit antiproliferative activities at the nanomolar level against sixteen cancer cell lines, block the cell cycle progression in G(2)/M phase, leading to cytoskeleton disruption and anoikis. These results were subjected to CoMFA and CoMSIA analyses to establish quantitative structure-activity relationships. These results evidence that the sulfonate and sulfonamide moieties are reciprocal bioisosteres and that phenylimidazolidin-2-one could mimic the trimethoxyphenyl moiety found in the structure of numerous potent antimicrotubule agents. Finally, compounds 16 and 17 exhibited potent antitumor and antiangiogenic activities on HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membrane similar to CA-4 without significant toxicity for the chick embryos, making this class of compounds a promising class of anticancer agents.

  13. Design, synthesis, and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents.

    Science.gov (United States)

    Ma, Junjie; Chen, Dong; Lu, Kuan; Wang, Lihui; Han, Xiaoqi; Zhao, Yanfang; Gong, Ping

    2014-10-30

    A series of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety were designed and synthesized and their cytotoxic activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN45, and MDA-MB-231) were screened in vitro. Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 15g (procaspase-3 EC50 = 1.42 μM) and 16b (procaspase-3 EC50 = 0.25 μM) exhibited excellent antitumor activity with IC50 values ranging from 0.14 μM to 0.98 μM against all cancer cell lines, which were 1.8-8.7 times more active than the first procaspase activating compound (PAC-1) (procaspase-3 EC50 = 4.08 μM). The structure-activity relationship (SAR) analyses indicated that the introduction of a lipophilic group (a benzyloxy or heteroaryloxy group) at the 4-position of the 2-hydroxy phenyl ring was beneficial to antitumor activity, and the presence of substituents containing nitrogen that are positively charged at physiological pH could also improve antitumor activity. It was also confirmed that the steric effect of the 4-position substituent of the benzyloxy group had a significant influence on cytotoxic activity.

  14. Screening of promising chemotherapeutic candidates against human adult T-cell leukemia/lymphoma from plants: active principles from Physalis pruinosa and structure-activity relationships with withanolides.

    Science.gov (United States)

    Nakano, Daisuke; Ishitsuka, Kenji; Hatsuse, Takahiro; Tsuchihashi, Ryota; Okawa, Masafumi; Okabe, Hikaru; Tamura, Kazuo; Kinjo, Junei

    2011-07-01

    Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell lymphotropic virus type I (HTLV-1). Clinical manifestations of ATL range from smoldering to chronic, lymphoma and acute subtypes. Patients with acute and lymphoma-type ATL require therapeutic intervention. Conventional chemotherapeutic regimens used against other malignant lymphoma have been administered to ATL patients, but the therapeutic outcomes of acute and lymphoma-type ATL remain very poor. In this study, 214 extracts from 162 plants belonging to 65 families were screened for the purpose of elucidating the anti-proliferative effect against HTLV-1-infected T-cell lines. Extracts from aerial parts of Physalis pruinosa showed potent inhibitory effect. We isolated five withanolides from the extracts by activity-guided fractionation and examined the structure-activity relationships. The presence of a 5β,6β-epoxy function is suggested to be essential for the activity, and the most active principle showed selective toxicity to HTLV-1-infected T-cell lines.

  15. Novel, unifying mechanism for mescaline in the central nervous system: electrochemistry, catechol redox metabolite, receptor, cell signaling and structure activity relationships.

    Science.gov (United States)

    Kovacic, Peter; Somanathan, Ratnasamy

    2009-01-01

    A unifying mechanism for abused drugs has been proposed previously from the standpoint of electron transfer. Mescaline can be accommodated within the theoretical framework based on redox cycling by the catechol metabolite with its quinone counterpart. Electron transfer may play a role in electrical effects involving the nervous system in the brain. This approach is in accord with structure activity relationships involving mescaline, abused drugs, catecholamines, and etoposide. Inefficient demethylation is in keeping with the various drug properties, such as requirement for high dosage and slow acting. There is a discussion of receptor binding, electrical effects, cell signaling and other modes of action. Mescaline is a nonselective, seretonin receptor agonist. 5-HTP receptors are involved in the stimulus properties. Research addresses the aspect of stereochemical requirements. Receptor binding may involve the proposed quinone metabolite and/or the amino sidechain via protonation. Electroencephalographic studies were performed on the effects of mescaline on men. Spikes are elicited by stimulation of a cortical area. The potentials likely originate in nonsynaptic dendritic membranes. Receptor-mediated signaling pathways were examined which affect mescaline behavior. The hallucinogen belongs to the class of 2AR agonists which regulate pathways in cortical neurons. The research identifies neural and signaling mechanisms responsible for the biological effects. Recently, another hallucinogen, psilocybin, has been included within the unifying mechanistic framework. This mushroom constituent is hydrolyzed to the phenol psilocin, also active, which is subsequently oxidized to an ET o-quinone or iminoquinone.

  16. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies.

    Science.gov (United States)

    Sato, Hiroyuki; Macchiarulo, Antonio; Thomas, Charles; Gioiello, Antimo; Une, Mizuho; Hofmann, Alan F; Saladin, Régis; Schoonjans, Kristina; Pellicciari, Roberto; Auwerx, Johan

    2008-03-27

    TGR5, a metabotropic receptor that is G-protein-coupled to the induction of adenylate cyclase, has been recognized as the molecular link connecting bile acids to the control of energy and glucose homeostasis. With the aim of disclosing novel selective modulators of this receptor and at the same time clarifying the molecular basis of TGR5 activation, we report herein the biological screening of a collection of natural occurring bile acids, bile acid derivatives, and some steroid hormones, which has resulted in the discovery of new potent and selective TGR5 ligands. Biological results of the tested collection of compounds were used to extend the structure-activity relationships of TGR5 agonists and to develop a binary classification model of TGR5 activity. This model in particular could unveil some hidden properties shared by the molecular shape of bile acids and steroid hormones that are relevant to TGR5 activation and may hence be used to address the design of novel selective and potent TGR5 agonists.

  17. Synthesis, antibacterial and anti-MRSA activity, in vivo toxicity and a structure-activity relationship study of a quinoline thiourea.

    Science.gov (United States)

    Dolan, Niamh; Gavin, Declan P; Eshwika, Ahmed; Kavanagh, Kevin; McGinley, John; Stephens, John C

    2016-01-15

    We report the synthesis, antibacterial evaluation of a series of thiourea-containing compounds. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)-((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea 5, was the most active against a range of Gram-positive and Gram-negative bacteria, and exhibited bacteriostatic activity against methicillin resistant Staphylococcus aureus (MRSA) comparable to that of the well-known antibacterial agent vancomycin. Quinoline thiourea 5 was subjected to a detailed structure-activity relationship study, with 5 and its derivatives evaluated for their bacteriostatic activity against both Gram-negative and Gram-positive bacteria. A number of structural features important for the overall activity of quinoline thiourea 5 have been identified. A selection of compounds, including 5, was also evaluated for their in vivo toxicity using the larvae of the Greater wax moth, Galleria mellonella. Compound 5, and a number of derivatives, were found to be non-toxic to the larvae of Galleria mellonella. A new class of antibiotic can result from the further development of this family of compounds.

  18. Optimization of 1,2,3,4-tetrahydroacridin-9(10H)-ones as antimalarials utilizing structure-activity and structure-property relationships.

    Science.gov (United States)

    Cross, R Matthew; Maignan, Jordany R; Mutka, Tina S; Luong, Lisa; Sargent, Justin; Kyle, Dennis E; Manetsch, Roman

    2011-07-14

    Antimalarial activity of 1,2,3,4-tetrahydroacridin-9(10H)-ones (THAs) has been known since the 1940s and has garnered more attention with the development of the acridinedione floxacrine (1) in the 1970s and analogues thereof such as WR 243251 (2a) in the 1990s. These compounds failed just prior to clinical development because of suboptimal activity, poor solubility, and rapid induction of parasite resistance. Moreover, detailed structure-activity relationship (SAR) studies of the THA core scaffold were lacking and SPR studies were nonexistent. To improve upon initial findings, several series of 1,2,3,4-tetrahydroacridin-9(10H)-ones were synthesized and tested in a systematic fashion, examining each compound for antimalarial activity, solubility, and permeability. Furthermore, a select set of compounds was chosen for microsomal stability testing to identify physicochemical liabilities of the THA scaffold. Several potent compounds (EC(50) < 100 nM) were identified to be active against the clinically relevant isolates W2 and TM90-C2B while possessing good physicochemical properties and little to no cross-resistance.

  19. Application of Density Functional Theoretic Descriptors to Quantitative Structure-Activity Relationships with Temperature Constrained Cascade Correlation Network Models of Nitrobenzene Derivatives

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    A temperature-constrained cascade correlation network(TCCCN), a back-propagation neural network(BP), and multiple linear regression(MLR) models were applied to quantitative structure-activity relationship(QSAR) modeling, on the basis of a set of 35 nitrobenzene derivatives and their acute toxicities. These structural quantum-chemical descriptors were obtained from the density functional theory(DFT). Stepwise multiple regression analysis was performed and the model was obtained. The value of the calibration correlation coefficient R is 0.925, and the value of cross-validation correlation coefficient R is 0.87. The standard error S=0.308 and the cross-validated(leave-one-out) standard error Scv=0.381. Principal component analysis(PCA) was carried out for parameter selection. RMS errors for training set via TCCCN and BP are 0.067 and 0.095, respectively, and RMS errors for testing set via TCCCN and BP are 0.090 and 0.111, respectively. The results show that TCCCN performs better than BP and MLR.

  20. Structure-activity relationship study of anticancer thymidine-quinoxaline conjugates under the low radiance of long wavelength ultraviolet light for photodynamic therapy.

    Science.gov (United States)

    Zhang, Dejun; Liu, Huaming; Wei, Qiong; Zhou, Qibing

    2016-01-01

    Thymidine quinoxaline conjugate (dT-QX) is a thymidine analog with selective cytotoxicity against different cancer cells. In this study, the structure activity relationship study of dT-QX analogs was carried out under the low radiance of black fluorescent (UVA-1) light. Significantly enhanced cytotoxicity was observed under UVA-1 activation among analogs containing both thymidine and quinoxaline moieties with different length of the linker, stereochemical configuration and halogenated substituents. Among these analogs, the thymidine dichloroquinoxaline conjugate exhibited potent activity under UVA-1 activation as the best candidate with EC50 at 0.67 μM and 1.3 μM against liver and pancreatic cancer cells, respectively. In contrast, the replacement of thymidine moiety with a galactosyl residue or the replacement of quinoxaline moiety with a fluorescent pyrenyl residue or a simplified diketone structure resulted in the full loss of activity. Furthermore, it was revealed that the low radiance of UVA-1 at 3 mW/cm(2) for 20 min was sufficient enough to induce the full cytotoxicity of thymidine dichloroquinoxaline conjugate and that the cytotoxic mechanism was achieved through a rapid and steady production of reactive oxygen species.

  1. Development of highly potent phosphodiesterase 4 inhibitors with anti-neuroinflammation potential: Design, synthesis, and structure-activity relationship study of catecholamides bearing aromatic rings.

    Science.gov (United States)

    Zhou, Zhong-Zhen; Ge, Bing-Chen; Zhong, Qiu-Ping; Huang, Chang; Cheng, Yu-Fang; Yang, Xue-Mei; Wang, Hai-Tao; Xu, Jiang-Ping

    2016-11-29

    In this study, catecholamides (7a-l) bearing different aromatic rings (such as pyridine-2-yl, pyridine-3-yl, phenyl, and 2-chlorophenyl groups) were synthesized as potent phosphodiesterase (PDE) 4 inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4A4, PDE4B1, PDE4C1, and PDE4D7 enzymes, and other PDE family members. Eight of the synthesized compounds were identified as having submicromolar IC50 values in the mid-to low-nanomolar range. Careful analysis on the structure-activity relationship of compounds 7a-l revealed that the replacement of the 4-methoxy group with the difluoromethoxy group improved inhibitory activities. More interesting, 4-difluoromethoxybenzamides 7i and 7j exhibited preference for PDE4 with higher selectivities of about 3333 and 1111-fold over other PDEs, respectively. In addition, compound 7j with wonderful PDE4D7 inhibitory activities inhibited LPS-induced TNF-α production in microglia.

  2. In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii.

    Science.gov (United States)

    Le Calvé, Benjamin; Lallemand, Benjamin; Perrone, Carmen; Lenglet, Gaëlle; Depauw, Sabine; Van Goietsenoven, Gwendoline; Bury, Marina; Vurro, Maurizio; Herphelin, Françoise; Andolfi, Anna; Zonno, Maria Chiara; Mathieu, Véronique; Dufrasne, François; Van Antwerpen, Pierre; Poumay, Yves; David-Cordonnier, Marie-Hélène; Evidente, Antonio; Kiss, Robert

    2011-07-01

    The in vitro anticancer activity and toxicity of phyllostictine A, a novel oxazatricycloalkenone recently isolated from a plant-pathogenic fungus (Phyllosticta cirsii) was characterized in six normal and five cancer cell lines. Phyllostictine A displays in vitro growth-inhibitory activity both in normal and cancer cells without actual bioselectivity, while proliferating cells appear significantly more sensitive to phyllostictine A than non-proliferating ones. The main mechanism of action by which phyllostictine displays cytotoxic effects in cancer cells does not seem to relate to a direct activation of apoptosis. In the same manner, phyllostictine A seems not to bind or bond with DNA as part of its mechanism of action. In contrast, phyllostictine A strongly reacts with GSH, which is a bionucleophile. The experimental data from the present study are in favor of a bonding process between GSH and phyllostictine A to form a complex though Michael attack at C=C bond at the acrylamide-like system. Considering the data obtained, two new hemisynthesized phyllostictine A derivatives together with three other natural phyllostictines (B, C and D) were also tested in vitro in five cancer cell lines. Compared to phyllostictine A, the two derivatives displayed a higher, phyllostictines B and D a lower, and phyllostictine C an almost equal, growth-inhibitory activity, respectively. These results led us to propose preliminary conclusions in terms of the structure-activity relationship (SAR) analyses for the anticancer activity of phyllostictine A and its related compounds, at least in vitro.

  3. Vibrational circular dichroism analysis reveals a conformational change of the baccatin III ring of paclitaxel: visualization of conformations using a new code for structure-activity relationships.

    Science.gov (United States)

    Izumi, Hiroshi; Ogata, Atsushi; Nafie, Laurence A; Dukor, Rina K

    2008-03-21

    The comparison between measured and conformer-weighted calculated VCD spectra of the baccatin III ring of paclitaxel and visualization of the conformations using the new code for structure-activity relationships are reported for the first time. The VCD spectrum of paclitaxel closely resembles that of the baccatin III ring. The large characteristic nuCO VCD bands with bisignate signs (1732 cm-1, Deltaepsilon = -1.6 x 10(-1); 1715 cm(-1), Deltaepsilon = 2.4 x 10(-1)) strongly reflect the structural property of the family of conformations bacc-ABC32F defined using the new code. The comparison with the conformation of the baccatin III core in the electron micrograph of the crystal structure of tubulin-paclitaxel (1JFF) suggests a conformational change of paclitaxel corresponding to a switch through the binding with beta-tublin and the intermolecular interactions involving the hydroxyl group (D) and carbonyl of acetoxy group (E). The representation of conformational codes allows complicated conformations to be very easily compared and facilitates future computational analyses such as those for the large-molecule calculations as well as genome analysis.

  4. Analysis of the internal representations developed by neural networks for structures applied to quantitative structure--activity relationship studies of benzodiazepines.

    Science.gov (United States)

    Micheli, A; Sperduti, A; Starita, A; Bianucci, A M

    2001-01-01

    An application of recursive cascade correlation (CC) neural networks to quantitative structure-activity relationship (QSAR) studies is presented, with emphasis on the study of the internal representations developed by the neural networks. Recursive CC is a neural network model recently proposed for the processing of structured data. It allows the direct handling of chemical compounds as labeled ordered directed graphs, and constitutes a novel approach to QSAR. The adopted representation of molecular structure captures, in a quite general and flexible way, significant topological aspects and chemical functionalities for each specific class of molecules showing a particular chemical reactivity or biological activity. A class of 1,4-benzodiazepin-2-ones is analyzed by the proposed approach. It compares favorably versus the traditional QSAR treatment based on equations. To show the ability of the model in capturing most of the structural features that account for the biological activity, the internal representations developed by the networks are analyzed by principal component analysis. This analysis shows that the networks are able to discover relevant structural features just on the basis of the association between the molecular morphology and the target property (affinity).

  5. Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

    DEFF Research Database (Denmark)

    Krogsgaard-Larsen, Niels; Storgaard, Morten; Møller, Charlotte;

    2015-01-01

    Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal...... carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD...... and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate...

  6. Structure-Activity Relationships in NH3-SCR over Cu-SSZ-13 as Probed by Reaction Kinetics and EPR Studies

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Feng; Walter, Eric D.; Karp, Eric M.; Luo, Jin-Yong; Tonkyn, Russell G.; Kwak, Ja Hun; Szanyi, Janos; Peden, Charles HF

    2013-04-01

    Cu-SSZ-13 catalysts with various Cu loadings were prepared via solution ion exchange. The hydrated samples were studied with Electron Paramagnetic Resonance (EPR). Cu2+ ion coordination numbers were obtained by analyzing the hyperfine structures while Cu-Cu distances were estimated from line broadening of the EPR features. By coupling EPR and temperature-programmed reduction (TPR) results, two Cu2+ ion locations were suggested. Standard and fast NH3-SCR, as well as non-selective NH3 oxidation reactions were carried out over these catalysts at high space velocities. For the SCR reaction, intra-particle diffusion limitation was found throughout the reaction temperatures investigated. Although clear structure-activity relationships cannot be derived, the reaction results allow for reactant diffusivities and Cu2+ ion locations to be estimated. The slower NH3 oxidation reaction, on the other hand, is kinetically limited at low temperatures, and, therefore, allows for a correlation between Cu2+ ion location and reaction kinetics to be made. Furthermore, the dynamic Cu2+ ion motion as a function of temperature could also be derived from the NH3 oxidation kinetics.

  7. Structure-activity relationship and substrate-dependent phenomena in effects of ginsenosides on activities of drug-metabolizing P450 enzymes.

    Directory of Open Access Journals (Sweden)

    Miao Hao

    Full Text Available Ginseng, a traditional herbal medicine, may interact with several co-administered drugs in clinical settings, and ginsenosides, the major active components of ginseng, may be responsible for these ginseng-drug interactions (GDIs. Results from previous studies on ginsenosides' effects on human drug-metabolizing P450 enzymes are inconsistent and confusing. Herein, we first evaluated the inhibitory effects of fifteen ginsenosides and sapogenins on human CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes by using commercially available fluorescent probes. The structure-activity relationship of their effects on the P450s was also explored and a pharmacophore model was established for CYP3A4. Moreover, substrate-dependent phenomena were found in ginsenosides' effects on CYP3A4 when another fluorescent probe was used, and were further confirmed in tests with conventional drug probes and human liver microsomes. These substrate-dependent effects of the ginsenosides may provide an explanation for the inconsistent results obtained in previous GDI reports.

  8. An orientation sensitive approach in biomolecule interaction quantitative structure-activity relationship modeling and its application in ion-exchange chromatography.

    Science.gov (United States)

    Kittelmann, Jörg; Lang, Katharina M H; Ottens, Marcel; Hubbuch, Jürgen

    2017-01-27

    Quantitative structure-activity relationship (QSAR) modeling for prediction of biomolecule parameters has become an established technique in chromatographic purification process design. Unfortunately available descriptor sets fail to describe the orientation of biomolecules and the effects of ionic strength in the mobile phase on the interaction with the stationary phase. The literature describes several special descriptors used for chromatographic retention modeling, all of these do not describe the screening of electrostatic potential by the mobile phase in use. In this work we introduce two new approaches of descriptor calculations, namely surface patches and plane projection, which capture an oriented binding to charged surfaces and steric hindrance of the interaction with chromatographic ligands with regard to electrostatic potential screening by mobile phase ions. We present the use of the developed descriptor sets for predictive modeling of Langmuir isotherms for proteins at different pH values between pH 5 and 10 and varying ionic strength in the range of 10-100mM. The resulting model has a high correlation of calculated descriptors and experimental results, with a coefficient of determination of 0.82 and a predictive coefficient of determination of 0.92 for unknown molecular structures and conditions. The agreement of calculated molecular interaction orientations with both, experimental results as well as molecular dynamic simulations from literature is shown. The developed descriptors provide the means for improved QSAR models of chromatographic processes, as they reflect the complex interactions of biomolecules with chromatographic phases.

  9. In silico exploratory study using structure-activity relationship models and metabolic information for prediction of mutagenicity based on the Ames test and rodent micronucleus assay.

    Science.gov (United States)

    Kamath, P; Raitano, G; Fernández, A; Rallo, R; Benfenati, E

    2015-12-01

    The mutagenic potential of chemicals is a cause of growing concern, due to the possible impact on human health. In this paper we have developed a knowledge-based approach, combining information from structure-activity relationship (SAR) and metabolic triggers generated from the metabolic fate of chemicals in biological systems for prediction of mutagenicity in vitro based on the Ames test and in vivo based on the rodent micronucleus assay. In the first part of the work, a model was developed, which comprises newly generated SAR rules and a set of metabolic triggers. These SAR rules and metabolic triggers were further externally validated to predict mutagenicity in vitro, with metabolic triggers being used only to predict mutagenicity of chemicals, which were predicted unknown, by SARpy. Hence, this model has a higher accuracy than the SAR model, with an accuracy of 89% for the training set and 75% for the external validation set. Subsequently, the results of the second part of this work enlist a set of metabolic triggers for prediction of mutagenicity in vivo, based on the rodent micronucleus assay. Finally, the results of the third part enlist a list of metabolic triggers to find similarities and differences in the mutagenic response of chemicals in vitro and in vivo.

  10. Discovery of an ultra-short linear antibacterial tetrapeptide with anti-MRSA activity from a structure-activity relationship study.

    Science.gov (United States)

    Lau, Qiu Ying; Ng, Fui Mee; Cheong, Jin Wei Darryl; Yap, Yi Yong Alvin; Tan, Yoke Yan Fion; Jureen, Roland; Hill, Jeffrey; Chia, Cheng San Brian

    2015-11-13

    The overuse and misuse of antibiotics has resulted in the emergence of drug-resistant pathogenic bacteria, including meticillin-resistant Staphylococcus aureus (MRSA), the primary pathogen responsible for human skin and soft-tissue infections. Antibacterial peptides are known to kill bacteria by rapidly disrupting their membranes and are deemed plausible alternatives to conventional antibiotics. One advantage of their membrane-targeting mode of action is that bacteria are unlikely to develop resistance as changing their cell membrane structure and morphology would likely involve extensive genetic mutations. However, major concerns in using peptides as antibacterial drugs include their instability towards plasma proteases, toxicity towards human cells due to their membrane-targeting mode of action and high manufacturing cost. These concerns can be mitigated by developing peptides as topical agents, by the judicial selection of amino acids and developing very short peptides respectively. In this preliminary report, we reveal a linear, non-hemolytic tetrapeptide with rapid bactericidal activity against MRSA developed from a structure-activity relationship study based on the antimicrobial hexapeptide WRWRWR-NH2. Our finding opens promising avenues for the development of ultra-short antibacterials to treat multidrug-resistant MRSA skin and soft tissue infections.

  11. Structure-activity relationship of Au-ZrO2 catalyst on formation of hydroxyl groups and its influence on CO oxidation

    Energy Technology Data Exchange (ETDEWEB)

    Karwacki, Christopher J [US Army Aberdeen Proving Ground; Ganesh, Panchapakesan [ORNL; Kent, P. R. C. [University of Tennessee, Knoxville (UTK); Gordon, Wesley O [ORNL; Peterson, Gregory W [US Army Aberdeen Proving Ground; Niu, Jun Jie [Drexel University; Gogotsi, Yury G. [Drexel University

    2013-01-01

    The effect of changes in morphology and surface hydroxyl species upon thermal treatment of zirconia on the oxidation activity of Au/ZrO2 catalyst was studied. We observed using transmission Fourier transform infrared (FTIR) spectroscopy progressive changes in the presence of monodentate (type I), bidentate (type II) and hydrogen bridged species (type III) for each of the thermally treated (85 to 500 C) supports consisting of bare zirconia and Au/ZrO2 catalysts. Furthermore, structural changes in zirconia were accompanied by an increase in crystal size (7 to 58 nm) and contraction of the supports porosity (SSA 532 to 7 m2 g 1) with increasing thermal treatment. Deposition of gold nanoparticles under similar preparation conditions on different thermally treated zirconia resulted in changes in the mean gold cluster size, ranging from 3.7 to 5.6 nm. Changes in the surface hydroxyl species, support structure and size of the gold centers are important parameters responsible for the observed decrease (>90%) in CO conversion activity for the Au/ZrO2 catalysts. Density functional theory calculations provide evidence of increased CO binding to Au nanoclusters in the presence of surface hydroxyls on zirconia, which increases charge transfer at the perimeter of the gold nanocluster on zirconia support. This further helps in reducing a model CO-oxidation reaction barrier in the presence of surface hydroxyls. This work demonstrates the need to understand the structure activity relationship of both the support and active particles for the design of catalytic materials.

  12. Quantitative structure-activity relationships predicting the antioxidant potency of 17β-estradiol-related polycyclic phenols to inhibit lipid peroxidation.

    Science.gov (United States)

    Prokai, Laszlo; Rivera-Portalatin, Nilka M; Prokai-Tatrai, Katalin

    2013-01-11

    The antioxidant potency of 17β-estradiol and related polycyclic phenols has been well established. This property is an important component of the complex events by which these types of agents are capable to protect neurons against the detrimental consequences of oxidative stress. In order to relate their molecular structure and properties with their capacity to inhibit lipid peroxidation, a marker of oxidative stress, quantitative structure-activity relationship (QSAR) studies were conducted. The inhibition of Fe3+-induced lipid peroxidation in rat brain homogenate, measured through an assay detecting thiobarbituric acid reactive substances for about seventy compounds were correlated with various molecular descriptors. We found that lipophilicity (modeled by the logarithm of the n-octanol/water partition coefficient, logP) was the property that influenced most profoundly the potency of these compounds to inhibit lipid peroxidation in the biological medium studied. Additionally, the important contribution of the bond dissociation enthalpy of the phenolic O-H group, a shape index, the solvent-accessible surface area and the energy required to remove an electron from the highest occupied molecular orbital were also confirmed. Several QSAR equations were validated as potentially useful exploratory tools for identifying or designing novel phenolic antioxidants incorporating the structural backbone of 17β-estradiol to assist therapy development against oxidative stress-associated neurodegeneration.

  13. Quantitative Structure-Activity Relationships Predicting the Antioxidant Potency of 17β-Estradiol-Related Polycyclic Phenols to Inhibit Lipid Peroxidation

    Directory of Open Access Journals (Sweden)

    Katalin Prokai-Tatrai

    2013-01-01

    Full Text Available The antioxidant potency of 17β-estradiol and related polycyclic phenols has been well established. This property is an important component of the complex events by which these types of agents are capable to protect neurons against the detrimental consequences of oxidative stress. In order to relate their molecular structure and properties with their capacity to inhibit lipid peroxidation, a marker of oxidative stress, quantitative structure-activity relationship (QSAR studies were conducted. The inhibition of Fe3+-induced lipid peroxidation in rat brain homogenate, measured through an assay detecting thiobarbituric acid reactive substances for about seventy compounds were correlated with various molecular descriptors. We found that lipophilicity (modeled by the logarithm of the n-octanol/water partition coefficient, logP was the property that influenced most profoundly the potency of these compounds to inhibit lipid peroxidation in the biological medium studied. Additionally, the important contribution of the bond dissociation enthalpy of the phenolic O-H group, a shape index, the solvent-accessible surface area and the energy required to remove an electron from the highest occupied molecular orbital were also confirmed. Several QSAR equations were validated as potentially useful exploratory tools for identifying or designing novel phenolic antioxidants incorporating the structural backbone of 17β-estradiol to assist therapy development against oxidative stress-associated neurodegeneration.

  14. Three-dimensional quantitative structure-activity relationships and docking studies of some structurally diverse flavonoids and design of new aldose reductase inhibitors

    Directory of Open Access Journals (Sweden)

    Utpal Chandra De

    2015-01-01

    Full Text Available Aldose reductase (AR plays an important role in the development of several long-term diabetic complications. Inhibition of AR activities is a strategy for controlling complications arising from chronic diabetes. Several AR inhibitors have been reported in the literature. Flavonoid type compounds are shown to have significant AR inhibition. The objective of this study was to perform a computational work to get an idea about structural insight of flavonoid type compounds for developing as well as for searching new flavonoid based AR inhibitors. The data-set comprising 68 flavones along with their pIC 50 values ranging from 0.44 to 4.59 have been collected from literature. Structure of all the flavonoids were drawn in Chembiodraw Ultra 11.0, converted into corresponding three-dimensional structure, saved as mole file and then imported to maestro project table. Imported ligands were prepared using LigPrep option of maestro 9.6 version. Three-dimensional quantitative structure-activity relationships and docking studies were performed with appropriate options of maestro 9.6 version installed in HP Z820 workstation with CentOS 6.3 (Linux. A model with partial least squares factor 5, standard deviation 0.2482, R 2 = 0.9502 and variance ratio of regression 122 has been found as the best statistical model.

  15. Synthesis and quantitative structure-activity relationship (QSAR) study of novel 4-acyloxypodophyllotoxin derivatives modified in the A and C rings as insecticidal agents.

    Science.gov (United States)

    He, Shuzhen; Shao, Yonghua; Fan, Lingling; Che, Zhiping; Xu, Hui; Zhi, Xiaoyan; Wang, Juanjuan; Yao, Xiaojun; Qu, Huan

    2013-01-23

    In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, we have synthesized three series of novel 4-acyloxy compounds derived from podophyllotoxin modified in the A and C rings, which is isolated as the main secondary metabolite from the roots and rhizomes of Podophyllum hexandrum . Their insecticidal activity was preliminarily evaluated against the pre-third-instar larvae of Mythimna separata in vivo. Compound 9g displayed the best promising insecticidal activity. It revealed that cleavage of the 6,7-methylenedioxy group of podophyllotoxin will lead to a less active compound and that the C-4 position of podophyllotoxin was the important modification location. A quantitative structure-activity relationship (QSAR) model was developed by genetic algorithm combined with multiple linear regression (GA-MLR). For this model, the squared correlation coefficient (R(2)) is 0.914, the leave-one-out cross-validation correlation coefficient (Q(2)(LOO)) is 0.881, and the root-mean-square error (RMSE) is 0.024. Five descriptors, BEHm2, Mor14v, Wap, G1v, and RDF020e, are likely to influence the biological activity of these compounds. Among them, two important ones are BEHm2 and Mor14v. This study will pave the way for further design, structural modification, and development of podophyllotoxin derivatives as insecticidal agents.

  16. Peptide-based inhibitors of the hepatitis C virus NS3 protease: structure-activity relationship at the C-terminal position.

    Science.gov (United States)

    Rancourt, Jean; Cameron, Dale R; Gorys, Vida; Lamarre, Daniel; Poirier, Martin; Thibeault, Diane; Llinàs-Brunet, Montse

    2004-05-06

    The structure-activity relationship at the C-terminal position of peptide-based inhibitors of the hepatitis C virus NS3 protease is presented. The observation that the N-terminal cleavage product (DDIVPC-OH) of a substrate derived from the NS5A/5B cleavage site was a competitive inhibitor of the NS3 protease was previously described. The chemically unstable cysteine residue found at the P1 position of these peptide-based inhibitors could be replaced with a norvaline residue, at the expense of a substantial drop in the enzymatic activity. The fact that an aminocyclopropane carboxylic acid (ACCA) residue at the P1 position of a tetrapeptide such as 1 led to a significant gain in the inhibitory enzymatic activity, as compared to the corresponding norvaline derivative 2, prompted a systematic study of substituent effects on the three-membered ring. We report herein that the incorporation of a vinyl group with the proper configuration onto this small cycle produced inhibitors of the protease with much improved in vitro potency. The vinyl-ACCA is the first reported carboxylic acid containing a P1 residue that produced NS3 protease inhibitors that are significantly more active than inhibitors containing a cysteine at the same position.

  17. Rational design of novel anti-microtubule agent (9-azido-noscapine) from quantitative structure activity relationship (QSAR) evaluation of noscapinoids.

    Science.gov (United States)

    Santoshi, Seneha; Naik, Pradeep K; Joshi, Harish C

    2011-10-01

    An anticough medicine, noscapine [(S)-3-((R)4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyiso-benzofuran-1(3H)-one], was discovered in the authors' laboratory as a novel type of tubulin-binding agent that mitigates polymerization dynamics of microtubule polymers without changing overall subunit-polymer equilibrium. To obtain systematic insight into the relationship between the structural framework of noscapine scaffold and its antitumor activity, the authors synthesized strategic derivatives (including two new ones in this article). The IC(50) values of these analogs vary from 1.2 to 56.0 µM in human acute lymphoblastic leukemia cells (CEM). Geometrical optimization was performed using semiempirical quantum chemical calculations at the 3-21G* level. Structures were in agreement with nuclear magnetic resonance analysis of molecular flexibility in solution and crystal structures. A genetic function approximation algorithm of variable selection was used to generate the quantitative structure activity relationship (QSAR) model. The robustness of the QSAR model (R(2) = 0.942) was analyzed by values of the internal cross-validated regression coefficient (R(2) (LOO) = 0.815) for the training set and determination coefficient (R(2) (test) = 0.817) for the test set. Validation was achieved by rational design of further novel and potent antitumor noscapinoid, 9-azido-noscapine, and reduced 9-azido-noscapine. The experimentally determined value of pIC(50) for both the compounds (5.585 M) turned out to be very close to predicted pIC(50) (5.731 and 5.710 M).

  18. Toxicity Assessment of Atrazine and Related Triazine Compounds in the Microtox Assay, and Computational Modeling for Their Structure-Activity Relationship

    Directory of Open Access Journals (Sweden)

    Jerzy Leszczynski

    2000-10-01

    Full Text Available The triazines are a group of chemically similar herbicides including atrazine, cyanazine, and propazine, primarily used to control broadleaf weeds. About 64 to 80 million lbs of atrazine alone are used each year in the United States, making it one of the two most widely used pesticides in the country. All triazines are somewhat persistent in water and mobile in soil. They are among the most frequently detected pesticides in groundwater. They are considered as possible human carcinogens (Group C based on an increase in mammary gland tumors in female laboratory animals. In this research, we performed the Microtox Assay to investigate the acute toxicity of a significant number of triazines including atrazine, atraton, ametryne, bladex, prometryne, and propazine, and some of their degradation products including atrazine desethyl, atrazine deisopropyl, and didealkyled triazine. Tests were carried out as described by Azur Environmental [1]. The procedure measured the relative acute toxicity of triazines, producing data for the calculation of triazine concentrations effecting 50% reduction in bioluminescence (EC50s. Quantitative structure-activity relationships (QSAR were examined based on the molecular properties obtained from quantum mechanical predictions performed for each compound. Toxicity tests yielded EC50 values of 39.87, 273.20, 226.80, 36.96, 81.86, 82.68, 12.74, 11.80, and 78.50 mg/L for atrazine, propazine, prometryne, atraton, atrazine desethyl, atrazine deisopropyl, didealkylated triazine, ametryne, and bladex, respectively; indicating that ametryne was the most toxic chemical while propazine was the least toxic. QSAR evaluation resulted in a coefficient of determination (r2 of 0.86, indicating a good value of toxicity prediction based on the chemical structures/properties of tested triazines.

  19. Aquatic toxicity structure-activity relationships for the zwitterionic surfactant alkyl dimethyl amine oxide to several aquatic species and a resulting species sensitivity distribution.

    Science.gov (United States)

    Belanger, Scott E; Brill, Jessica L; Rawlings, Jane M; McDonough, Kathleen M; Zoller, Ann C; Wehmeyer, Kenneth R

    2016-12-01

    Amine oxide (AO) is a cationically charged surfactant at environmental pH and has previously been assessed in the OECD (Organization for Economic Cooperation and Development) High Production Volume (HPV) chemicals program. Typical of cationic chemicals, AO is highly aquatically toxic. In this study we vastly improve the knowledge of AO toxicity by developing acute Quantitative Structure Activity Relationships (QSARs) for an alga (Desmodesmus subspicatus), an invertebrate (Daphnia magna) and a fish (Danio rerio) using the appropriate array of OECD Test Guidelines. A chronic toxicity QSAR was also determined for the most sensitive taxon, Desmodesmus. Pure AO spanning the chain lengths of C8 to C16 were tested individually with trace analytical confirmation of exposures in all tests. The QSARs were all of high quality (R(2) 0.92-0.98) with slopes ranging from -0.338 to -0.484. QSARs were then used to normalize toxicity outcomes for a larger, previously published data set used in HPV, European REACH (Registration, Evaluation, and Authorization of Chemicals), and peer reviewed publications. Two additional species, Lemna gibba (macrophyte) and Ankistrodesmus falcatus (alga) were studied in exposures to dodecyl (C12) AO to provide sufficient taxonomic diversity to conduct a Species Sensitivity Distribution (SSD) analysis. The SSD 5th percentile hazardous concentration (HC5) to C12 AO was found to be 0.052mg/L which is similar to an existing AO 28-d, 3-community periphyton community bioassay normalized to C12 AO (No-observed-effect-concentration or NOEC=0.152mg/L). The statistical properties of the SSD was probed suggesting that new studies of additional taxa would be required that were at least 10-fold more sensitive than the most sensitive taxon to move the HC5 lower by a factor of 3. The overall AO hazard assessment suggests a large margin of safety relative to published environmental exposure data.

  20. Molecular recognition of CYP26A1 binding pockets and structure-activity relationship studies for design of potent and selective retinoic acid metabolism blocking agents.

    Science.gov (United States)

    Sun, Bin; Song, Shuai; Hao, Chen-Zhou; Huang, Wan-Xu; Liu, Chun-Chi; Xie, Hong-Lei; Lin, Bin; Cheng, Mao-Sheng; Zhao, Dong-Mei

    2015-03-01

    All-trans-retinoic acid (ATRA), the biologically most active metabolite of vitamin A, plays a major role in the regulation of cellular differentiation and proliferation, and it is also an important pharmacological agent particularly used in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. However, ATRA is very easy to be metabolized into 4-hydroxyl-RA in vivo by CYP26A1, an inducible cytochrome P450 enzyme, eventually into more polar metabolites. Therefore, it is vital to develop specific retinoic acid metabolism blocking agents (RAMBAs) to inhibit the metabolic enzyme CYP26A1 in the treatment of relevant diseases aforementioned. In this study, CYP26A1 and its interactions with retinoic acid-competitive metabolism blocking agents were investigated by a combined ligand- and structure-based approach. First, since the crystal structure of CYP26A1 protein has not been determined, we constructed the 3D structure of CYP26A1 using homology modeling. In order to achieve a deeper insight into the mode of action of RAMBAs in the active site, the molecular superimposition model and the common feature pharmacophore model were constructed, and molecular docking was performed. The molecular superimposition model is composed of three features: the main chain groups, side chain groups, and azole groups. The common feature pharmacophore model consists of five chemical features: four hydrophobic groups and one hydrogen acceptor (HHHHA). The results of molecular docking show that the characteristic groups of RAMBAs were mapped into three different active pockets, respectively. A structure-activity relationship (SAR) was obtained by a combination of the molecular superimposition and docking results with the pharmacophore model. This study gives more insight into the interaction model inside the CYP26A1 active site and provides guidance for the design of more potent and possibly more selective RAMBAs.

  1. Support vector regression-guided unravelling: antioxidant capacity and quantitative structure-activity relationship predict reduction and promotion effects of flavonoids on acrylamide formation

    Science.gov (United States)

    Huang, Mengmeng; Wei, Yan; Wang, Jun; Zhang, Yu

    2016-09-01

    We used the support vector regression (SVR) approach to predict and unravel reduction/promotion effect of characteristic flavonoids on the acrylamide formation under a low-moisture Maillard reaction system. Results demonstrated the reduction/promotion effects by flavonoids at addition levels of 1-10000 μmol/L. The maximal inhibition rates (51.7%, 68.8% and 26.1%) and promote rates (57.7%, 178.8% and 27.5%) caused by flavones, flavonols and isoflavones were observed at addition levels of 100 μmol/L and 10000 μmol/L, respectively. The reduction/promotion effects were closely related to the change of trolox equivalent antioxidant capacity (ΔTEAC) and well predicted by triple ΔTEAC measurements via SVR models (R: 0.633-0.900). Flavonols exhibit stronger effects on the acrylamide formation than flavones and isoflavones as well as their O-glycosides derivatives, which may be attributed to the number and position of phenolic and 3-enolic hydroxyls. The reduction/promotion effects were well predicted by using optimized quantitative structure-activity relationship (QSAR) descriptors and SVR models (R: 0.926-0.994). Compared to artificial neural network and multi-linear regression models, SVR models exhibited better fitting performance for both TEAC-dependent and QSAR descriptor-dependent predicting work. These observations demonstrated that the SVR models are competent for predicting our understanding on the future use of natural antioxidants for decreasing the acrylamide formation.

  2. Optimization of pyrrolamides as mycobacterial GyrB ATPase inhibitors: structure-activity relationship and in vivo efficacy in a mouse model of tuberculosis.

    Science.gov (United States)

    P, Shahul Hameed; Solapure, Suresh; Mukherjee, Kakoli; Nandi, Vrinda; Waterson, David; Shandil, Radha; Balganesh, Meenakshi; Sambandamurthy, Vasan K; Raichurkar, Anand Kumar; Deshpande, Abhijeet; Ghosh, Anirban; Awasthy, Disha; Shanbhag, Gajanan; Sheikh, Gulebahar; McMiken, Helen; Puttur, Jayashree; Reddy, Jitendar; Werngren, Jim; Read, Jon; Kumar, Mahesh; R, Manjunatha; Chinnapattu, Murugan; Madhavapeddi, Prashanti; Manjrekar, Praveena; Basu, Reetobrata; Gaonkar, Sheshagiri; Sharma, Sreevalli; Hoffner, Sven; Humnabadkar, Vaishali; Subbulakshmi, Venkita; Panduga, Vijender

    2014-01-01

    Moxifloxacin has shown excellent activity against drug-sensitive as well as drug-resistant tuberculosis (TB), thus confirming DNA gyrase as a clinically validated target for discovering novel anti-TB agents. We have identified novel inhibitors in the pyrrolamide class which kill Mycobacterium tuberculosis through inhibition of ATPase activity catalyzed by the GyrB domain of DNA gyrase. A homology model of the M. tuberculosis H37Rv GyrB domain was used for deciphering the structure-activity relationship and binding interactions of inhibitors with mycobacterial GyrB enzyme. Proposed binding interactions were later confirmed through cocrystal structure studies with the Mycobacterium smegmatis GyrB ATPase domain. The most potent compound in this series inhibited supercoiling activity of DNA gyrase with a 50% inhibitory concentration (IC50) of <5 nM, an MIC of 0.03 μg/ml against M. tuberculosis H37Rv, and an MIC90 of <0.25 μg/ml against 99 drug-resistant clinical isolates of M. tuberculosis. The frequency of isolating spontaneous resistant mutants was ∼10(-6) to 10(-8), and the point mutation mapped to the M. tuberculosis GyrB domain (Ser208 Ala), thus confirming its mode of action. The best compound tested for in vivo efficacy in the mouse model showed a 1.1-log reduction in lung CFU in the acute model and a 0.7-log reduction in the chronic model. This class of GyrB inhibitors could be developed as novel anti-TB agents.

  3. Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function

    Energy Technology Data Exchange (ETDEWEB)

    Schormann, N.; Senkovich, O.; Walker, K.; Wright, D.L.; Anderson, A.C.; Rosowsky, A.; Ananthan, S.; Shinkre, B.; Velu, S.; Chattopadhyay, D. (UAB); (Connecticut); (Southern Research); (DFCI)

    2009-07-10

    We have employed a structure-based three-dimensional quantitative structure-activity relationship (3D-QSAR) approach to predict the biochemical activity for inhibitors of T. cruzi dihydrofolate reductase-thymidylate synthase (DHFR-TS). Crystal structures of complexes of the enzyme with eight different inhibitors of the DHFR activity together with the structure in the substrate-free state (DHFR domain) were used to validate and refine docking poses of ligands that constitute likely active conformations. Structural information from these complexes formed the basis for the structure-based alignment used as input for the QSAR study. Contrary to indirect ligand-based approaches the strategy described here employs a direct receptor-based approach. The goal is to generate a library of selective lead inhibitors for further development as antiparasitic agents. 3D-QSAR models were obtained for T. cruzi DHFR-TS (30 inhibitors in learning set) and human DHFR (36 inhibitors in learning set) that show a very good agreement between experimental and predicted enzyme inhibition data. For crossvalidation of the QSAR model(s), we have used the 10% leave-one-out method. The derived 3D-QSAR models were tested against a few selected compounds (a small test set of six inhibitors for each enzyme) with known activity, which were not part of the learning set, and the quality of prediction of the initial 3D-QSAR models demonstrated that such studies are feasible. Further refinement of the models through integration of additional activity data and optimization of reliable docking poses is expected to lead to an improved predictive ability.

  4. Optimization and structure-activity relationships of a series of potent inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase as novel antimicrobial agents.

    Science.gov (United States)

    Kumar, Nag S; Amandoron, Emily A; Cherkasov, Artem; Finlay, B Brett; Gong, Huansheng; Jackson, Linda; Kaur, Sukhbir; Lian, Tian; Moreau, Anne; Labrière, Christophe; Reiner, Neil E; See, Raymond H; Strynadka, Natalie C; Thorson, Lisa; Wong, Edwin W Y; Worrall, Liam; Zoraghi, Roya; Young, Robert N

    2012-12-15

    A novel series of hydrazones were synthesized and evaluated as inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). PK has been identified as one of the most highly connected 'hub proteins' in MRSA. PK has been shown to be critical for bacterial survival which makes it a potential target for development of novel antibiotics and the high degree of connectivity implies it should be very sensitive to mutations and thus less able to develop resistance. PK is not unique to bacteria and thus a critical requirement for such a PK inhibitor would be that it does not inhibit the homologous human enzyme(s) at therapeutic concentrations. Several MRSA PK inhibitors (including 8d) were identified using in silico screening combined with enzyme assays and were found to be selective for bacterial enzyme compared to four human PK isoforms (M1, M2, R and L). However these lead compounds did not show significant inhibitory activity for MRSA growth presumably due to poor bacterial cell penetration. Structure-activity relationship (SAR) studies were carried out on 8d and led us to discover more potent compounds with enzyme inhibiting activities in the low nanomolar range and some were found to effectively inhibit bacteria growth in culture with minimum inhibitory concentrations (MIC) as low as 1 μg/mL. These inhibitors bind in two elongated flat clefts found at the minor interfaces in the homo-tetrameric enzyme complex and the observed SAR is in keeping with the size and electronic constraints of these binding sites. Access to the corresponding sites in the human enzyme is blocked.

  5. Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure-activity relationships with Trypanosoma brucei GSK-3

    Energy Technology Data Exchange (ETDEWEB)

    Ojo, Kayode K; Arakaki, Tracy L; Napuli, Alberto J; Inampudi, Krishna K; Keyloun, Katelyn R; Zhang, Li; Hol, Wim G.J.; Verlind, Christophe L.M.J.; Merritt, Ethan A; Van Voorhis, Wesley C [UWASH

    2012-04-24

    Glycogen synthase kinase-3 (GSK-3) is a drug target under intense investigation in pharmaceutical companies and constitutes an attractive piggyback target for eukaryotic pathogens. Two different GSKs are found in trypanosomatids, one about 150 residues shorter than the other. GSK-3 short (GeneDB: Tb927.10.13780) has previously been validated genetically as a drug target in Trypanosoma brucei by RNAi induced growth retardation; and chemically by correlation between enzyme and in vitro growth inhibition. Here, we report investigation of the equivalent GSK-3 short enzymes of L. major (LmjF18.0270) and L. infantum (LinJ18_V3.0270, identical in amino acid sequences to LdonGSK-3 short) and a crystal structure of LmajGSK-3 short at 2 Å resolution. The inhibitor structure-activity relationships (SARs) of L. major and L. infantum are virtually identical, suggesting that inhibitors could be useful for both cutaneous and visceral leishmaniasis. Leishmania spp. GSK-3 short has different inhibitor SARs than TbruGSK-3 short, which can be explained mostly by two variant residues in the ATP-binding pocket. Indeed, mutating these residues in the ATP-binding site of LmajGSK-3 short to the TbruGSK-3 short equivalents results in a mutant LmajGSK-3 short enzyme with SAR more similar to that of TbruGSK-3 short. The differences between human GSK-3β (HsGSK-3β) and LmajGSK-3 short SAR suggest that compounds which selectively inhibit LmajGSK-3 short may be found.

  6. Structure activity relationship of pyridoxazinone substituted RHS analogs of oxabicyclooctane-linked 1,5-naphthyridinyl novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-6).

    Science.gov (United States)

    Singh, Sheo B; Kaelin, David E; Wu, Jin; Miesel, Lynn; Tan, Christopher M; Meinke, Peter T; Olsen, David B; Lagrutta, Armando; Wei, Changqing; Liao, Yonggang; Peng, Xuanjia; Wang, Xiu; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Yajima, Masanobu; Shibue, Taku; Shibata, Takeshi; Ohata, Kohei; Nishimura, Akinori; Fukuda, Yasumichi

    2015-09-01

    Oxabicyclooctane linked 1,5-naphthyridinyl-pyridoxazinones are novel broad-spectrum bacterial topoisomerase inhibitors (NBTIs) targeting bacterial DNA gyrase and topoisomerase IV at a site different than quinolones. Due to lack of cross-resistance to known antibiotics they present excellent opportunity to combat drug-resistant bacteria. A structure activity relationship of the pyridoxazinone moiety is described in this Letter. Chemical synthesis and activities of NBTIs with substitutions at C-3, C-4 and C-7 of the pyridoxazinone moiety with halogens, alkyl groups and methoxy group has been described. In addition, substitutions of the linker NH proton and its transformation into amide analogs of AM-8085 and AM-8191 have been reported. Fluoro, chloro, and methyl groups at C-3 of the pyridoxazinone moiety retained the potency and spectrum. In addition, a C-3 fluoro analog showed 4-fold better oral efficacy (ED50 3.9 mg/kg) as compared to the parent AM-8085 in a murine bacteremia model of infection of Staphylococcus aureus. Even modest polarity (e.g., methoxy) is not tolerated at C-3 of the pyridoxazinone unit. The basicity and NH group of the linker is important for the activity when CH2 is at the linker position-8. However, amides (with linker position-8 ketone) with a position-7 NH or N-methyl group retained potency and spectrum suggesting that neither basicity nor hydrogen-donor properties of the linker amide NH is essential for the activity. This would suggest likely an altered binding mode of the linker position-7,8 amide containing compounds. The amides showed highly improved hERG (functional IC50 >30 μM) profile.

  7. Structure-activity relationship of alkyl 9-nitrocamptothecin esters%烷基9-氮硝基喜树碱酯类的构效关系

    Institute of Scientific and Technical Information of China (English)

    Zhi-Song CAO; Panayotis PANTAZIS; John MENDOZA; Janet EARLY; Anthony KOZIELSKI; Nick HARRIS; Beppino GIOVANELLA

    2003-01-01

    AIM:To study the structure-activity relationship of alkyl 9-nitrocamptothecin esters. METHODS: Two alkyl9-nitrocamptothecin (9NC) esters 5g and 5h were prepared by esterification reactions of 9NC with valeric anhy-dride and heptanoic anhydride, respectively. Eight 9NC esters 5a-5h were tested for cytotoxicity against humanleukemia cell lines HL-60 and U-937. Flow cytometry analysis was used to identify the cell cycle phase targeted bythe esters and quantify the extent of ester-induced cell death (apoptosis). RESULTS: Esters 5b and 5c demonstratedgreat abilities to inhibit growth of the leukemia cells followed by induction of apoptosis; esters 5a, 5e, and 5ginduced slight perturbations in the cell cycle at high concentrations; and esters 5d, 5f, and 5h were completelyinactive against the cell lines tested. Thus these esters showed the cell anti-proliferative activity in an order of5b≈5c>5a≈5e≈5g>5d≈5f≈5h. Esters 5b, 5c, and 5e were tested in vivo against various human carcinomas in nudemice grown as xenografts. Only 5b and 5c showed a significant antitumor activity. Particularly, ester 5b demon-strated an antitumor activity agalnst a broad spectrum of human carcinomas including breast, lung, colon, pancreas,stomach, ovarian, and melanoma, etc. CONCLUSION: These esters act like prodrugs of their parental9-nitrocamptothecin. High drug doses need to be administered to animals in order to inhibit growth, and induceregression, of human tumor xenografts in nude mice. These compounds may be developed into potent anticancerdrugs due to their low toxicity.

  8. Structure-activity relationships for hydroxylated polychlorinated biphenyls as inhibitors of the sulfation of dehydroepiandrosterone catalyzed by human hydroxysteroid sulfotransferase SULT2A1.

    Science.gov (United States)

    Ekuase, Edugie J; Liu, Yungang; Lehmler, Hans-Joachim; Robertson, Larry W; Duffel, Michael W

    2011-10-17

    Polychlorinated biphenyls (PCBs) are persistent worldwide pollutants that are of concern due to their bioaccumulation and health effects. Metabolic oxidation of PCBs results in the formation of hydroxylated metabolites (OHPCBs). Among their biological effects, OHPCBs have been shown to alter the metabolism of endocrine hormones, including inhibition of mammalian cytosolic sulfotransferases (SULTs) that are responsible for the inactivation of thyroid hormones and phenolic steroids (i.e., hSULT1A1, hSULT1B1, and hSULT1E1). OHPCBs also interact with a human hydroxysteroid sulfotransferase that plays a role in the sulfation of endogenous alcohol-containing steroid hormones and bile acids (i.e., hSULT2A1). The objectives of our current study were to examine the effects of a series of OHPCB congeners on the activity of hSULT2A1 and to develop a three-dimensional quantitative structure-activity relationship (3D-QSAR) model for OHPCBs as inhibitors of the enzyme. A total of 15 OHPCBs were examined, and the sulfation of 1 μM [(3)H] dehydroepiandrosterone (DHEA) was utilized as a model reaction catalyzed by the enzyme. All 15 OHPCBs inhibited the sulfation of DHEA, with IC(50) values ranging from 0.6 μM to 96 μM, and eight of these OHPCBs were also substrates for the enzyme. Comparative molecular field analysis (CoMFA) provided a predictive 3D-QSAR model with a q(2) value of 0.697 and an r(2) value of 0.949. The OHPCBs that had the highest potency as inhibitors of DHEA sulfation were those with a 3, 5-dichloro-4-hydroxy substitution pattern on the biphenyl ring system, and these congeners were also substrates for sulfation catalyzed by hSULT2A1.

  9. Quantitative structure-activity relationship and molecular docking studies of a series of quinazolinonyl analogues as inhibitors of gamma amino butyric acid aminotransferase

    Directory of Open Access Journals (Sweden)

    Usman Abdulfatai

    2017-01-01

    Full Text Available Quantitative structure-activity relationship and molecular docking studies were carried out on a series of quinazolinonyl analogues as anticonvulsant inhibitors. Density Functional Theory (DFT quantum chemical calculation method was used to find the optimized geometry of the anticonvulsants inhibitors. Four types of molecular descriptors were used to derive a quantitative relation between anticonvulsant activity and structural properties. The relevant molecular descriptors were selected by Genetic Function Algorithm (GFA. The best model was validated and found to be statistically significant with squared correlation coefficient (R2 of 0.934, adjusted squared correlation coefficient (R2adj value of 0.912, Leave one out (LOO cross validation coefficient (Q2 value of 0.8695 and the external validation (R2pred of 0.72. Docking analysis revealed that the best compound with the docking scores of −9.5 kcal/mol formed hydrophobic interaction and H-bonding with amino acid residues of gamma aminobutyric acid aminotransferase (GABAAT. This research has shown that the binding affinity generated was found to be better than the commercially sold anti-epilepsy drug, vigabatrin. Also, it was found to be better than the one reported by other researcher. Our QSAR model and molecular docking results corroborate with each other and propose the directions for the design of new inhibitors with better activity against GABAAT. The present study will help in rational drug design and synthesis of new selective GABAAT inhibitors with predetermined affinity and activity and provides valuable information for the understanding of interactions between GABAAT and the anticonvulsants inhibitors.

  10. Structure-activity relationships for interaction with multidrug resistance protein 2 (ABCC2/MRP2): the role of torsion angle for a series of biphenyl-substituted heterocycles.

    Science.gov (United States)

    Lai, Yurong; Xing, Li; Poda, Gennadiy I; Hu, Yiding

    2007-06-01

    Multidrug resistance protein 2 (ABCC2/MRP2) is an ATP-binding cassette transporter involved in the absorption, distribution, and excretion of drugs and xenobiotics. Identifying compounds that are ABCC2/MRP2 substrates and/or inhibitors and understanding their structure-activity relationships (SARs) are important considerations in the selection and optimization of drug candidates. In the present study, the interactions between ABCC2/MRP2 and a series of biphenyl-substituted heterocycles were evaluated using Caco-2 cells and human ABCC2/MRP2 gene-transfected Madin-Darby canine kidney cells. It was observed that ABCC2/MRP2 transport and/or inhibition profile, both in nature and in magnitude, depends strongly on the substitution patterns of the biphenyl system. In particular, different ortho-substitutions cause various degrees of twisting between the two-phenyl rings, resulting in changing interactions between the ligands and ABCC2/MRP2. The compounds with small ortho functions (hydrogen, fluorine, and oxygen) and, thus, the ones displaying the smallest torsion angles of biphenyl (37-45 degrees) are neither substrates nor inhibitors of human ABCC2/MRP2. The transporter interactions increase as the steric bulkiness of the ortho-substitutions increase. When the tested compounds are 2-methyl substituted biphenyls, they exhibit moderate torsion angles (54-65 degrees) and behave as ABCC2/MRP2 substrates as well as mild inhibitors [10-40% compared with 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethyl-sulfanyl)methylsulfanyl] propionic acid (MK571)]. For the 2,2'-dimethyl substituted biphenyls, the torsions are enhanced (78-87 degrees) and so is the inhibition of ABCC2/MRP2. This class of compounds behaves as strong inhibitors of ABCC2/MRP2. These results can be used to define the three-dimensional structural requirements of ABCC2/MRP2 interaction with their substrates and inhibitors, as well as to provide SAR guidance to support drug discovery.

  11. Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling.

    Directory of Open Access Journals (Sweden)

    Megan Leander

    Full Text Available Peptidergic signaling regulates cardiac contractility; thus, identifying molecular switches, ligand-receptor contacts, and antagonists aids in exploring the underlying mechanisms to influence health. Myosuppressin (MS, a decapeptide, diminishes cardiac contractility and gut motility. Myosuppressin binds to G protein-coupled receptor (GPCR proteins. Two Drosophila melanogaster myosuppressin receptors (DrmMS-Rs exist; however, no mechanism underlying MS-R activation is reported. We predicted DrmMS-Rs contained molecular switches that resembled those of Rhodopsin. Additionally, we believed DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 interactions would reflect our structure-activity relationship (SAR data. We hypothesized agonist- and antagonist-receptor contacts would differ from one another depending on activity. Lastly, we expected our study to apply to other species; we tested this hypothesis in Rhodnius prolixus, the Chagas disease vector. Searching DrmMS-Rs for molecular switches led to the discovery of a unique ionic lock and a novel 3-6 lock, as well as transmission and tyrosine toggle switches. The DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 contacts suggested tissue-specific signaling existed, which was in line with our SAR data. We identified R. prolixus (RhpMS-R and discovered it, too, contained the unique myosuppressin ionic lock and novel 3-6 lock found in DrmMS-Rs as well as transmission and tyrosine toggle switches. Further, these motifs were present in red flour beetle, common water flea, honey bee, domestic silkworm, and termite MS-Rs. RhpMS and DrmMS decreased R. prolixus cardiac contractility dose dependently with EC50 values of 140 nM and 50 nM. Based on ligand-receptor contacts, we designed RhpMS analogs believed to be an active core and antagonist; testing on heart confirmed these predictions. The active core docking mimicked RhpMS, however, the antagonist did not. Together, these data were consistent with the unique ionic lock, novel 3-6 lock

  12. Effect of green tea catechins and hydrolyzable tannins on benzo[a]pyrene-induced DNA adducts and structure-activity relationship.

    Science.gov (United States)

    Cao, Pengxiao; Cai, Jian; Gupta, Ramesh C

    2010-04-19

    Green tea catechins and hydrolyzable tannins are gaining increasing attention as chemopreventive agents. However, their mechanism of action is poorly understood. We investigated the effects of four green tea catechins and two hydrolyzable tannins on microsome-induced benzo[a]pyrene (BP)-DNA adducts and the possible structure-activity relationship. BP (1 microM) was incubated with rat liver microsomes and DNA in the presence of the test compound (1-200 microM) or vehicle. The purified DNA was analyzed by (32)P-postlabeling. The inhibitory activity of the catechins was in the following descending order: epigallocatechin gallate (IC(50) = 16 microM) > epicatechin gallate (24 microM) > epigallocatechin (146 microM) > epicatechin (462 microM), suggesting a correlation between the number of adjacent aromatic hydroxyl groups in the molecular structure and their potencies. Tannic acid (IC(50) = 4 microM) and pentagalloglucose (IC(50) = 26 microM) elicited as much DNA adduct inhibitory activity as the catechins or higher presumably due to the presence of more functional hydroxyl groups. To determine if the activity of these compounds was due to direct interaction of phenolic groups with electrophilic metabolite(s) of BP, DNA was incubated with anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (anti-BPDE) (0.5 microM) in the presence of test compounds (200 microM) or vehicle. Significant inhibition of DNA adduct formation was found (tannic acid > pentagalloglucose > epigallocatechin gallate > epicatechin gallate). This notion was confirmed by analysis of the reaction products of anti-BPDE with the catechins and pentagalloglucose by electrospray ionization mass spectrometry and liquid chromatography-mass spectrometry. In conclusion, our data demonstrate that green tea catechins and the hydrolyzable tannins are highly effective in inhibiting BP-DNA adduct formation at least, in part, due to direct interaction of adjacent hydroxyl groups in their structures and that the activity is

  13. Quantitative structure-activity relationship for the ozonation of phenols%酚类物质臭氧氧化降解的定量构效关系

    Institute of Scientific and Technical Information of China (English)

    杨静; 王建兵; 王亚华; 张峰源; 何绪文

    2015-01-01

    Ozonation rates of twenty⁃three phenols were measured. Their Quantitative Structure Activity Relationship ( QSAR ) models were developed by the method of genetic algorithm ( GA ) combining with Partial Least Squares (PLS) and Artificial Neural Networks (ANN), respectively. The degradation rate of phenols can be described by the pseudo⁃first⁃order reaction rate model. The capacity of releasing or taking electron of the substitution group in the ring has obvious effect on the ozonation rate of the phenols. The QSAR model developed by GA⁃PLS is lgk=3.439-0.206lgP ( the logarithm of octanol⁃water partition coefficients)+0.122×pKa(dissociation constant)-0.3464χpc(four order path/cluster molecular connectivity index )-0. 0236qC-( the maximum negative charge of carbon atom). The QSAR model developed by GA⁃ANN model has the descriptors of lgP,4χpc, pKa and α ( molecular average polarizability) . Based on leave⁃one⁃out cross validation, the QSAR model constructed by GA⁃ANN has better robustness than that by GA⁃PLS. The study of QSAR shows that the ozonation rate of phenols has a close relationship with electron cloud distribution and the properties of substitution groups in benzene ring. It also shows that the solvent effect of water obviously influences the ozonation rate of phenols.%测定了23种酚的臭氧氧化速率,分别采用遗传算法( GA)结合偏最小二乘法( PLS)、遗传算法结合人工神经网络( ANN)建立了酚类物质臭氧氧化速率的定量构效关系( QSAR)模型.研究表明,臭氧氧化酚的速率可用伪一级反应速率模型描述,苯环上取代基得失电子的能力对酚的氧化速率影响较大.基于GA⁃PLS算法建立的QSAR模型为lgk=3.439-0.206lgP(辛醇⁃水分配系数对数值)+0.122×pKa(解离常数)+0.3464χpc (四阶路径/簇分子连接性指数)-0.0236qC-(碳原子所带最大负电荷).基于GA⁃ANN算法建

  14. Biases in categorization

    NARCIS (Netherlands)

    Das-Smaal, E.A.

    1990-01-01

    On what grounds can we conclude that an act of categorization is biased? In this chapter, it is contended that in the absence of objective norms of what categories actually are, biases in categorization can only be specified in relation to theoretical understandings of categorization. Therefore, the

  15. Modeling Chemical Interaction Profiles: I. Spectral Data-Activity Relationship and Structure-Activity Relationship Models for Inhibitors and Non-inhibitors of Cytochrome P450 CYP3A4 and CYP2D6 Isozymes

    Directory of Open Access Journals (Sweden)

    Richard D. Beger

    2012-03-01

    Full Text Available An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals—drugs, pesticides, and environmental pollutants—interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP enzymes. In the present work, spectral data-activity relationship (SDAR and structure-activity relationship (SAR approaches were used to develop machine-learning classifiers of inhibitors and non-inhibitors of the CYP3A4 and CYP2D6 isozymes. The models were built upon 602 reference pharmaceutical compounds whose interactions have been deduced from clinical data, and 100 additional chemicals that were used to evaluate model performance in an external validation (EV test. SDAR is an innovative modeling approach that relies on discriminant analysis applied to binned nuclear magnetic resonance (NMR spectral descriptors. In the present work, both 1D 13C and 1D 15N-NMR spectra were used together in a novel implementation of the SDAR technique. It was found that increasing the binning size of 1D 13C-NMR and 15N-NMR spectra caused an increase in the tenfold cross-validation (CV performance in terms of both the rate of correct classification and sensitivity. The results of SDAR modeling were verified using SAR. For SAR modeling, a decision forest approach involving from 6 to 17 Mold2 descriptors in a tree was used. Average rates of correct classification of SDAR and SAR models in a hundred CV tests were 60% and 61% for CYP3A4, and 62% and 70% for CYP2D6, respectively. The rates of correct classification of SDAR and SAR models in the EV test were 73% and 86% for CYP3A4, and 76% and 90% for CYP2D6, respectively. Thus, both SDAR and SAR methods demonstrated a comparable performance in modeling a large set of structurally diverse data. Based on unique NMR structural descriptors, the new SDAR modeling method complements the existing SAR

  16. Modeling chemical interaction profiles: I. Spectral data-activity relationship and structure-activity relationship models for inhibitors and non-inhibitors of cytochrome P450 CYP3A4 and CYP2D6 isozymes.

    Science.gov (United States)

    McPhail, Brooks; Tie, Yunfeng; Hong, Huixiao; Pearce, Bruce A; Schnackenberg, Laura K; Ge, Weigong; Valerio, Luis G; Fuscoe, James C; Tong, Weida; Buzatu, Dan A; Wilkes, Jon G; Fowler, Bruce A; Demchuk, Eugene; Beger, Richard D

    2012-03-15

    An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals--drugs, pesticides, and environmental pollutants--interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP) enzymes. In the present work, spectral data-activity relationship (SDAR) and structure-activity relationship (SAR) approaches were used to develop machine-learning classifiers of inhibitors and non-inhibitors of the CYP3A4 and CYP2D6 isozymes. The models were built upon 602 reference pharmaceutical compounds whose interactions have been deduced from clinical data, and 100 additional chemicals that were used to evaluate model performance in an external validation (EV) test. SDAR is an innovative modeling approach that relies on discriminant analysis applied to binned nuclear magnetic resonance (NMR) spectral descriptors. In the present work, both 1D ¹³C and 1D ¹⁵N-NMR spectra were used together in a novel implementation of the SDAR technique. It was found that increasing the binning size of 1D ¹³C-NMR and ¹⁵N-NMR spectra caused an increase in the tenfold cross-validation (CV) performance in terms of both the rate of correct classification and sensitivity. The results of SDAR modeling were verified using SAR. For SAR modeling, a decision forest approach involving from 6 to 17 Mold2 descriptors in a tree was used. Average rates of correct classification of SDAR and SAR models in a hundred CV tests were 60% and 61% for CYP3A4, and 62% and 70% for CYP2D6, respectively. The rates of correct classification of SDAR and SAR models in the EV test were 73% and 86% for CYP3A4, and 76% and 90% for CYP2D6, respectively. Thus, both SDAR and SAR methods demonstrated a comparable performance in modeling a large set of structurally diverse data. Based on unique NMR structural descriptors, the new SDAR modeling method complements the existing SAR

  17. 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

  18. Semantic home video categorization

    Science.gov (United States)

    Min, Hyun-Seok; Lee, Young Bok; De Neve, Wesley; Ro, Yong Man

    2009-02-01

    Nowadays, a strong need exists for the efficient organization of an increasing amount of home video content. To create an efficient system for the management of home video content, it is required to categorize home video content in a semantic way. So far, a significant amount of research has already been dedicated to semantic video categorization. However, conventional categorization approaches often rely on unnecessary concepts and complicated algorithms that are not suited in the context of home video categorization. To overcome the aforementioned problem, this paper proposes a novel home video categorization method that adopts semantic home photo categorization. To use home photo categorization in the context of home video, we segment video content into shots and extract key frames that represent each shot. To extract the semantics from key frames, we divide each key frame into ten local regions and extract lowlevel features. Based on the low level features extracted for each local region, we can predict the semantics of a particular key frame. To verify the usefulness of the proposed home video categorization method, experiments were performed with home video sequences, labeled by concepts part of the MPEG-7 VCE2 dataset. To verify the usefulness of the proposed home video categorization method, experiments were performed with 70 home video sequences. For the home video sequences used, the proposed system produced a recall of 77% and an accuracy of 78%.

  19. Anti-leishmanial and structure-activity relationship of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl-2-propen-1-one derivatives

    Directory of Open Access Journals (Sweden)

    Asunción Burguete

    2008-12-01

    Full Text Available A series of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl-2-propen-1-one derivatives were synthesized and tested for in vitro leishmanicidal activity against amastigotes of Leishmania amazonensis in axenical cultures and murine infected macrophages. Structure-activity relationships demonstrated the importance of a radical methoxy at position R3', R4' and R5'. (2E-3-(3,4,5-trimethoxy-phenyl-1-(3,6,7-trimethyl-1,4-dioxy-quinoxalin-2-yl-propenone was the most active. Cytotoxicity on macrophages revealed that this product was almost six times more active than toxic.

  20. Categorizing Video Game Audio

    DEFF Research Database (Denmark)

    Westerberg, Andreas Rytter; Schoenau-Fog, Henrik

    2015-01-01

    This paper dives into the subject of video game audio and how it can be categorized in order to deliver a message to a player in the most precise way. A new categorization, with a new take on the diegetic spaces, can be used a tool of inspiration for sound- and game-designers to rethink how they ...

  1. Structure-Activity Relationships of the Antimicrobial Peptide Arasin 1 — And Mode of Action Studies of the N-Terminal, Proline-Rich Region

    Science.gov (United States)

    Paulsen, Victoria S.; Blencke, Hans-Matti; Benincasa, Monica; Haug, Tor; Eksteen, Jacobus J.; Styrvold, Olaf B.; Scocchi, Marco; Stensvåg, Klara

    2013-01-01

    Arasin 1 is a 37 amino acid long proline-rich antimicrobial peptide isolated from the spider crab, Hyas araneus. In this work the active region of arasin 1 was identified through structure-activity studies using different peptide fragments derived from the arasin 1 sequence. The pharmacophore was found to be located in the proline/arginine-rich NH2 terminus of the peptide and the fragment arasin 1(1–23) was almost equally active to the full length peptide. Arasin 1 and its active fragment arasin 1(1–23) were shown to be non-toxic to human red blood cells and arasin 1(1–23) was able to bind chitin, a component of fungal cell walls and the crustacean shell. The mode of action of the fully active N-terminal arasin 1(1–23) was explored through killing kinetic and membrane permeabilization studies. At the minimal inhibitory concentration (MIC), arasin 1(1–23) was not bactericidal and had no membrane disruptive effect. In contrast, at concentrations of 5×MIC and above it was bactericidal and interfered with membrane integrity. We conclude that arasin 1(1–23) has a different mode of action than lytic peptides, like cecropin P1. Thus, we suggest a dual mode of action for arasin 1(1–23) involving membrane disruption at peptide concentrations above MIC, and an alternative mechanism of action, possibly involving intracellular targets, at MIC. PMID:23326415

  2. Structure-activity relationships of the antimicrobial peptide arasin 1 - and mode of action studies of the N-terminal, proline-rich region.

    Directory of Open Access Journals (Sweden)

    Victoria S Paulsen

    Full Text Available Arasin 1 is a 37 amino acid long proline-rich antimicrobial peptide isolated from the spider crab, Hyas araneus. In this work the active region of arasin 1 was identified through structure-activity studies using different peptide fragments derived from the arasin 1 sequence. The pharmacophore was found to be located in the proline/arginine-rich NH(2 terminus of the peptide and the fragment arasin 1(1-23 was almost equally active to the full length peptide. Arasin 1 and its active fragment arasin 1(1-23 were shown to be non-toxic to human red blood cells and arasin 1(1-23 was able to bind chitin, a component of fungal cell walls and the crustacean shell. The mode of action of the fully active N-terminal arasin 1(1-23 was explored through killing kinetic and membrane permeabilization studies. At the minimal inhibitory concentration (MIC, arasin 1(1-23 was not bactericidal and had no membrane disruptive effect. In contrast, at concentrations of 5×MIC and above it was bactericidal and interfered with membrane integrity. We conclude that arasin 1(1-23 has a different mode of action than lytic peptides, like cecropin P1. Thus, we suggest a dual mode of action for arasin 1(1-23 involving membrane disruption at peptide concentrations above MIC, and an alternative mechanism of action, possibly involving intracellular targets, at MIC.

  3. Structure-activity relationships of the antimicrobial peptide arasin 1 - and mode of action studies of the N-terminal, proline-rich region.

    Science.gov (United States)

    Paulsen, Victoria S; Blencke, Hans-Matti; Benincasa, Monica; Haug, Tor; Eksteen, Jacobus J; Styrvold, Olaf B; Scocchi, Marco; Stensvåg, Klara

    2013-01-01

    Arasin 1 is a 37 amino acid long proline-rich antimicrobial peptide isolated from the spider crab, Hyas araneus. In this work the active region of arasin 1 was identified through structure-activity studies using different peptide fragments derived from the arasin 1 sequence. The pharmacophore was found to be located in the proline/arginine-rich NH(2) terminus of the peptide and the fragment arasin 1(1-23) was almost equally active to the full length peptide. Arasin 1 and its active fragment arasin 1(1-23) were shown to be non-toxic to human red blood cells and arasin 1(1-23) was able to bind chitin, a component of fungal cell walls and the crustacean shell. The mode of action of the fully active N-terminal arasin 1(1-23) was explored through killing kinetic and membrane permeabilization studies. At the minimal inhibitory concentration (MIC), arasin 1(1-23) was not bactericidal and had no membrane disruptive effect. In contrast, at concentrations of 5×MIC and above it was bactericidal and interfered with membrane integrity. We conclude that arasin 1(1-23) has a different mode of action than lytic peptides, like cecropin P1. Thus, we suggest a dual mode of action for arasin 1(1-23) involving membrane disruption at peptide concentrations above MIC, and an alternative mechanism of action, possibly involving intracellular targets, at MIC.

  4. Synthesis of octahedral, truncated octahedral, and cubic Rh2Ni nanocrystals and their structure-activity relationship for the decomposition of hydrazine in aqueous solution to hydrogen

    Science.gov (United States)

    Li, Chun; Wang, Tao; Chu, Wei; Wu, Ping; Tong, Dong Ge

    2016-03-01

    We developed a co-reduction method to synthesize octahedral, truncated octahedral, and cubic Rh2Ni nanocrystals. The shape/size distribution, structural characteristics, and composition of the Rh2Ni nanocrystals are investigated, and their possible formation mechanism at high temperatures in margaric acid/1-aminoheptadecane solution in the presence of tetraethylgermanium and borane trimethylamine complexes is proposed. A preliminary probing of the structure-activity dependence of the surface ``clean'' Rh2Ni nanocrystals supported on carbon towards hydrazine (N2H4) in aqueous solution dehydrogenation revealed that the higher the percentage of {111} facets, the higher is the activity and H2 selectivity of the nanocrystals. This result was attributed to the {111} facets not only introducing more basic sites, but also weakening the interaction between the produced adspecies (including H2 and NHx) and surface metal atoms in comparison with those of {100} facets. Furthermore, the as-prepared Rh2Ni nanooctahedra exhibited 100% H2 selectivity and high activity at room temperature for H2 generation via N2H4 decomposition. The activation energy of the Rh2Ni nanooctahedra was 41.6 +/- 1.2 kJ mol-1. The Rh2Ni nanooctahedra were stable catalysts for the hydrolytic dehydrogenation of N2H4, providing 27 723 total turnovers in 30 h. Our work provides a new perspective concerning the possibility of constructing hydrogen-producing systems based on N2H4 and surface ``clean'' Rh2Ni nanocrystal catalysts with defined shapes supported on carbon that possess a competitive performance in comparison with NaBH4 and NH3BH3 hydrogen-producing systems for fuel cell applications.We developed a co-reduction method to synthesize octahedral, truncated octahedral, and cubic Rh2Ni nanocrystals. The shape/size distribution, structural characteristics, and composition of the Rh2Ni nanocrystals are investigated, and their possible formation mechanism at high temperatures in margaric acid/1

  5. Redox biotransformation and delivery of anthracycline anticancer antibiotics: How interpretable structure-activity relationships of lethality using electrophilicity and the London formula for dispersion interaction work.

    Science.gov (United States)

    Pang, Siu-Kwong

    2017-03-30

    Quantum chemical methods and molecular mechanics approaches face a lot of challenges in drug metabolism study because of their either insufficient accuracy or huge computational cost, or lack of clear molecular level pictures for building computational models. Low-cost QSAR methods can often be carried out even though molecular level pictures are not well defined; however, they show difficulty in identifying the mechanisms of drug metabolism and delineating the effects of chemical structures on drug toxicity because a certain amount of molecular descriptors are difficult to be interpreted. In order to make a breakthrough, it was proposed that mechanistically interpretable molecular descriptors were used to correlate with biological activity to establish structure-activity plots. The mechanistically interpretable molecular descriptors used in this study include electrophilicity and the mathematical function in the London formula for dispersion interaction, and they were calculated using quantum chemical methods. The biological activity is the lethality of anthracycline anticancer antibiotics denoted as log LD50, which were obtained by intraperitoneal injection into mice. The results reveal that the plots for electrophilicity, which can be interpreted as redox reactivity of anthracyclines, can describe oxidative degradation for detoxification and reductive bioactivation for toxicity induction. The plots for the dispersion interaction function, which represent the attraction between anthracyclines and biomolecules, can describe efflux from and influx into target cells of toxicity. The plots can also identify three structural scaffolds of anthracyclines that have different metabolic pathways, resulting in their different toxicity behavior. This structure-dependent toxicity behavior revealed in the plots can provide perspectives on design of anthracycline anticancer antibiotics.

  6. Ignorability for categorical data

    DEFF Research Database (Denmark)

    Jaeger, Manfred

    2005-01-01

    We study the problem of ignorability in likelihood-based inference from incomplete categorical data. Two versions of the coarsened at random assumption (car) are distinguished, their compatibility with the parameter distinctness assumption is investigated and several conditions for ignorability...

  7. Quantitative structure-activity relationship of phenoxyphenyl-methanamine compounds with 5HT2A, SERT, and hERG activities.

    Science.gov (United States)

    Mente, Scot; Gallaschun, Randall; Schmidt, Anne; Lebel, Lorrie; Vanase-Frawley, Michelle; Fliri, Anton

    2008-12-01

    QSAR models have been used to evaluate activities for compounds in the phenoxyphenyl-methanamine (PPMA) class of compounds. These models utilize Hammett-type donating-withdrawing substituent values as well as simple parameters to describe substituent size and elucidate the SAR of the 'A' and 'B' rings. Using this methodology, intuitive QSAR relationships were found for the three biological activities with R(2) values of 0.73, 0.45, and 0.58 for 5HT(2A), SerT, and hERG activities.

  8. Structure-Activity Relationship and in Vivo Anti-Tumor Evaluations of Dictyoceratin-A and -C, Hypoxia-Selective Growth Inhibitors from Marine Sponge

    Directory of Open Access Journals (Sweden)

    Yuji Sumii

    2015-12-01

    Full Text Available Oral dictyoceratin-C (1 and A (2, hypoxia-selective growth inhibitors, showed potent in vivo antitumor effects in mice subcutaneously inoculated with sarcoma S180 cells. Structurally modified analogs were synthesized to assess the structure–activity relationship of the natural compounds 1 and 2 isolated from a marine sponge. Biological evaluation of these analogs showed that the exo-olefin and hydroxyl and methyl ester moieties were important for the hypoxia-selective growth inhibitory activities of 1 and 2. Thus far, only substitution of the methyl ester with propargyl amide in 1 was found to be effective for the synthesis of probe molecules for target identification.

  9. Structure-activity relationships of alkylxanthines: alkyl chain elongation at the N1- or N7-position decreases cardiotonic activity in the isolated guinea pig heart.

    Science.gov (United States)

    Sanae, F; Ohmae, S; Kurita, M; Sawanishi, H; Takagi, K; Miyamoto, K

    1995-10-01

    Relationships between the alkyl substitutions (C1-C6) and cardiac inotropic activities of xanthine derivatives were studied in isolated guinea pig heart muscles. Most of the alkylxanthines exhibited positive inotropic activity on the left atrium, which was increased with an elongation of alkyl chain at the N3-position but decreased by substitution of a long alkyl group at the N1- or N7-position of the xanthine skeleton. Although positive inotropic activity in the right ventricular papillary muscle was also increased by longer alkyl groups at the N3-position, the inotropic activity became negative with an increment in alkyl chain length at the N1- or N7-position. The positive inotropic activity of alkylxanthines was correlated with their inhibitory activity on the phosphodiesterase (PDE) III isoenzyme. Adenosine A1 antagonism and PDE IV inhibitory activity were also partly associated with the inotropic activity because H-89, an inhibitor of cyclic AMP-dependent protein kinase, diminished the positive inotropic action and potentiated the negative inotropic action. These results indicate that the positive inotropic activity of alkylxanthines becomes weak with elongation of alkyl chains at the N1- and N7-positions; In particular, xanthines having two long alkyl chains show a negative inotropic activity on the right ventricular papillary muscle, an effect that could not be elucidated from their cyclic AMP-dependent action.

  10. Cyclopaldic acid, seiridin, and sphaeropsidin A as fungal phytotoxins, and larvicidal and biting deterrents against Aedes aegypti (Diptera: Culicidae): structure-activity relationships.

    Science.gov (United States)

    Cimmino, Alessio; Andolfi, Anna; Avolio, Fabiana; Ali, Abbas; Tabanca, Nurhayat; Khan, Ikhlas A; Evidente, Antonio

    2013-07-01

    Aedes aegypti L. is the major vector of the arboviruses responsible for dengue fever, one of the most devastating human diseases. From a preliminary screening of fungal phytotoxins, cyclopaldic acid (1), seiridin (2), sphaeropsidin A (4), and papyracillic acid (5) were evaluated for their biting deterrent and larvicidal activities against Ae. aegypti L. Because compounds 1, 2, 4, and 5 exhibited mosquito biting deterrent activities and 1 and 4 demonstrated larvicidal activities, further structureactivity relationship studies were initiated on these toxins. In biting-deterrence bioassays, 1, 2, 4, and 5, 3,8-didansylhydrazone of cyclopaldic acid, 1F, 5-azidopentanoate of cyclopaldic acid A, 1G, the reduced derivative of cyclopaldic acid, 1 H, isoseiridin (3), 2'-O-acetylseiridin (2A), 2'-oxoseiridin (2C), 6-O-acetylsphaeropsidin A (4A), 8,14-methylensphaeropsidin A methyl ester (4B), and sphaeropsidin B (4C) showed activities higher than the solvent control. Sphaeropsidin B (4C) was the most active compound followed by 2A, while the other compounds were less active. Biting-deterrence activity of compound 4C was statistically similar to DEET. In the larvicidal screening bioassays, only compounds 1 and 4 demonstrated larvicidal activities. Based on LD50 values, compound 4 (LD50 36.8 ppm) was significantly more active than compound 1 (LD50 58.2 ppm). However, the activity of these compounds was significantly lower than permethrin.

  11. 2-(Substituted phenyl-3,4-dihydroisoquinolin-2-iums as Novel Antifungal Lead Compounds: Biological Evaluation and Structure-Activity Relationships

    Directory of Open Access Journals (Sweden)

    Xin-Juan Yang

    2013-08-01

    Full Text Available The title compounds are a class of structurally simple analogues of quaternary benzo[c]phenanthridine alkaloids (QBAs. In order to develop novel QBA-like antifungal drugs, in this study, 24 of the title compounds with various substituents on the N-phenyl ring were evaluated for bioactivity against seven phytopathogenic fungi using the mycelial growth rate method and their SAR discussed. Almost all the compounds showed definite activities in vitro against each of the test fungi at 50 μg/mL and a broad antifungal spectrum. In most cases, the mono-halogenated compounds 2–12 exhibited excellent activities superior to the QBAs sanguinarine and chelerythrine. Compound 8 possessed the strongest activities on each of the fungi with EC50 values of 8.88–19.88 µg/mL and a significant concentration-dependent relationship. The SAR is as follows: the N-phenyl group is a high sensitive structural moiety for the activity and the characteristics and position of substituents intensively influence the activity. Generally, electron-withdrawing substituents remarkably enhance the activity while electron-donating substituents cause a decrease of the activity. In most cases, ortha- and para-halogenated isomers were more active than the corresponding m-halogenated isomers. Thus, the title compounds emerged as promising lead compounds for the development of novel biomimetic antifungal agrochemicals. Compounds 8 and 2 should have great potential as new broad spectrum antifungal agents for plant protection.

  12. Determination of structure-activity relationships between fentanyl analogs and human μ-opioid receptors based on active binding site models

    Institute of Scientific and Technical Information of China (English)

    Ming Liu; Xiaoli Liu; Ping Wan; Qiangsan Wu; Wenxiang Hu

    2011-01-01

    Fentanyl is a potent and widely used clinical narcotic analgesic, as well as a highly selective μ-opioid agonist. The present study established a homologous model of the human μ-opioid receptor; an intercomparison of three types of μ-opioid receptor protein sequence homologous rates was made. The secondary receptor structure was predicted, the model reliability was assessed and verified using the Ramachandran plot and ProTab analysis. The predictive ability of the CoMFA model was further validated using an external test set. Using the Surflex-Dock program, a series of fentanyl analog molecules were docked to the receptor, the calculation results from Biopolymer/SiteID showed that the receptor had a deep binding area situated in the extracellular side of the transmembrane domains (TM) among TM3, TM5, TM6, and TM7. Results suggested that there might be 5 active areas in the receptor. The important residues were Asp147, Tyr148, and Tyr149 in TM3, Trp293, and His297 in TM6, and Trp318, His319, Ile322, and Tyr326 in TM7, which were located at the 5 active areas. The best fentanyl docking orientation position was the piperidine ring, which was nearly perpendicular to the membrane surface in the 7 TM domains. Molecular dynamic simulations were applied to evaluate potential relationships between ligand conformation and fentanyl substitution.

  13. Structure-activity relationship of Cr/Ti-PILC catalysts using a pre-modification method for NO oxidation and their surface species study.

    Science.gov (United States)

    Zhong, Lei; Yu, Yang; Cai, Wei; Geng, Xinxin; Zhong, Qin

    2015-06-14

    The performances of Cr/Ti-PILC catalysts, which were prepared by the pre-modification method, are studied for the selective catalytic oxidation of NO. The aim of this paper is to elucidate the detailed relationship between physical nanoparticle structure and chemical properties. The maximum NO conversion over the Cr-HP(3)/TP catalyst reached 71.4% at 280 °C. The catalysts were characterized by powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), temperature-programmed reduction of H2 (H2-TPR), temperature-programmed desorption (TPD) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) techniques. The characterization results demonstrated that the enhanced catalytic activity was ascribed to several beneficial effects, which were caused by the pre-modification such as the inhibition of crystallite size, improvement of Cr species dispersion and increase of the amount of active sites. XPS and FTIR experiments indicated that two Cr(VI) species, oxidized state CrO3 and chromate species with the anionic form, were generated via pre-modification, which played different roles in the catalytic reaction. In addition, the TPR and TPD results suggest that the increased active sites (Cr(VI) species) were conducive for the preferential adsorption and activation of NO. Furthermore, DRIFTS results revealed that the intermediates, NO(+) and nitrates, interacted quickly to generate gaseous NO2.

  14. Modification of a synthetic LPS-binding domain of anti-lipopolysaccharide factor from shrimp reveals strong structure-activity relationship in their antimicrobial characteristics.

    Science.gov (United States)

    Guo, Shuyue; Li, Shihao; Li, Fuhua; Zhang, Xiaojun; Xiang, Jianhai

    2014-08-01

    Anti-lipopolysaccharide factor (ALF) is a small protein with broad-spectrum antimicrobial activities and certain antiviral property. Its putative lipopolysaccharide (LPS) binding domain was deduced to be important for its activities. However, there is still no report revealing how the structure of the LPS-binding domain affects its biological function until now. In the present study, we designed and synthesized a peptide corresponding to the LPS-binding domain of ALF from the Chinese shrimp (designated as FcALF-LBDc) and its structure-modified isoforms in order to analyze the relationship between its structure and antimicrobial activities. Results showed that FcALF-LBDc exhibited apparent antibacterial activities against both Gram-negative bacteria Escherichia coli and Vibrio anguillarum and Gram-positive bacteria Micrococcus luteus and Micrococcus lysodeikticus with MIC ranges of 32-64, 2-4, 1-2, and 32-64μM, respectively. The disulfide loop and the basic amino acids in the LPS-binding domain (LBD) of ALF played key roles in its antibacterial activities. In addition, FcALF-LBDc could reduce the propagation of white spot syndrome virus (WSSV) in vivo, and its lysine residue is indispensable for its antiviral property. This is the first attempt to testify the effects of the sequence features of the LPS-binding domain on its antimicrobial activities.

  15. Synthesis, structure-activity relationships, and in vitro antibacterial and antifungal activity evaluations of novel pyrazole carboxylic and dicarboxylic acid derivatives.

    Science.gov (United States)

    Mert, Samet; Kasımoğulları, Rahmi; İça, Tuba; Çolak, Ferdağ; Altun, Ahmet; Ok, Salim

    2014-05-06

    A series of pyrazole-3-carboxylic acid and pyrazole-3,4-dicarboxylic acid derivatives were synthesized, the structures were confirmed by their NMR ((1)H and (13)C) and FT-IR spectra, and elemental analyses. The antibacterial and antifungal activities of the compounds against five bacterial and five fungal pathogens were screened using modified agar well diffusion assay. Most of the molecules have inhibitory effects on both standard and clinical Candida albicans strains. However, only the molecules 8, 10, 21, and 22 demonstrate some inhibitory effects on Candida parapsilosis, Candida tropicalis, and Candida glabrata strains. The structure-antifungal activity relationships of the compounds on the C. albicans strains were investigated by electron-conformational method. The pharmacophores and antipharmacophores responsible for the inhibition and non-inhibition of the C. albicans strains were obtained by electronic and geometrical characteristics of the reactive fragments of the molecules. These fragments along with the associated parameters can be used in designing the future more potent antifungal agents. It has been shown that both the positions of electronegative atoms like F and O in the pyrazole substituents and the amount of the associated charges on such atoms are crucial in regulating the strength of antifungal activity for the C. albicans strain.

  16. From Sphingosine Kinase to Dihydroceramide Desaturase: A Structure-Activity Relationship (SAR) Study of the Enzyme Inhibitory and Anticancer Activity of 4-((4-(4-Chlorophenyl)thiazol-2-yl)amino)phenol (SKI-II).

    Science.gov (United States)

    Aurelio, Luigi; Scullino, Carmen V; Pitman, Melissa R; Sexton, Anna; Oliver, Victoria; Davies, Lorena; Rebello, Richard J; Furic, Luc; Creek, Darren J; Pitson, Stuart M; Flynn, Bernard L

    2016-02-11

    The sphingosine kinase (SK) inhibitor, SKI-II, has been employed extensively in biological investigations of the role of SK1 and SK2 in disease and has demonstrated impressive anticancer activity in vitro and in vivo. However, interpretations of results using this pharmacological agent are complicated by several factors: poor SK1/2 selectivity, additional activity as an inducer of SK1-degradation, and off-target effects, including its recently identified capacity to inhibit dihydroceramide desaturase-1 (Des1). In this study, we have delineated the structure-activity relationship (SAR) for these different targets and correlated them to that required for anticancer activity and determined that Des1 inhibition is primarily responsible for the antiproliferative effects of SKI-II and its analogues. In the course of these efforts, a series of novel SK1, SK2, and Des1 inhibitors have been generated, including compounds with significantly greater anticancer activity.

  17. Definitive Metabolite Identification Coupled with Automated Ligand Identification System (ALIS) Technology: A Novel Approach to Uncover Structure-Activity Relationships and Guide Drug Design in a Factor IXa Inhibitor Program.

    Science.gov (United States)

    Zhang, Ting; Liu, Yong; Yang, Xianshu; Martin, Gary E; Yao, Huifang; Shang, Jackie; Bugianesi, Randal M; Ellsworth, Kenneth P; Sonatore, Lisa M; Nizner, Peter; Sherer, Edward C; Hill, Susan E; Knemeyer, Ian W; Geissler, Wayne M; Dandliker, Peter J; Helmy, Roy; Wood, Harold B

    2016-03-10

    A potent and selective Factor IXa (FIXa) inhibitor was subjected to a series of liver microsomal incubations, which generated a number of metabolites. Using automated ligand identification system-affinity selection (ALIS-AS) methodology, metabolites in the incubation mixture were prioritized by their binding affinities to the FIXa protein. Microgram quantities of the metabolites of interest were then isolated through microisolation analytical capabilities, and structurally characterized using MicroCryoProbe heteronuclear 2D NMR techniques. The isolated metabolites recovered from the NMR experiments were then submitted directly to an in vitro FIXa enzymatic assay. The order of the metabolites' binding affinity to the Factor IXa protein from the ALIS assay was completely consistent with the enzymatic assay results. This work showcases an innovative and efficient approach to uncover structure-activity relationships (SARs) and guide drug design via microisolation-structural characterization and ALIS capabilities.

  18. Toward the discovery of novel anti-HIV drugs. Second-generation inhibitors of the cellular ATPase DDX3 with improved anti-HIV activity: synthesis, structure-activity relationship analysis, cytotoxicity studies, and target validation.

    Science.gov (United States)

    Maga, Giovanni; Falchi, Federico; Radi, Marco; Botta, Lorenzo; Casaluce, Gianni; Bernardini, Martina; Irannejad, Hamid; Manetti, Fabrizio; Garbelli, Anna; Samuele, Alberta; Zanoli, Samantha; Esté, José A; Gonzalez, Emmanuel; Zucca, Elisa; Paolucci, Stefania; Baldanti, Fausto; De Rijck, Jan; Debyser, Zeger; Botta, Maurizio

    2011-08-01

    A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD-box RNA helicase DDX3 led to the design and synthesis of second-generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV-1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure-activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti-HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV-1 host cofactors.

  19. Accepting the Invitation to Open Innovation in Malaria Drug Discovery: Synthesis, Biological Evaluation, and Investigation on the Structure-Activity Relationships of Benzo[b]thiophene-2-carboxamides as Antimalarial Agents.

    Science.gov (United States)

    Pieroni, Marco; Azzali, Elisa; Basilico, Nicoletta; Parapini, Silvia; Zolkiewski, Michal; Beato, Claudia; Annunziato, Giannamaria; Bruno, Agostino; Vacondio, Federica; Costantino, Gabriele

    2017-03-09

    Malaria eradication is a global health priority, but current therapies are not always suitable for providing a radical cure. Artemisinin has paved the way for the current malaria treatment, the so-called Artemisinin-based Combination Therapy (ACT). However, with the detection of resistance to ACT, innovative compounds active against multiple parasite species and at multiple life stages are needed. GlaxoSmithKline has recently disclosed the results of a phenotypic screening of an internal library, publishing a collection of 400 antimalarial chemotypes, termed the "Malaria Box". After analysis of the data set, we have carried out a medicinal chemistry campaign in order to define the structure-activity relationships for one of the released compounds, which embodies a benzothiophene-2-carboxamide core. Thirty-five compounds were prepared, and a description of the structural features responsible for the in vitro activity against different strains of P. falciparum, the toxicity, and the metabolic stability is herein reported.

  20. Quantitative structure-activity relationship (QSAR) study of interleukin-1 receptor associated kinase 4 (IRAK-4) inhibitor activity by the genetic algorithm and multiple linear regression (GA-MLR) method.

    Science.gov (United States)

    Pourbasheer, Eslam; Riahi, Siavash; Ganjali, Mohammad Reza; Norouzi, Parviz

    2010-12-01

    A linear quantitative structure-activity relationship (QSAR) model is presented for the modelling and prediction for the interleukin-1 receptor associated kinase 4 (IRAK-4) inhibition activity of amides and imidazo[1,2-α] pyridines. The model was produced using the multiple linear regression (MLR) technique on a database that consisted of 65 recently discovered amides and imidazo[1,2- α] pyridines. Among the different constitutional, topological, geometrical, electrostatic and quantum-chemical descriptors that were considered as inputs to the model, seven variables were selected using the genetic algorithm subset selection method (GA). The accuracy of the proposed MLR model was illustrated using the following evaluation techniques: cross-validation, validation through an external test set, and Y-randomisation. The predictive ability of the model was found to be satisfactory and could be used for designing a similar group of compounds.

  1. Investigating the Quantitative Structure-Activity Relationships for Antibody Recognition of Two Immunoassays for Polycyclic Aromatic Hydrocarbons by Multiple Regression Methods

    Directory of Open Access Journals (Sweden)

    Yan-Feng Zhang

    2012-07-01

    Full Text Available Polycyclic aromatic hydrocarbons (PAHs are ubiquitous contaminants found in the environment. Immunoassays represent useful analytical methods to complement traditional analytical procedures for PAHs. Cross-reactivity (CR is a very useful character to evaluate the extent of cross-reaction of a cross-reactant in immunoreactions and immunoassays. The quantitative relationships between the molecular properties and the CR of PAHs were established by stepwise multiple linear regression, principal component regression and partial least square regression, using the data of two commercial enzyme-linked immunosorbent assay (ELISA kits. The objective is to find the most important molecular properties that affect the CR, and predict the CR by multiple regression methods. The results show that the physicochemical, electronic and topological properties of the PAH molecules have an integrated effect on the CR properties for the two ELISAs, among which molar solubility (Sm and valence molecular connectivity index (3χv are the most important factors. The obtained regression equations for RisC kit are all statistically significant (p < 0.005 and show satisfactory ability for predicting CR values, while equations for RaPID kit are all not significant (p > 0.05 and not suitable for predicting. It is probably because that the RisC immunoassay employs a monoclonal antibody, while the RaPID kit is based on polyclonal antibody. Considering the important effect of solubility on the CR values, cross-reaction potential (CRP is calculated and used as a complement of CR for evaluation of cross-reactions in immunoassays. Only the compounds with both high CR and high CRP can cause intense cross-reactions in immunoassays.

  2. Structure-activity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a class of 5-HT7 receptor agents. 2.

    Science.gov (United States)

    Leopoldo, Marcello; Lacivita, Enza; Contino, Marialessandra; Colabufo, Nicola A; Berardi, Francesco; Perrone, Roberto

    2007-08-23

    Here we report the synthesis of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides 16-29 that were designed to elucidate both structure-affinity and -activity relationships for the 5-HT7 receptor, by targeting the substituent in 2-position of the aryl linked to the piperazine ring. The affinities of 16-29 for 5-HT7, 5-HT1A, 5-HT2A, and D2 receptors were assessed by radioligand binding assays. The intrinsic activities at the 5-HT7 receptor of the most potent compounds were determined. A series of substituents covering a wide range of electronic, steric, and polar properties was evaluated, revealing a key role on 5-HT7 receptor affinity and intrinsic activity. Certain lipophilic substituents (SCH3, CH(CH3)2, N(CH3)2, CH3, Ph) led to high-affinity agonists, whereas OH and NHCH3 substituents switched intrinsic activity toward antagonism. 4-[2-(1-Methylethyl)phenyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (19), 4-(2-diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (21), and 4-(2-dimethylaminophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (22) were identified as potent 5-HT7 receptor agonists (Ki = 0.13-1.1 nM, EC50 = 0.90-1.77 microM), showing selectivity over 5-HT1A, 5-HT2A, and D2 receptors.

  3. Biocatalytic oxidation of phenolic compounds by bovine methemoglobin in the presence of H{sub 2}O{sub 2}: Quantitative structure-activity relationships

    Energy Technology Data Exchange (ETDEWEB)

    Perez-Prior, M. Teresa, E-mail: MariaTeresa.Perez@uclm.es [Department of Physical Chemistry, University of Castilla-La Mancha, Campus Universitario, E-02071 Albacete (Spain); Gomez-Bombarelli, Rafael, E-mail: R.GomezBombarelli@hw.ac.uk [Department of Physics, Heriot-Watt University, David Brewster Building G.45, Edinburgh (United Kingdom); Gonzalez-Sanchez, M. Isabel, E-mail: MIsabel.Gonzalez@uclm.es [Department of Physical Chemistry, University of Castilla-La Mancha, Campus Universitario, E-02071 Albacete (Spain); Valero, Edelmira, E-mail: Edelmira.Valero@uclm.es [Department of Physical Chemistry, University of Castilla-La Mancha, Campus Universitario, E-02071 Albacete (Spain)

    2012-11-30

    Highlights: Black-Right-Pointing-Pointer The kinetics of metHb-catalyzed oxidation of a group of phenols were analyzed. Black-Right-Pointing-Pointer Unusual kinetic behaviour was observed for the phenols here tested. Black-Right-Pointing-Pointer QSAR equations for a number of physicochemical parameters were established. Black-Right-Pointing-Pointer A relationship between the peroxidase and catalase activities of metHb was found. Black-Right-Pointing-Pointer Bovine metHb might represent a good economical alternative to other peroxidases. - Abstract: In the present work, 13 p-substituted phenols with different functional groups have been systematically evaluated as metHb substrates by means of HPLC analysis. Non-hyperbolic kinetics were observed and Hill coefficients in the 0.37-1.00 range were obtained. The catalytic constants and the Hill coefficients were found to be quantitatively correlated with two independent variables: the energy level of the highest-occupied molecular orbital (E{sub HOMO}), which describes the intrinsic redox activity of the substrates and the pK{sub a}-values, which are related to substrate ionization. Oxygen evolution in the presence of each phenol derivative was also measured, and good correlation between peroxidase-like and catalase-like activities of the protein was observed. It is also shown that bovine metHb, although less active than other peroxidases, may represent a good alternative from an economical point of view for phenol removal processes. The equations here obtained may serve as a basis to further explore the potential use of metHb-mediated reactions in the treatment of phenols in wastewaters and to predict which phenol will be removed most efficiently under this treatment with satisfactory reliability.

  4. Learning Context for Text Categorization

    CERN Document Server

    Haribhakta, Y V

    2011-01-01

    This paper describes our work which is based on discovering context for text document categorization. The document categorization approach is derived from a combination of a learning paradigm known as relation extraction and an technique known as context discovery. We demonstrate the effectiveness of our categorization approach using reuters 21578 dataset and synthetic real world data from sports domain. Our experimental results indicate that the learned context greatly improves the categorization performance as compared to traditional categorization approaches.

  5. Structure Activity Relationship of Brevenal Hydrazide Derivatives

    Directory of Open Access Journals (Sweden)

    Allan Goodman

    2014-03-01

    Full Text Available Brevenal is a ladder frame polyether produced by the dinoflagellate Karenia brevis. This organism is also responsible for the production of the neurotoxic compounds known as brevetoxins. Ingestion or inhalation of the brevetoxins leads to adverse effects such as gastrointestinal maladies and bronchoconstriction. Brevenal shows antagonistic behavior to the brevetoxins and shows beneficial attributes when administered alone. For example, in an asthmatic sheep model, brevenal has been shown to increase tracheal mucosal velocity, an attribute which has led to its development as a potential treatment for Cystic Fibrosis. The mechanism of action of brevenal is poorly understood and the exact binding site has not been elucidated. In an attempt to further understand the mechanism of action of brevenal and potentially develop a second generation drug candidate, a series of brevenal derivatives were prepared through modification of the aldehyde moiety. These derivatives include aliphatic, aromatic and heteroaromatic hydrazide derivatives. The brevenal derivatives were tested using in vitro synaptosome binding assays to determine the ability of the compounds to displace brevetoxin and brevenal from their native receptors. A sheep inhalation model was used to determine if instillation of the brevenal derivatives resulted in bronchoconstriction. Only small modifications were tolerated, with larger moieties leading to loss of affinity for the brevenal receptor and bronchoconstriction in the sheep model.

  6. The structure activity relationship of discodermolide analogues.

    Science.gov (United States)

    Shaw, Simon J

    2008-03-01

    The marine polyketide discodermolide is a member of a class of natural products that stabilize microtubules. Many analogues have been synthesized suggesting that few changes can be made to the internal carbon backbone. Both ends of the molecule, however, can be modified. The majority of analogues have been generated via modification of the lactone region. This suggests that significant simplifications can be made in this region provided that the lactone moiety is maintained.

  7. Quantitative structure- activity/property relationship approach and its application in food research%定量结构—活性/性质相关研究及其在食品领域的应用

    Institute of Scientific and Technical Information of China (English)

    周如金; 张庆; 邱松山; 黄敏

    2011-01-01

    定量结构—活性/性质相关研究(Quantitative Structure -Activity/Property Relationship,QSAR/ QSPR)描述化合物分子结构与生物活性及理化性质之间的因果关系.通过QSAR/QSPR研究,不仅可以发现并确定对化合物活性/性质起关键影响作用的化合物结构因素,有效指导高效、低毒新型化合物的合成,而且可以对进入环境的数以千万计化学物质的毒性和生物效应的评价提供一个经济、简便的方法.本文概述了定量结构—活性/性质相关原理及其研究方法,从食品抗氧化剂、食品防腐剂、食品风味成分和食品成分安全性评价等方面阐述了定量结构—活性/性质相关研究在食品领域的应用现状,并从推动食品向绿色、安全、营养方向发展,展望了QSAR/QSPR在食品成分的毒性及其致毒机理研究、食用化学品安全性评价以及有效指导新型、低毒食用化学品的开发等方面在食品领域的应用前景.%Quantitative structure - activity/ property relationship (QSAR/QSRR) is an important method to analysis the correlation between structure of molecules and its bioactivity or physical - chemical property. QSAR/QSPR can not only determine the structure which is a key role in activity, property and synthesis of organic compound, but it also provides an economic and brief evaluation of toxicity and the biological effect of hundreds of thousands of compounds in the environment. The principle and research methods of QSAR/QSPR as well as its application situation in the field of food research, such as food antioxidants, food preservatives, food flavoring and food safety evaluation were reviewed. Then the possible applications in food toxicity and its mechanisms, food chemicals safety evaluation, as well as guiding the development of new, safe food chemicals were also prospected.

  8. A Quantitative Structure-Activity Relationship and Molecular Modeling Study on a Series of Heteroaryl- and Heterocyclyl-Substituted Imidazo[1,2-a]Pyridine Derivatives Acting as Acid Pump Antagonists

    Directory of Open Access Journals (Sweden)

    Neeraj Agarwal

    2013-01-01

    Full Text Available A quantitative structure-activity relationship (QSAR and molecular docking study has been performed on a series of heteroaryl- and heterocyclyl-substituted imidazo[1,2-a]pyridine derivatives acting as acid pump antagonists in order to have a better understanding of the mechanism of H+/K+-ATPase inhibition. The QSAR study shows a significant correlation of activity with Global Topological Charge Indices (GTCI of the compounds and the hydrophobic constant of some substituents, indicating that the charge transfer within the molecule and the hydrophobic property of some substituents will be the controlling factor of the activity of these compounds and that there can be dispersion interaction between the molecules and the receptor, where some substituents may have hydrophobic interaction, too. Based on this correlation some new compounds with higher potency have been predicted and their docking study has been performed to see if they can have better interaction with the receptor. The ADME properties of these predicted compounds have also been reported that follow Lipinski’s rule of five.

  9. Structure-activity relationship studies of chalcone leading to 3-hydroxy-4,3',4',5'-tetramethoxychalcone and its analogues as potent nuclear factor kappaB inhibitors and their anticancer activities.

    Science.gov (United States)

    Srinivasan, Balasubramanian; Johnson, Thomas E; Lad, Rahul; Xing, Chengguo

    2009-11-26

    Chalcone is a privileged structure, demonstrating promising anti-inflammatory and anticancer activities. One potential mechanism is to suppress nuclear factor kappa B (NF-kappaB) activation. The structures of chalcone-based NF-kappaB inhibitors vary significantly that there is minimum information about their structure-activity relationships (SAR). This study aims to establish SAR of chalcone-based compounds to NF-kappaB inhibition, to explore the feasibility of developing simple chalcone-based potent NF-kappaB inhibitors, and to evaluate their anticancer activities. Three series of chalcones were synthesized in one to three steps with the key step being aldol condensation. These candidates demonstrated a wide range of NF-kappaB inhibitory activities, some of low micromolar potency, establishing that structural complexity is not required for NF-kappaB inhibition. Lead compounds also demonstrate potent cytotoxicity against lung cancer cells. Their cytotoxicities correlate moderately well with their NF-kappaB inhibitory activities, suggesting that suppressing NF-kappaB activation is likely responsible for at least some of the cytotoxicities. One lead compound effectively inhibits lung tumor growth with no signs of adverse side effects.

  10. Influence of the structural diversity of data sets on the statistical quality of three-dimensional quantitative structure-activity relationship (3D-QSAR) models: predicting the estrogenic activity of xenoestrogens.

    Science.gov (United States)

    Yu, Seong Jae; Keenan, Susan M; Tong, Weida; Welsh, William J

    2002-10-01

    Federal legislation has resulted in the two-tiered in vitro and in vivo screening of some 80 000 structurally diverse chemicals for possible endocrine disrupting effects. To maximize efficiency and minimize expense, prioritization of these chemicals with respect to their estrogenic disrupting potential prior to this time-consuming and labor-intensive screening process is essential. Computer-based quantitative structure-activity relationship (QSAR) models, such as those obtained using comparative molecular field analysis (CoMFA), have been demonstrated as useful for risk assessment in this application. In general, however, CoMFA models to predict estrogenicity have been developed from data sets with limited structural diversity. In this study, we constructed CoMFA models based on biological data for a structurally diverse set of compounds spanning eight chemical families. We also compared two standard alignment schemes employed in CoMFA, namely, atom-fit and flexible field-fit, with respect to the predictive capabilities of their respective models for structurally diverse data sets. The present analysis indicates that flexible field-fit alignment fares better than atom-fit alignment as the structural diversity of the data set increases. Values of log(RP), where RP = relative potency, predicted by the final flexible field-fit CoMFA models are in good agreement with the corresponding experimental values. These models should be effective for predicting the endocrine disrupting potential of existing chemicals as well as prospective and newly prepared chemicals before they enter the environment.

  11. Antitumor agents 286. Design, synthesis, and structure-activity relationships of 3'R,4'R-disubstituted-2',2'-dimethyldihydropyrano[2,3-f]chromone (DSP) analogues as potent chemosensitizers to overcome multidrug resistance.

    Science.gov (United States)

    Zhou, Ting; Shi, Qian; Bastow, Kenneth F; Lee, Kuo-Hsiung

    2010-12-23

    In this study, various 3'R,4'R-disubstituted-2',2'-dimethydihydropyrano[2,3-f]chromone (DSP) derivatives were discovered as potent chemosensitizers in the treatment of multidrug resistant cancer cells. Twenty-four DSP analogues (5-28) were synthesized and evaluated against a multidrug resistant (MDR) cell line (KB-Vin) with and without vincristine (VCR). All DSP analogues exhibited low intrinsic cytotoxicity. However, in combination treatment, most DSPs reversed resistance to VCR and lowered the GI₅₀ value of VCR by 12-349-fold. At a concentration of 1 μg/mL, three compounds, 11, 14, and 21, fully reversed resistance to VCR in KB-Vin cancer cells, a 2-fold increase compared to verapamil, a first-generation chemosensitizer. Detailed structure-activity relationship (SAR) conclusions were established based on 3' and 4' substitutions. Moreover, a preliminary mechanism study indicated that the chemosensitizing activity of DSP analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells.

  12. Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2',2'-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents.

    Science.gov (United States)

    Zhou, Ting; Shi, Qian; Chen, Chin-Ho; Zhu, Hao; Huang, Li; Ho, Phong; Lee, Kuo-Hsiung

    2010-09-15

    In a continued study, 23 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5-27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 microM to 0.14 microM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 microM; TI 310 and 200, respectively), and were twofold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 microM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5-10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates.

  13. Structure activity relationship of C-2 ether substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-5).

    Science.gov (United States)

    Singh, Sheo B; Kaelin, David E; Meinke, Peter T; Wu, Jin; Miesel, Lynn; Tan, Christopher M; Olsen, David B; Lagrutta, Armando; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Takeuchi, Tomoko; Takano, Hisashi; Ohata, Kohei; Kurasaki, Haruaki; Nishimura, Akinori; Shibata, Takeshi; Fukuda, Yasumichi

    2015-09-01

    Oxabicyclooctane linked novel bacterial topoisomerase inhibitors (NBTIs) are new class of recently reported broad-spectrum antibacterial agents. They target bacterial DNA gyrase and topoisomerase IV and bind to a site different than quinolones. They show no cross-resistance to known antibiotics and provide opportunity to combat drug-resistant bacteria. A structure activity relationship of the C-2 substituted ether analogs of 1,5-naphthyridine oxabicyclooctane-linked NBTIs are described. Synthesis and antibacterial activities of a total of 63 analogs have been summarized representing alkyl, cyclo alkyl, fluoro alkyl, hydroxy alkyl, amino alkyl, and carboxyl alkyl ethers. All compounds were tested against three key strains each of Gram-positive and Gram-negative bacteria as well as for hERG binding activities. Many key compounds were also tested for the functional hERG activity. Six compounds were evaluated for efficacy in a murine bacteremia model of Staphylococcus aureus infection. Significant tolerance for the ether substitution (including polar groups such as amino and carboxyl) at C-2 was observed for S. aureus activity however the same was not true for Enterococcus faecium and Gram-negative strains. Reduced clogD generally showed reduced hERG activity and improved in vivo efficacy but was generally associated with decreased overall potency. One of the best compounds was hydroxy propyl ether (16), which mainly retained the potency, spectrum and in vivo efficacy of AM8085 associated with the decreased hERG activity and improved physical property.

  14. Research of Web Pages Categorization

    Institute of Scientific and Technical Information of China (English)

    Zhongda Lin; Kun Deng; Yanfen Hong

    2006-01-01

    In this paper, we discuss several issues related to automated classification of web pages, especially text classification of web pages. We analyze features selection and categorization algorithms of web pages and give some suggestions for web pages categorization.

  15. Categorical database generalization in GIS

    NARCIS (Netherlands)

    Liu, Y.

    2002-01-01

    Key words: Categorical database, categorical database generalization, Formal data structure, constraints, transformation unit, classification hierarchy, aggregation hierarchy, semantic similarity, data model, Delaunay triangulation

  16. Nonlinear quantitative structure-activity relationship of the aromatic carboxylic acid repellents%芳香羧酸衍生物驱避剂的非线性定量构效关系

    Institute of Scientific and Technical Information of China (English)

    李颗; 李向辉; 徐西林; 袁哲明

    2014-01-01

    [Aim] Repellent can protect the users by driving target pests away from them.It is important to establish a nonlinear quantitative structure-activity relationship (QSAR) model with high precision and strong interpretation for designing and synthesizing the new insect repellent with higher bioactivity.[Methods] Based on the repellent activities of 37 aromatic carboxylic acid derivatives against the housefly,Musca domestica,the initial descriptors were generated with stoichiometry software PCLIENT,and then the binary matrix shuffling filter (BMSF) and worst descriptor elimination multi-round method (WDEM) were successively used to conduct the nonlinear selection for initial descriptors.With the reserved descriptors,a support vector regression (SVR) model was established for the QSAR analysis of these 37 repellent derivatives.The influence of reserved descriptors on repellent activities was further analyzed with SVR interpretation system.[Results] The F-score of SVR model with original 1 542 descriptors was 1.2.However,it was 184.6 with the retained six descriptors after feature screening,indicating that feature screening has important effects on the precision of QSAR model.The importance of six molecular descriptors was as follows:p4BCD > GATS7v > T(O..O) > JGI8 > SssO > nArCONR2.[Conclusion] The nonlinear relationship between reserved descriptors and the repellent activities of aromatic carboxylic acid derivatives against M.domestica was remarkable,and a high-performance SVR-QSAR model for repellent derivatives was constructed.%[目的]驱避剂可使害虫不敢接近受用者从而保护受用者免遭其害.建立高精度、可解释性强的非线性定量构效关系(quantitative structure-activity relationship,QSAR)模型对设计合成新的高效昆虫驱避剂有重要意义.[方法]基于37个芳香羧酸类化合物对家蝇Musca domestica的驱避活性,以量子化学计算软件PCLIENT获取每一化合物初始描述符,以二元矩阵重

  17. Working Memory Capacity and Categorization: Individual Differences and Modeling

    Science.gov (United States)

    Lewandowsky, Stephan

    2011-01-01

    Working memory is crucial for many higher-level cognitive functions, ranging from mental arithmetic to reasoning and problem solving. Likewise, the ability to learn and categorize novel concepts forms an indispensable part of human cognition. However, very little is known about the relationship between working memory and categorization, and…

  18. Categorical Tensor Network States

    Directory of Open Access Journals (Sweden)

    Jacob D. Biamonte

    2011-12-01

    Full Text Available We examine the use of string diagrams and the mathematics of category theory in the description of quantum states by tensor networks. This approach lead to a unification of several ideas, as well as several results and methods that have not previously appeared in either side of the literature. Our approach enabled the development of a tensor network framework allowing a solution to the quantum decomposition problem which has several appealing features. Specifically, given an n-body quantum state |ψ〉, we present a new and general method to factor |ψ〉 into a tensor network of clearly defined building blocks. We use the solution to expose a previously unknown and large class of quantum states which we prove can be sampled efficiently and exactly. This general framework of categorical tensor network states, where a combination of generic and algebraically defined tensors appear, enhances the theory of tensor network states.

  19. Categorization of Radioxenon

    Energy Technology Data Exchange (ETDEWEB)

    Keller, Paul E.

    2012-04-26

    This report summarizes a study into some false positive issues in the use of radioxenon as a method to verify a clandestine nuclear weapons explosion. False positives arise due to similarities between the radioxenon signature generated in medical isotope production and that generated in a nuclear weapon explosion. This report also discusses how to categorize the radioxenon by levels of urgency for manual analysis and interpretation and recommends applying machine learning and time series analysis techniques in the automation of radioxenon characterization. The literature indicates that medical isotope production is a major contributor to atmospheric radioxenon and is the main source of confusion in determining the source of radioxenon. While radioxenon emissions from nuclear power plants can be distinguished from that from nuclear weapon explosions, emissions from medical isotope production generate signatures similar to certain nuclide ratios found in nuclear weapons explosions. Different techniques for analyzing nuclide concentrations and ratios as well as including other sensing modalities via sensor fusion are discussed.

  20. New platinum(II) complexes conjugated at position 7α of 17β-acetyl-testosterone as new combi-molecules against prostate cancer: design, synthesis, structure-activity relationships and biological evaluation.

    Science.gov (United States)

    Fortin, Sébastien; Brasseur, Kevin; Morin, Nathalie; Asselin, Éric; Bérubé, Gervais

    2013-10-01

    Prostate cancer is a major public health problem worldwide and, more specifically, new treatments for hormone-refractory cancers are highly sought by several research groups. Although platinum(II)-based chemotherapy and other strategies grow in interest to treat castration-resistant prostate cancer (CRPC), they still exhibit modest activity on CRPC and overall patient survival. In this study, we designed and prepared new combi-molecules using 17β-acetyl-testosterone and amino acid platinum(II) complexes linked at the position 7α to target and to improve the antiproliferative activity of platinum(II)-based chemotherapy on prostate cancer cells. Twelve chemical intermediates and six new combi-molecules were prepared and characterized. Structure-activity relationships studies show that the platinum complex moiety is essential for an optimal cytocidal activity. Moreover, stereochemistry of the amino acid involved in the platinum complexes had only minor effects on the antiproliferative activity whereas pyridinyl (10a and b) and thiazolyl (10f) complexes exhibited the highest cytocidal activities that are significantly superior to that of cisplatin used as control on human prostate adenocarcinoma LNCaP (AR+), PC3 (AR-) and DU145 (AR-). Compounds 10a, b and f arrested the cell cycle progression in S-phase and induced double strand breaks as confirmed by the phosphorylation of histone H2AX into γH2AX. Compounds 10a and f showed 33 and 30% inhibition, respectively of the growth of HT-1080 tumors grafted onto chick chorioallantoic membranes. Finally, compounds 10a and 10f exhibited low toxicity on the chick embryos (18 and 21% of death, respectively), indicating that these new combi-molecules might be a promising new class of anticancer agents for prostate cancer.

  1. New N- and O-arylpiperazinylalkyl pyrimidines and 2-methylquinazolines derivatives as 5-HT7 and 5-HT1A receptor ligands: Synthesis, structure-activity relationships, and molecular modeling studies.

    Science.gov (United States)

    Intagliata, Sebastiano; Modica, Maria N; Pittalà, Valeria; Salerno, Loredana; Siracusa, Maria A; Cagnotto, Alfredo; Salmona, Mario; Kurczab, Rafał; Romeo, Giuseppe

    2017-02-01

    Based on our earlier studies of structure activity relationships on 4-substituted piperazine derivatives, in this work we synthesized a novel set of long-chain arylpiperazines with the purpose of elucidating if some structural modifications in the terminal fragment could affect the binding affinity for the 5-HT7 and 5-HT1A receptors. In this new series, the quinazolinone system of the previous derivatives was replaced by a 6-phenylpyrimidine or a 2-methylquinazoline, which were used as versatile building blocks for the preparation of new compounds. A 4-arylpiperazine moiety through a five methylene chain was anchored at the nitrogen or oxygen atom of the heterocyclic scaffolds. The substituents borne by the piperazine nucleus were phenyl, phenylmethyl, 3- or 4-chlorophenyl, and 2-ethoxyphenyl. Binding tests, performed on human cloned 5-HT7 and 5-HT1A receptors, showed that, among the newly synthesized derivatives, 4-[5-[4-(2-ethoxyphenyl)-1-piperazinyl]pentoxy]-6-phenyl-pyrimidine (13) and 3-[5-[4-(2-ethoxyphenyl)-1-piperazinyl]pentyl]-2-methyl-4(3H)-quinazolinone (20) displayed the best affinity values, Ki=23.5 and 8.42nM for 5-HT7 and 6.96 and 2.99nM for 5-HT1A receptors, respectively. Moreover, the functional properties for both compounds were further evaluated using the cAMP assay. Finally, a molecular modeling study has been performed for 5-HT7 and 5-HT1A receptor homology models to investigate the binding mode of N- and O-alkylated pyrimidinones/pyrimidines 4-13, 2-methylquinazolinones/quinazolines 17-22, and previously reported 2- and 3-substituted quinazolinones 23-30.

  2. 辨识药物定量构效关系的模糊神经网络方法研究%Studies on Quantitative Structure-activity Relationships of Benzodiazepines Using Fuzzy Neural Networks

    Institute of Scientific and Technical Information of China (English)

    刘平; 程翼宇

    2000-01-01

    提出一种基于遗传算法的新型模糊神经网络方法,用于计算Benzodiazepines(BZs)类药物的定量构效关系.这类模糊神经网络综合了神经网络、遗传算法与模糊逻辑的各自优势,具有优良的定量构效关系辨识能力,其学习速度较快,不易陷入局部最小区域;网络知识以模糊语言变量的形式加以表达,不仅易于理解,而且能有效地利用已有的专家经验.一旦通过学习获得规律后,不仅能很好地预测化合物的活性,还能对后续的药物分子设计提供有益的理论指导.%In this paper, a new fuzzy neural network based on genetic algorithms is proposed for quantitative structure-activity relationship (QSAR) studies of benzodiazepines. The method based on GA+FL +-NN allows supervised learning of fuzzy rules from significant examples and is affected unsusceptibly by the problem of local extremes. The network′ s knowledge base has a linguistic representation. This makes it easy for pharmaceutical chemists to understand and interpret. It is possible to introduce current knowledge acquired by researchers simply by adding one or more fuzzy rules to the network′ s knowledge base. Once the fuzzy knowledge base extracted from examples, it can predict the pharmacological activity of compounds at a high precision. The obtained fuzzy rules can also provide useful guidelines for synthesizing new compounds with a high pharmacological activity.

  3. Discovery, characterization and structure-activity relationships of an inhibitor of inward rectifier potassium (Kir channels with preference for Kir2.3, Kir3.X and Kir7.1

    Directory of Open Access Journals (Sweden)

    Jerod S Denton

    2011-11-01

    Full Text Available The inward rectifier family of potassium (Kir channels is comprised of at least 16 family members exhibiting broad and often overlapping cellular, tissue or organ distributions. The discovery of disease-causing mutations in humans and experiments on knockout mice has underscored the importance of Kir channels in physiology and in some cases raised questions about their potential as drug targets. However, the paucity of potent and selective small-molecule modulators targeting specific family members has with few exceptions mired efforts to understand their physiology and assess their therapeutic potential. A growing body of evidence suggests that GIRK (G protein-regulated inward rectifier K channels of the Kir3.X subfamily may represent novel targets for the treatment of atrial fibrillation. In an effort to expand the molecular pharmacology of GIRK, we performed a thallium (Tl+ flux-based high-throughput screen (HTS of a Kir1.1 inhibitor library for modulators of GIRK. One compound, termed VU573, exhibited 10-fold selectivity for GIRK over Kir1.1 (IC50 = 1.9 M and 19 M, respectively and was therefore selected for further study. In electrophysiological experiments performed on Xenopus laevis oocytes and mammalian cells, VU573 inhibited Kir3.1/3.2 (neuronal GIRK and Kir3.1/3.4 (cardiac GIRK channels with equal potency and preferentially inhibited GIRK, Kir2.3 and Kir7.1 over Kir1.1 and Kir2.1. Tl+ flux assays were established for Kir2.3 and the M125R pore mutant of Kir7.1 to support medicinal chemistry efforts to develop more potent and selective analogs for these channels. The structure-activity relationships of VU573 revealed few analogs with improved potency, however two compounds retained most of their activity toward GIRK and Kir2.3 and lost activity toward Kir7.1. We anticipate that the VU573 series will be useful for exploring the physiology and structure-function relationships of these Kir channels.

  4. Motivation to control prejudice predicts categorization of multiracials.

    Science.gov (United States)

    Chen, Jacqueline M; Moons, Wesley G; Gaither, Sarah E; Hamilton, David L; Sherman, Jeffrey W

    2014-05-01

    Multiracial individuals often do not easily fit into existing racial categories. Perceivers may adopt a novel racial category to categorize multiracial targets, but their willingness to do so may depend on their motivations. We investigated whether perceivers' levels of internal motivation to control prejudice (IMS) and external motivation to control prejudice (EMS) predicted their likelihood of categorizing Black-White multiracial faces as Multiracial. Across four studies, IMS positively predicted perceivers' categorizations of multiracial faces as Multiracial. The association between IMS and Multiracial categorizations was strongest when faces were most racially ambiguous. Explicit prejudice, implicit prejudice, and interracial contact were ruled out as explanations for the relationship between IMS and Multiracial categorizations. EMS may be negatively associated with the use of the Multiracial category. Therefore, perceivers' motivations to control prejudice have important implications for racial categorization processes.

  5. Analysis of Ordinal Categorical Data

    CERN Document Server

    Agresti, Alan

    2012-01-01

    Statistical science's first coordinated manual of methods for analyzing ordered categorical data, now fully revised and updated, continues to present applications and case studies in fields as diverse as sociology, public health, ecology, marketing, and pharmacy. Analysis of Ordinal Categorical Data, Second Edition provides an introduction to basic descriptive and inferential methods for categorical data, giving thorough coverage of new developments and recent methods. Special emphasis is placed on interpretation and application of methods including an integrated comparison of the available st

  6. Mechanism and the structure-activity relationship of imperatorin and isoimperatorin with DNA%欧前胡素及同分异构体与DNA的作用机理及构效关系研究

    Institute of Scientific and Technical Information of China (English)

    张爱平; 郝娟; 黄茜; 高晓亚; 文雯

    2012-01-01

    在模拟人体生理条件下,采用紫外光谱法、荧光光谱法、DNA热变性及黏度法研究欧前胡素及同分异构体异欧前胡素与DNA的作用机制,并探讨其构效关系.紫外光谱表明,加入DNA后,欧前胡素和异欧前胡素的紫外光谱均呈现减色效应;荧光光谱显示,随着欧前胡素或异欧前胡素浓度的增大,DNA-BR的荧光被猝灭,表明欧前胡素和异欧前胡素对BR与DNA的结合存在竞争性抑制;盐效应、DNA热变性温度、黏度法等实验进一步证明欧前胡素和异欧前胡素与DNA的作用模式均为嵌插与静电混合作用模式.研究表明,欧前胡素和异欧前胡素均与DNA发生作用,且欧前胡素与DNA作用强于异欧前胡素.%The mechanism and the structure-activity relationship of imperatorin and its isomer isoimperatorin with DNA were studied by ultraviolet spectroscopy,fluorescence spectroscopy,salt effect,DNA denaturation temperature and DNA viscosity measurement under the simulative human physiological condition. The results of ultraviolet spectroscopy showed that in the presence of DNA, the hypo-chromisity was observed on the absorption spectra of imperatorin and isoimperatorin. The fluorescence of BR-DNA was quenched with addition of imperatorin or isoimperatorin, which indicated that a strong competition for DNA binding between imperatorin and isoimperatorin with BR existed. The results of DNA denaturation temperature test and salt effects demonstrated that the binding mode of imperatorin and isoimperatorin with DNA were the intercalation and electrostatic interaction. Both imperatorin and isoimperatorin interacted with DNA and the interaction strength of imperatorin and DNA was stronger than that of isoimperatorin.

  7. Pharmacophore modeling of nilotinib as an inhibitor of ATP-binding cassette drug transporters and BCR-ABL kinase using a three-dimensional quantitative structure-activity relationship approach.

    Science.gov (United States)

    Shukla, Suneet; Kouanda, Abdul; Silverton, Latoya; Talele, Tanaji T; Ambudkar, Suresh V

    2014-07-07

    Nilotinib (Tasigna) is a tyrosine kinase inhibitor approved by the FDA to treat chronic phase chronic myeloid leukemia patients. It is also a transport substrate of the ATP-binding cassette (ABC) drug efflux transporters ABCB1 (P-glycoprotein, P-gp) and ABCG2 (BCRP), which may have an effect on the pharmacokinetics and toxicity of this drug. The goal of this study was to identify pharmacophoric features of nilotinib in order to potentially develop specific inhibitors of BCR-ABL kinase with minimal interactions with ABC drug transporters. Three-dimensional pharmacophore modeling and quantitative structure-activity relationship (QSAR) studies were carried out on a series of nilotinib analogues to identify chemical features that contribute to inhibitory activity of nilotinib against BCR-ABL kinase activity, P-gp, and ABCG2. Twenty-five derivatives of nilotinib were synthesized and were then tested to measure their activity to inhibit BCR-ABL kinase and to inhibit the function of ABC drug transporters. A set of in vitro experiments including kinase activity and cell-based transport assays and photolabeling of P-gp and ABCG2 with a transport substrate, [(125)I]-iodoarylazido-prazosin (IAAP), were carried out in isolated membranes to evaluate the potency of the derivatives to inhibit the function of ABC drug transporters and BCR-ABL kinase. Sixteen, fourteen, and ten compounds were selected as QSAR data sets, respectively, to generate PHASE v3.1 pharmacophore models for BCR-ABL kinase, ABCG2, and P-gp inhibitors. The IC50 values of these derivatives against P-gp, ABCG2, or BCR-ABL kinase were used to generate pharmacophore features required for optimal interactions with these targets. A seven-point pharmacophore (AADDRRR) for BCR-ABL kinase inhibitory activity, a six-point pharmacophore (ADHRRR) for ABCG2 inhibitory activity, and a seven-point pharmacophore (AADDRRR) for P-gp inhibitory activity were generated. The derived models clearly demonstrate high predictive power

  8. Students' Categorizations of Organic Compounds

    Science.gov (United States)

    Domin, Daniel S.; Al-Masum, Mohammad; Mensah, John

    2008-01-01

    Categorization is a fundamental psychological ability necessary for problem solving and many other higher-level cognitive tasks. In organic chemistry, students must establish groupings of different chemical compounds in order not only to solve problems, but also to understand course content. Classic models of categorization emphasize similarity as…

  9. Observing behaviour categorically

    DEFF Research Database (Denmark)

    Nielsen, Mogens; Cheng, Allan

    1995-01-01

    In an attempt to understand the relationships and differences between the extensive amount of research within the field of bisimulation equivalences, Joyal, Nielsen, and Winskel recently proposed an abstract category-theoretic definition of bisimulation. They identify spans of morphisms satisfyin......, in fact, captures not only bisimulations but many other behavioural equivalences. We also briefly present presheaf models as an abstract model of computation....

  10. Haptic categorical perception of shape.

    Science.gov (United States)

    Gaißert, Nina; Waterkamp, Steffen; Fleming, Roland W; Bülthoff, Isabelle

    2012-01-01

    Categorization and categorical perception have been extensively studied, mainly in vision and audition. In the haptic domain, our ability to categorize objects has also been demonstrated in earlier studies. Here we show for the first time that categorical perception also occurs in haptic shape perception. We generated a continuum of complex shapes by morphing between two volumetric objects. Using similarity ratings and multidimensional scaling we ensured that participants could haptically discriminate all objects equally. Next, we performed classification and discrimination tasks. After a short training with the two shape categories, both tasks revealed categorical perception effects. Training leads to between-category expansion resulting in higher discriminability of physical differences between pairs of stimuli straddling the category boundary. Thus, even brief training can alter haptic representations of shape. This suggests that the weights attached to various haptic shape features can be changed dynamically in response to top-down information about class membership.

  11. Anti-HIV-1 activity and structure-activity relationship of pyranocoumarin analogs%吡喃香豆素衍生物对HIV-1的抑制作用及其构效关系

    Institute of Scientific and Technical Information of China (English)

    董飚; 马涛; 章天; 周春梅; 刘刚; 王琳; 陶佩珍; 张兴权

    2011-01-01

    The purpose of this study is to find out anti-HIV-1 reverse transcriptase (RT)/protease (PR) activity and inhibition of virus replication in cell cultures of novel coumarin analogs and determine their structure-activity relationship. Coumarin derivatives have been demonstrated to inhibit the activity of HIV-1 RT/PR in cell free system. It also shows inhibition effects to HIV-1 replication in cell culture. Based on the Chinese traditional pharmacological characteristics and protein three dimension computer aided design, analogs of tetracyclic dipyranocoumarin were synthesized from natural leading compounds. We studied the relationship of antiviral effects and chemical structures via HIV-1 PR/RT enzyme models and cell culture model system. Seven compounds were designed and tested. Several compounds showed anti-HIV-1 activity in varying degrees, especially V0201 showed much higher anti-HIV-1 activity with 3.56 and 0.78 μmol·L-1 of IC50 against HIV-1 PR/RT and 0.036 μmol·L-1 against HIV-1 replication in PBMC cultures. V0201 with a novel structure may be a new leading compound. These new compounds are valuable for development of new anti-HIV drugs in the future.%研究香豆素衍生物对人类免疫缺陷病毒l型逆转录酶(HIV-1 RT)、蛋白酶(HIV-1 PR)和细胞内复制的抑制作用及其构效关系.不同香豆素衍生物具有抑制HIV-1 RT、HIV-1 PR活性,且在细胞内显示出抑制HIV-1复制的作用已见报道.本课题根据国内传统药学的特点,考察以天然产物为先导化合物、结合HIV-1蛋白酶三维结构计算机辅助药物设计、合成的四环双吡喃香豆素及其类似物.以HIV-1 RT及HIV-1 PR以及细胞内病毒复制为靶点,利用酶学模型和细胞培养模型进行药物筛选及其构效关系研究,设计合成的7个化合物的药效学实验结果显示.部分化合物显示了不同程度的抗HIV-1活性.其中V0201作用最强,它对HIV-1 PR和HIV-1 RT的IC50分别为3.56和0.78 μmol·L-1;

  12. Quantitative Structure-Activity Relationship and Virtual Screening ofω-Conotoxins%ω-芋螺毒素的定量构效关系与虚拟筛选

    Institute of Scientific and Technical Information of China (English)

    丁俊杰; 丁晓琴; 李大禹; 潘里; 陈冀胜

    2014-01-01

    ω-芋螺毒素属于海洋生物活性多肽,由24-31个氨基酸残基组成.特异性作用于电压敏感的钙离子通道(VGCCs),能够直接开发成药物或作为先导化合物进行新药开发.本文应用新型氨基酸残基结构描述符c-scales和遗传偏最小二乘算法,对ω-芋螺毒素进行定量构效关系(QSAR)研究,并设计、构建了容量为2244个化合物的N-型和P/Q-型VGCC拮抗剂虚拟组合多肽库,然后分别采用QSAR模型预测和相似性搜索方法对组合多肽库进行了虚拟筛选.研究结果表明,建立的N-型和P/Q-型VGCC拮抗剂QSAR模型均具有较好的预测能力,交叉验证相关系数(CV-r2)均大于0.89.主成分分析和聚类分析结果表明,虚拟组合多肽库中化合物具有较好的结构多样性和差异性.通过虚拟筛选,得到了具有高预测活性的6个N-型和19个P/Q-型钙离子通道拮抗剂,为进一步的合成和活性评价奠定了理论基础.同时,本文建立的多肽QSAR预测模型和虚拟筛选策略,为其它多肽类化合物的定量构效关系研究和虚拟筛选提供了参考.%ω-Conotoxins are active peptides composed of 24-31 amino acids isolated from venomous marine predatory cone snails.ω-Conotoxins selectively inhibit voltage-gated calcium channels (VGCCs) in nociceptors, so are considered attractive molecules for drug design. In this study, based on a set of new amino acid structure descriptors (c-scales) and genetic partial least squares (G/PLS) regression method, quantitative structure-activity relationship (QSAR) models for N-type and P/Q-type VGCC antagonists ofω-conotoxins were developed. Two virtual polypeptide libraries with 2244 peptides were designed and established for N-type and P/Q-type VGCC antagonists, respectively. Then, based on the biological activities predicted from the constructed QSAR models and chemical similarities to the probes MVIIA and MVIIC, the polypeptide libraries were virtual y

  13. Categorical Pairs and the Indicative Shift

    CERN Document Server

    Kauffman, Louis H

    2011-01-01

    This paper introduces the notion of a categorical pair, a pair of categories (C,C') such that every morphism in C is an object in C'. Categorical pairs are precursors to 2-categories. Arrows in C' can express relationships among the morphisms of C. In particular we show that by using a model of the linguistic process of naming, we can ensure that every morphism in C has an indirect self-reference of the form a -----> Fa where this arrow occurs in the category C'. This result is shown to generalize and clarify known fixed point theorems in logic and categories, and is applied to Goedel's Incompleteness Theorem, the Cantor Diagonal Process and the Lawvere Fixed Point Theorem. In particular we show that the indirect self-reference that is central to Goedel's Theorem is an instance of a general pattern here called the indicative shift.

  14. Humanizing Outgroups Through Multiple Categorization

    Science.gov (United States)

    Prati, Francesca; Crisp, Richard J.; Meleady, Rose; Rubini, Monica

    2016-01-01

    In three studies, we examined the impact of multiple categorization on intergroup dehumanization. Study 1 showed that perceiving members of a rival university along multiple versus simple categorical dimensions enhanced the tendency to attribute human traits to this group. Study 2 showed that multiple versus simple categorization of immigrants increased the attribution of uniquely human emotions to them. This effect was explained by the sequential mediation of increased individuation of the outgroup and reduced outgroup threat. Study 3 replicated this sequential mediation model and introduced a novel way of measuring humanization in which participants generated attributes corresponding to the outgroup in a free response format. Participants generated more uniquely human traits in the multiple versus simple categorization conditions. We discuss the theoretical implications of these findings and consider their role in informing and improving efforts to ameliorate contemporary forms of intergroup discrimination. PMID:26984016

  15. Study on Reaction Mechanism and Their Structure -Activity Relationship between Three Amphetamines and Lysozyme%3种苯丙胺类药物与溶菌酶的作用机制及构效关系研究

    Institute of Scientific and Technical Information of China (English)

    张爱平; 黄茜; 郝娟; 文雯; 高晓亚

    2011-01-01

    在模拟人体生理条件下,采用荧光光谱法研究了3种不同结构的苯丙胺类药物(麻黄碱、伪麻黄碱和甲基麻黄碱)与溶菌酶之间的相互作用,计算了其结合常数、结合位点数和热力学参数,并探讨了3种药物对溶菌酶构象的影响.研究发现,三者可对溶菌酶内源性荧光产生强烈的猝灭作用,其猝灭过程均为静态猝灭.麻黄碱、伪麻黄碱和甲基麻黄碱与溶菌酶均形成1 :1复合物,在308 K温度下的结合常数K分别为5.11×103、4.04×103、2.80×103 L·mol-1,结合距离r分别为0.241、0.350、0.422 nm,与溶菌酶结合的焓变分别为-123、-126、-52.1 kJ·mol-1,熵变分别为-329、-339、-103 J·mol-1·K-1.研究结果表明,苯丙胺类药物的构型和取代基对其与溶菌酶的相互作用有重要影响,3种苯丙胺类药物与溶菌酶的作用力顺序为麻黄碱>伪麻黄碱>甲基麻黄碱,体系的主要作用力为氢键和范德华力.溶菌酶与3种药物的同步荧光光谱也表明,溶菌酶的构象在作用前后基本不变.%The interactions of lysozyme with ephedrine, pseudoephedrine and methylephedrine, as well as their structure -activity relationship were investigated by fluorescence spectrometry under simulative physiological conditions. The binding constant, the number of binding sites and the thermodynamic parameters were calculated and the effects of ephedrine, pseudoephedrine and methylephedrine on the conformation of lysozyme were studied. The results showed that the endogenous fluorescence of lysozyme was significantly quenched by ephedrine, pseudoephedrine and methylephedrine.The mechanism of fluorescence quenching was static quenching. The 1 : 1 complex was formed between each amphetamine and lysozyme. The binding constants K of ephedrine, pseudoephedrine and methylephedrine were 5.11×103, 4. 04 × 103 , 2. 80 × 103 L · mol-1, respectively. According to the theory of Fǒster dipole -dipole non-radiation energy

  16. Analysis of structure -activity relationship and toxicity of organophosphorus pesticide to plankton%有机磷农药的构效关系及其对浮游生物的毒性效应

    Institute of Scientific and Technical Information of China (English)

    王娜; 刘莉莉; 孙凯峰; 段舜山

    2012-01-01

    The toxicity of six organophosphorus pesticides to Scenedesmus quadricanda and Moina macrocopa were studied using quantitative structure-activity relationship theory (QSAR) and acute toxicity tests. According to QSAR theory, the toxicity of organophosphorus pesticides was determined mainly by the electropositivity of center phosphorus atom, which was influenced by the type. More specifically, toxicity was reduced as P=O bonds were replaced by P=S bonds. Replacement of hydroxy(-OH) by methoxy(-CH3O), ethoxy(-CH3CH2O) and propoxy(-CH3CH2CH2O), however, successively increased. Toxicity of organophosphorus pesticides was also reduced as P-0 bond were replaced by P-C bond. Specifically, the toxicity of chlorpyrifos and phoxim was higher than four other organophosphorus pesticides as -CH3CH2O replaced -CH3O, dichlorovos and trichlorphon were more toxic than glyphosate compared, while dichlorovos was more toxic than trichlorphon. Glyphosate-isophopylammianium was the least toxic compound as hydroxy(-OH) replaced by glycine isophopylammianium. Toxicity tests demonstrated that the EC-50 concentrations of chlorpyrifos, phoxim, trichlorphon, dichlorovos, dimethoate, glyphosate-isophopylammianium on S. Quadricanda were 6.34, 6.62, 59.53, 82.12, 141.37 and 7.25 mg·L-1 at 96 h, respectively, while, those on M. Macrocopa were 0.20, 0.12, 0.28, 0.17, 1.12 and 5.03 mg·L-1 at 48 h, respectively. The toxicity of the six organophosphorus pesticide to M. Macrocopa was generally ordered as -OH>=O >-O. In conclusion, this study demonstrates the utility of using QSAR with acute toxicity test for the assessment of ecological risks of organophosphorus pesticides to plankton.%以定量构效关系理论和实验室内急性毒性试验相结合研究了六种有机磷农药对四尾栅藻(S.quadricanda)和多刺裸腹溞(Moina macrocopa)的生态毒性.有机磷农药的毒性取决于磷原子的电正性,各取代基种类和构象对电荷分布作用显著.根据构效关系原理,磷

  17. Unstructured Documents Categorization: A Study

    Directory of Open Access Journals (Sweden)

    Debnath Bhattacharyya

    2008-12-01

    Full Text Available The main purpose of communication is to transfer information from onecorner to another of the world. The information is basically stored in forms of documents or files created on the basis of requirements. So, the randomness of creation and storage makes them unstructured in nature. As a consequence, data retrieval and modification become hard nut to crack. The data, that is required frequently, should maintain certain pattern. Otherwise, problems like retrievingerroneous data or anomalies in modification or time consumption in retrieving process may hike. As every problem has its own solution, these unstructured documents have also given the solution named unstructured document categorization. That means, the collected unstructured documents will be categorized based on some given constraints. This paper is a review which deals with different techniques like text and data mining, genetic algorithm, lexicalchaining, binarization method to reach the fulfillment of desired unstructured document categorization appeared in the literature.

  18. 36 CFR 907.10 - Categorical exclusion.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Categorical exclusion. 907.10... ENVIRONMENTAL QUALITY § 907.10 Categorical exclusion. The CEQ Regulations provide for the categorical exclusion... administrative operations of the Corporation. (b) List of categorical exclusions. Categories of...

  19. Atomic toposes and countable categoricity

    OpenAIRE

    Caramello, Olivia

    2008-01-01

    We give a model-theoretic characterization of the class of geometric theories classified by an atomic topos having enough points; in particular, we show that every complete geometric theory classified by an atomic topos is countably categorical. Some applications are also discussed.

  20. Categorical perception of tactile distance.

    Science.gov (United States)

    Knight, Frances Le Cornu; Longo, Matthew R; Bremner, Andrew J

    2014-05-01

    The tactile surface forms a continuous sheet covering the body. And yet, the perceived distance between two touches varies across stimulation sites. Perceived tactile distance is larger when stimuli cross over the wrist, compared to when both fall on either the hand or the forearm. This effect could reflect a categorical distortion of tactile space across body-part boundaries (in which stimuli crossing the wrist boundary are perceptually elongated) or may simply reflect a localised increased in acuity surrounding anatomical landmarks (in which stimuli near the wrist are perceptually elongated). We tested these two interpretations across two experiments, by comparing a well-documented bias to perceive mediolateral tactile distances across the forearm/hand as larger than proximodistal ones along the forearm/hand at three different sites (hand, wrist, and forearm). According to the 'categorical' interpretation, tactile distances should be elongated selectively in the proximodistal axis thus reducing the anisotropy. According to the 'localised acuity' interpretation, distances will be perceptually elongated in the vicinity of the wrist regardless of orientation, leading to increased overall size without affecting anisotropy. Consistent with the categorical account, we found a reduction in the magnitude of anisotropy at the wrist, with no evidence of a corresponding localised increase in precision. These findings demonstrate that we reference touch to a representation of the body that is categorically segmented into discrete parts, which consequently influences the perception of tactile distance.

  1. Latent Scope Bias in Categorization

    Science.gov (United States)

    2014-01-01

    Stangor, Lynch, Duan, & Glass, 1992; Tajfel , Billig, Bundy, & Claude, 1971), as well as broader aspects of judgment and decision making (for a review, see...Psychology, 207–218. Tajfel , H., Billig, M. G., Bundy, R. P., & Claude, F. (1971). Social categorization and inter- group behavior. European Journal of

  2. Comparison of Text Categorization Algorithms

    Institute of Scientific and Technical Information of China (English)

    SHI Yong-feng; ZHAO Yan-ping

    2004-01-01

    This paper summarizes several automatic text categorization algorithms in common use recently, analyzes and compares their advantages and disadvantages.It provides clues for making use of appropriate automatic classifying algorithms in different fields.Finally some evaluations and summaries of these algorithms are discussed, and directions to further research have been pointed out.

  3. Colour displays for categorical images

    NARCIS (Netherlands)

    Glasbey, C.; Heijden, van der G.W.A.M.; Toh, V.F.K.; Gray, A.J.

    2007-01-01

    We propose a method for identifying a set of colours for displaying 2D and 3D categorical images when the categories are unordered labels. The principle is to find maximally distinct sets of colours. We either generate colours sequentially, to maximize the dissimilarity or distance between a new col

  4. Categorical perception of tactile distance

    OpenAIRE

    Knight, F. L. C.; Longo, M. R.; Bremner, A.J.

    2014-01-01

    The tactile surface forms a continuous sheet covering the body. And yet, the perceived distance between two touches varies across stimulation sites. Perceived tactile distance is larger when stimuli cross over the wrist, compared to when both fall on either the hand or the forearm. This effect could reflect a categorical distortion of tactile space across body-part boundaries (in which stimuli crossing the wrist boundary are perceptually elongated) or may simply reflect a localised increased ...

  5. Categorical Algebra and its Applications

    CERN Document Server

    1988-01-01

    Categorical algebra and its applications contain several fundamental papers on general category theory, by the top specialists in the field, and many interesting papers on the applications of category theory in functional analysis, algebraic topology, algebraic geometry, general topology, ring theory, cohomology, differential geometry, group theory, mathematical logic and computer sciences. The volume contains 28 carefully selected and refereed papers, out of 96 talks delivered, and illustrates the usefulness of category theory today as a powerful tool of investigation in many other areas.

  6. Study on the structure-activity relationship of stem bromelain in different inhibitors and activators%不同抑制剂和激活剂对菠萝茎蛋白酶酶学特性的影响

    Institute of Scientific and Technical Information of China (English)

    赵力超; 陈洁兰; 王燕; 刘欣

    2013-01-01

    菠萝蛋白酶作为一种典型的巯基类蛋白酶,具有稳定性差、易失活的特性.本文通过研究多种抑制剂和激活剂对菠萝茎蛋白酶活力、动力学参数及光谱特性等的影响,总结其构效变化规律,试图解释菠萝蛋白酶失活及激活机理.结果表明:抑制剂与激活剂作用下菠萝茎蛋白酶的CD图谱均表现为o-螺旋度降低,β-折叠、β-转角以及无规卷曲含量不同程度提高,但抑制剂作用下螺旋降低,折叠与卷曲的升高程度更明显.此外,抑制剂与激活剂作用下菠萝茎蛋白酶的紫外差吸收光谱也显示差异,激活剂作用下主要表现为230nm以下的二级结构变化,而抑制剂除上述变化外,还显示生色基团Trp、Tyr、Phe的暴露吸收,表明抑制剂作用下酶分子构象变化更剧烈.本文可为菠萝茎蛋白酶的改性研究提供理论基础.%Stem bromelain was a typical sulfhydryl protease,featured as poor stability and easy of inactivation.Inactivation and activation mechanisms to stem bromelain were examined in this paper,by studying the effects of inhibitors and activators on stem bromelain activity,kinetic parameters and spectral characteristics,and summarizing rule stem bromelain structural activity variation.Results showed that the CD spectra of stem bromelain effected by inhibitors and activators appears as decreasing α-Helix,and increasing β-Sheet,β-Tum and Random in varied degree.The inhibitors impacted on molecular conformation more than activators do.Such impact caused also UV absorption spectra varying.Activator impacted a secondary-structure reaction mainly below 230nm,while alcotate and inhibitors additionally caused exposure of Trp,Tyr and Phe,which meant a significant enzyme molecule conformation react.This study provided a theoretical basis for the consequent research of enzymatic modification.

  7. Detecting categorical perception in continuous discrimination data

    NARCIS (Netherlands)

    Boersma, P.; Chládková, K.

    2010-01-01

    We present a method for assessing categorical perception from continuous discrimination data. Until recently, categorical perception of speech has exclusively been measured by discrimination and identification experiments with a small number of repeatedly presented stimuli. Experiments by Rogers and

  8. 12 CFR 1815.110 - Categorical exclusion.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Categorical exclusion. 1815.110 Section 1815... ENVIRONMENTAL QUALITY § 1815.110 Categorical exclusion. The CEQ regulations provide for the categorical exclusion of actions that do not individually or cumulatively have a significant effect on the...

  9. 40 CFR 1508.4 - Categorical exclusion.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 32 2010-07-01 2010-07-01 false Categorical exclusion. 1508.4 Section 1508.4 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY TERMINOLOGY AND INDEX § 1508.4 Categorical exclusion. Categorical exclusion means a category of actions which do not individually...

  10. Decision Making Under Uncertain Categorization

    Directory of Open Access Journals (Sweden)

    Stephanie Ying-Fen Chen

    2014-09-01

    Full Text Available Two experiments investigated how category information is used in decision making under uncertainty and whether the framing of category information influences how it is used. Subjects were presented with vignettes in which the categorization of a critical item was ambiguous and were asked to choose among a set of actions with the goal of attaining the desired outcome for the main character in the story. The normative decision making strategy was to base the decision on all possible categories; however, research on a related topic, category-based induction, has found that people often only consider a single category when making predictions when categorization is uncertain. These experiments found that subjects tend to consider multiple categories when making decisions, but do so both when it is and is not appropriate, suggesting that use of multiple categories is not driven by an understanding of what categories are and are not relevant to the decision. Similarly, although a framing manipulation increased the rate of multiple-category use, it did so in situations in which multiple-category use was and was not appropriate.

  11. Design of New Benzo[h]chromene Derivatives: Antitumor Activities and Structure-Activity Relationships of the 2,3-Positions and Fused Rings at the 2,3-Positions

    Directory of Open Access Journals (Sweden)

    Rawda M. Okasha

    2017-03-01

    Full Text Available A series of novel 4H-benzo[h]chromenes 4, 6–11, 13, 14; 7H-benzo[h]chromeno[2,3-d]pyrimidines 15–18, 20, and 14H-benzo[h]chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 19a–e, 24 was prepared. The structures of the synthesized compounds were characterized on the basis of their spectral data. Some of the target compounds were examined for their antiproliferative activity against three cell lines; breast carcinoma (MCF-7, human colon carcinoma (HCT-116 and hepatocellular carcinoma (HepG-2. The cytotoxic behavior has been tested using MTT assay and the inhibitory activity was referenced to three standard anticancer drugs: vinblastine, colchicine and doxorubicin. The bioassays demonstrated that some of the new compounds exerted remarkable inhibitory effects as compared to the standard drugs on the growth of the three tested human tumor cell lines. The structure–activity relationships (SAR study highlights that the antitumor activity of the target compounds was significantly affected by the lipophilicity of the substituent at 2- or 3- and fused rings at the 2,3-positions.

  12. The timing of visual object categorization.

    Science.gov (United States)

    Mack, Michael L; Palmeri, Thomas J

    2011-01-01

    AN OBJECT CAN BE CATEGORIZED AT DIFFERENT LEVELS OF ABSTRACTION: as natural or man-made, animal or plant, bird or dog, or as a Northern Cardinal or Pyrrhuloxia. There has been growing interest in understanding how quickly categorizations at different levels are made and how the timing of those perceptual decisions changes with experience. We specifically contrast two perspectives on the timing of object categorization at different levels of abstraction. By one account, the relative timing implies a relative timing of stages of visual processing that are tied to particular levels of object categorization: Fast categorizations are fast because they precede other categorizations within the visual processing hierarchy. By another account, the relative timing reflects when perceptual features are available over time and the quality of perceptual evidence used to drive a perceptual decision process: Fast simply means fast, it does not mean first. Understanding the short-term and long-term temporal dynamics of object categorizations is key to developing computational models of visual object recognition. We briefly review a number of models of object categorization and outline how they explain the timing of visual object categorization at different levels of abstraction.

  13. The timing of visual object categorization

    Directory of Open Access Journals (Sweden)

    Michael L. Mack

    2011-07-01

    Full Text Available An object can be categorized at different levels of abstraction: as natural or man-made, animal or plant, bird or dog, or as a Northern Cardinal or Pyrrhuloxia. There has been growing interest in understanding how quickly categorizations at different levels are made and how the timing of those perceptual decisions changes with experience. We specifically contrast two perspectives on the timing of object categorization at different levels of abstraction. By one account, the relative timing implies a relative timing of stages of visual processing that are tied to particular levels of object categorization: Fast categorizations are fast because they precede other categorizations within the visual processing hierarchy. By another account, the relative timing reflects when perceptual features are available over time and the quality of perceptual evidence used to drive a perceptual decision process: Fast simply means fast, it does not mean first. Understanding the short-term and long-term temporal dynamics of object categorizations is key to developing computational models of visual object recognition. We briefly review a number of models of object categorization and outline how they explain the timing of visual object categorization at different levels of abstraction.

  14. Content-Based Video Description for Automatic Video Genre Categorization

    OpenAIRE

    Ionescu, Bogdan; Seyerlehner, Klaus; Rasche, Christoph; Vertan, Constantin; Lambert, Patrick

    2012-01-01

    International audience; In this paper, we propose an audio-visual approach to video genre categorization. Audio information is extracted at block-level, which has the advantage of capturing local temporal information. At temporal structural level, we asses action contents with respect to human perception. Further, color perception is quantified with statistics of color distribution, elementary hues, color properties and relationship of color. The last category of descriptors determines statis...

  15. Theoretical elucidation of structure-activity relationship of flavonoid antioxidants

    Institute of Scientific and Technical Information of China (English)

    张红雨

    1999-01-01

    AM1 method was employed to calculate flavonoid antioxidants, and the results obtained are as follows. Firstly, flavonoid hydroxyls at ortho position were more active than the hydroxyls at meta position in scavenging oxygen-free radicals, which resulted from the facts that (ⅰ) the former were stabilized by forming intramolecular hydrogen bond and (ⅱ) ortho benzoquinone formed in the former structures through resonance, which resulted in large percentage of distribution of spin density on ortho oxygen and low internal energy. Secondly, electron-attracting effect of ring C of chromone-flavonoids showed some passive effects on hydroxyls of ring A, making the OH less active. As ring C had little effect on ring B and hydroxyls of ring B in most flavonoids were at ortho position, the rule summarized from experiments showing that hydroxyls of ring B were more active in scavenging oxygen-free radicals was elucidated.

  16. Structure-activity relationship of immunostimulatory effects of phthalates

    Directory of Open Access Journals (Sweden)

    Nielsen Gunnar D

    2008-10-01

    Full Text Available Abstract Background Some chemicals, including some phthalate plasticizers, have been shown to have an adjuvant effect in mice. However, an adjuvant effect, defined as an inherent ability to stimulate the humoral immune response, was only observed after exposure to a limited number of the phthalates. An adjuvant effect may be due to the structure or physicochemical characteristics of the molecule. The scope of this study was to investigate which molecular characteristics that determine the observed adjuvant effect of the most widely used phthalate plasticizer, the di-(2-ethylhexyl phthalate (DEHP, which is documented as having a strong adjuvant effect. To do so, a series of nine lipophilic compounds with structural and physicochemical relations to DEHP were investigated. Results Adjuvant effect of phthalates and related compounds were restricted to the IgG1 antibody formation. No effect was seen on IgE. It appears that lipophilicity plays a crucial role, but lipophilicity does not per se cause an adjuvant effect. In addition to lipophilicity, a phthalate must also possess specific stereochemical characteristics in order for it to have adjuvant effect. Conclusion The adjuvant effect of phthalates are highly influenced by both stereochemical and physico-chemical properties. This knowledge may be used in the rational development of plasticizers without adjuvant effect as well as in the design of new immunological adjuvants.

  17. Quantitative Structure-Activity Relationships (QSARs) - Applications and Methodology

    Science.gov (United States)

    Cronin, Mark T. D.

    The aim of this introduction is to describe briefly the applications and methodologies involved in (Q)SAR and relate these to the various chapters in this volume. This chapter gives the reader an overview of how, why and where in silico methods, including (Q)SAR, have been utilized to predict endpoints as diverse as those from pharmacology and toxicology. It provides an illustration of how all the various topics in this book interweave to form a single coherent area of science.

  18. Structure-Activity Relationship of Chlorotoxin-Like Peptides

    Directory of Open Access Journals (Sweden)

    Syed Abid Ali

    2016-02-01

    Full Text Available Animal venom (e.g., scorpion is a rich source of various protein and peptide toxins with diverse physio-/pharmaco-logical activities, which generally exert their action via target-specific modulation of different ion channel functions. Scorpion venoms are among the most widely-known source of peptidyl neurotoxins used for callipering different ion channels, such as; Na+, K+, Ca+, Cl−, etc. A new peptide of the chlorotoxin family (i.e., Bs-Tx7 has been isolated, sequenced and synthesized from scorpion Buthus sindicus (family Buthidae venom. This peptide demonstrates 66% with chlorotoxin (ClTx and 82% with CFTR channel inhibitor (GaTx1 sequence identities reported from Leiurus quinquestriatus hebraeus venom. The toxin has a molecular mass of 3821 Da and possesses four intra-chain disulphide bonds. Amino acid sequence analysis of Bs-Tx7 revealed the presence of a scissile peptide bond (i.e., Gly-Ile for human MMP2, whose activity is increased in the case of tumour malignancy. The effect of hMMP2 on Bs-Tx7, or vice versa, observed using the FRET peptide substrate with methoxycoumarin (Mca/dinitrophenyl (Dnp as fluorophore/quencher, designed and synthesized to obtain the lowest Km value for this substrate, showed approximately a 60% increase in the activity of hMMP2 upon incubation of Bs-Tx7 with the enzyme at a micromolar concentration (4 µM, indicating the importance of this toxin in diseases associated with decreased MMP2 activity.

  19. Aromatic-Aromatic Interactions in Biological System: Structure Activity Relationships

    Energy Technology Data Exchange (ETDEWEB)

    Rajagopal, Appavu; Deepa, Mohan [Molecular Biophysics Unit, Indian Institute of Sciences-Bangalore, Karnataka (India); Govindaraju, Munisamy [Bio-Spatial Technology Research Unit, Department of Environmental Biotechnology, School of Environmental Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu (India)

    2016-02-26

    While, intramolecular hydrogen bonds have attracted the greatest attention in studies of peptide conformations, the recognition that several other weakly polar interactions may be important determinants of folded structure has been growing. Burley and Petsko provided a comprehensive overview of the importance of weakly polar interactions, in shaping protein structures. The interactions between aromatic rings, which are spatially approximate, have attracted special attention. A survey of the proximal aromatic residue pairs in proteins, allowed Burley and Petsko to suggest that, “phenyl ring centroids are separated by a preferential distance of between 4.5 and 7 Å, and dihedral angles approximately 90° are most common”.

  20. Aladan scanning: The structure-activity relationship of dynorphin A

    Institute of Scientific and Technical Information of China (English)

    CHEN He-Ru; YANG Yang; WENG Jiang-Duo

    2009-01-01

    An unnatural amino acid, β-[6'-(N, N-dimethyl)amino-2'-naphthoyl]alanine (Ald) showing polarity-sen sitive fluorescence characteristics, was synthesized. A thorough Aid-scan of dynorphin A (Dyn A), the putative endogenous ligand for κ opioid receptors, was then performed. Replacement of the amino acid residues in positions 5, 8, 10, 12 or 14 of Dyn A(1-13)-NH2 with Ald resulted in compounds that had almost equal κ binding affinity compared with that of the parent compound; on the other hand, substi-tution of residues in position 1 or 4 with Aid decreased x-receptor binding affinity. These results indi-cate that Tyr and Phe in Dyn A are very important for maintaining its κ-opioid activity. Evidence from receptor binding assay clearly displays that [Ald5]Dyn A(1-13)-NH2 is a highly selective κ-opioid re-ceptor agonist. An evaluation of the interaction of Aid-containing Dyn A(1-13)-NH2 analogues with SDS and DPC micelles was also performed. Interestingly, [Ald1]Dyn A(1-13)-NH2 and [Ald4]Dyn A(1-13)-NH2 showed quite different fluorescence emission maxima in SDS and DPC micelles. This indicates that both peptides are sensitive to electronic properties of the polar surface of the micelles.

  1. Aladan scanning: The structure-activity relationship of dynorphin A

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    An unnatural amino acid, β-[6′-(N, N-dimethyl)amino-2′-naphthoyl]alanine (Ald) showing polarity-sen sitive fluorescence characteristics, was synthesized. A thorough Ald-scan of dynorphin A (Dyn A), the putative endogenous ligand for κ opioid receptors, was then performed. Replacement of the amino acid residues in positions 5, 8, 10, 12 or 14 of Dyn A(1-13)-NH2 with Ald resulted in compounds that had almost equal κ binding affinity compared with that of the parent compound; on the other hand, substi-tution of residues in position 1 or 4 with Ald decreased κ-receptor binding affinity. These results indi-cate that Tyr and Phe in Dyn A are very important for maintaining its κ-opioid activity. Evidence from receptor binding assay clearly displays that [Ald5]Dyn A(1-13)-NH2 is a highly selective κ-opioid re-ceptor agonist. An evaluation of the interaction of Ald-containing Dyn A(1-13)-NH2 analogues with SDS and DPC micelles was also performed. Interestingly, [Ald1]Dyn A(1-13)-NH2 and [Ald4]Dyn A(1-13)-NH2 showed quite different fluorescence emission maxima in SDS and DPC micelles. This indicates that both peptides are sensitive to electronic properties of the polar surface of the micelles.

  2. Structure-activity relationships in carbohydrates revealed by their hydration.

    Science.gov (United States)

    Maugeri, Laura; Busch, Sebastian; McLain, Sylvia E; Pardo, Luis Carlos; Bruni, Fabio; Ricci, Maria Antonietta

    2016-12-21

    One of the more intriguing aspects of carbohydrate chemistry is that despite having very similar molecular structures, sugars have very different properties. For instance, there is a sensible difference in sweet taste between glucose and trehalose, even though trehalose is a disaccharide that comprised two glucose units, suggesting a different ability of these two carbohydrates to bind to sweet receptors. Here we have looked at the hydration of specific sites and at the three-dimensional configuration of water molecules around three carbohydrates (glucose, cellobiose, and trehalose), combining neutron diffraction data with computer modelling. Results indicate that identical chemical groups can have radically different hydration patterns depending on their location on a given molecule. These differences can be linked with the specific activity of glucose, cellobiose, and trehalose as a sweet substance, as building block of cellulose fiber, and as a bioprotective agent, respectively. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader.

  3. Quantitative Structure-activity Relationship of TIBO HIV-1 Inhibitors

    Institute of Scientific and Technical Information of China (English)

    LI Xiao-Hong; ZHANG Rui-Zhou; CHENG Xin-Lu; YANG Xiang-Dong

    2007-01-01

    Density functional theory (DFT) was used to calculate a set of molecular descriptors (properties) for 14 TIBO derivatives with anti-HIV activity. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed in order to reduce dimensionality and investigate which subset of variables should be more effective for classifying TIBO derivatives according to their degree of anti-HIV activity. The PCA showed that the EHOMO, μ, LogP, QA, QB and MR variables are responsible for the separation between compounds with higher and lower anti-HIV activity. The HCA results are similar to those obtained with PCA. By using the chemometric results, four synthetic compounds were analyzed through PCA and HCA and three of them are proposed as active molecules against HIV, which is consistent with the results of clinic experiments. The methodologies of PCA and HCA provide a reliable rule for classifying new TIBO derivatives with anti-HIV activity. The model obtained showed not only statistical significance but also predictive ability.

  4. Thapsigargin, origin, chemistry, structure-activity relationships and prodrug development

    DEFF Research Database (Denmark)

    Doan, Thi Quynh Nhu; Christensen, Søren Brøgger

    2015-01-01

    Thapsigargin was originally isolated from the roots of the Mediterranean umbelliferous plant Thapsia garganica in order to characterize the skin irritant principle. The biological activity was related to the subnanomolar affinity for the sarco-endoplasmic reticulum calcium ATPase. Prolonged inhib...

  5. Synthesis and structure-activity relationships of skin ceramides.

    Science.gov (United States)

    Novotný, J; Hrabálek, A; Vávrová, K

    2010-01-01

    Ceramides are a complex group of lipids that has gained much attention as cell signaling molecules and skin barrier constituents. In the skin, these sphingolipids form a major part of the stratum corneum intercellular lipid matrix, which is the barrier for penetration of most compounds. The development of such a protective layer was a critical step in the evolution of life on a dry land. Moreover, prominent skin diseases such as psoriasis and atopic dermatitis are associated with diminished ceramide levels and may be effectively improved by exogenous ceramides or their analogues. Since ceramides are not obtained from natural sources in pure form, they are of synthetic interest since 1950's. In this review, we describe sphingosine syntheses from 1998 until 2008, and the synthetic approaches to the unique epidermal ceramides, including the 6-hydroxysphingosine-based ones, the alpha- and omega-hydroxy forms and the omega-acyloxy species. Moreover, the structural requirements of ceramides for a competent skin barrier are discussed, including acyl chain length, trans double bond, acyl alpha-hydroxyl, stereochemistry, omega-linoleyloxy species and ceramide conformation.

  6. Using Theoretical Descriptors in Structural Activity Relationships. 2. Polarizability Index

    Science.gov (United States)

    1988-09-01

    Konnemann measured the LC 0 of 24 aliphatic and aromatic compounds on guppies * ( Poecilia Reticulata ). The resultant multiple linear regressions for the...taken from a report by Konnemann involving LC 5 0 experiments on guppies (Poecilha Reticulata ) using 50 industrial pollutants.’ 7 The Charcoal

  7. Structure-Activity Relationships of Agents Modifying Cholinergic Transmissions

    Science.gov (United States)

    1983-09-01

    8217ieOH and 2 mL of conc l2,S0.,, and wns li:iL,.d ,v.,rni 6;% .,od!r I.tu’. The r., action t-dxture was poured over Lco ice .in .,-. I i ; "•Lj." :i...oxidase betaine + 2H 2 0 2 Protocol p The mobile phase consists of 0.01 X sodium acetate wffered to pH 5 with 0.02 K citric acid containing 5.0 mg/liter...then extraction in 0.01 1 PCA with EHC is a possible method to investigate the mechanisms by which hemicholinium-3 or hemichnli-tium-3 like compounds

  8. Distributing Correlation Coefficients of Linear Structure-Activity/Property Models

    Directory of Open Access Journals (Sweden)

    Sorana D. BOLBOACA

    2011-12-01

    Full Text Available Quantitative structure-activity/property relationships are mathematical relationships linking chemical structure and activity/property in a quantitative manner. These in silico approaches are frequently used to reduce animal testing and risk-assessment, as well as to increase time- and cost-effectiveness in characterization and identification of active compounds. The aim of our study was to investigate the pattern of correlation coefficients distribution associated to simple linear relationships linking the compounds structure with their activities. A set of the most common ordnance compounds found at naval facilities with a limited data set with a range of toxicities on aquatic ecosystem and a set of seven properties was studied. Statistically significant models were selected and investigated. The probability density function of the correlation coefficients was investigated using a series of possible continuous distribution laws. Almost 48% of the correlation coefficients proved fit Beta distribution, 40% fit Generalized Pareto distribution, and 12% fit Pert distribution.

  9. 32 CFR 989.13 - Categorical exclusion.

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Categorical exclusion. 989.13 Section 989.13 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ENVIRONMENTAL PROTECTION ENVIRONMENTAL IMPACT ANALYSIS PROCESS (EIAP) § 989.13 Categorical exclusion. (a) CATEXs define those...

  10. Accelerating Visual Categorization with the GPU

    NARCIS (Netherlands)

    van de Sande, K.E.A.; Gevers, T.; Snoek, C.G.M.

    2012-01-01

    Visual categorization is important to manage large collections of digital images and video, where textual meta-data is often incomplete or simply unavailable. The bag-of-words model has become the most powerful method for visual categorization of images and video. Despite its high accuracy, a severe

  11. Empowering Visual Categorization with the GPU

    NARCIS (Netherlands)

    van de Sande, K.E.A.; Gevers, T.; Snoek, C.G.M.

    2011-01-01

    Visual categorization is important to manage large collections of digital images and video, where textual metadata is often incomplete or simply unavailable. The bag-of-words model has become the most powerful method for visual categorization of images and video. Despite its high accuracy, a severe

  12. Measuring Category Intuitiveness in Unconstrained Categorization Tasks

    Science.gov (United States)

    Pothos, Emmanuel M.; Perlman, Amotz; Bailey, Todd M.; Kurtz, Ken; Edwards, Darren J.; Hines, Peter; McDonnell, John V.

    2011-01-01

    What makes a category seem natural or intuitive? In this paper, an unsupervised categorization task was employed to examine observer agreement concerning the categorization of nine different stimulus sets. The stimulus sets were designed to capture different intuitions about classification structure. The main empirical index of category…

  13. Categorizing words through semantic memory navigation

    Science.gov (United States)

    Borge-Holthoefer, J.; Arenas, A.

    2010-03-01

    Semantic memory is the cognitive system devoted to storage and retrieval of conceptual knowledge. Empirical data indicate that semantic memory is organized in a network structure. Everyday experience shows that word search and retrieval processes provide fluent and coherent speech, i.e. are efficient. This implies either that semantic memory encodes, besides thousands of words, different kind of links for different relationships (introducing greater complexity and storage costs), or that the structure evolves facilitating the differentiation between long-lasting semantic relations from incidental, phenomenological ones. Assuming the latter possibility, we explore a mechanism to disentangle the underlying semantic backbone which comprises conceptual structure (extraction of categorical relations between pairs of words), from the rest of information present in the structure. To this end, we first present and characterize an empirical data set modeled as a network, then we simulate a stochastic cognitive navigation on this topology. We schematize this latter process as uncorrelated random walks from node to node, which converge to a feature vectors network. By doing so we both introduce a novel mechanism for information retrieval, and point at the problem of category formation in close connection to linguistic and non-linguistic experience.

  14. Class I Microcins: Their Structures, Activities, and Mechanisms of Resistance

    Science.gov (United States)

    Severinov, Konstantin; Semenova, Ekaterina; Kazakov, Teymur

    Microcin J25, microcin B17, and microcin C7-C51 are the three known members of class I posttranslationally modified microcins (heavily posttranslationally modified antibacterial peptides produced by Enterobacteriaceae with molecular weights of less than 5 kDa). The three microcins are unrelated to each other; they have structures that are highly atypical for ribosomally synthesized peptides and target essential molecular machines that are validated drug targets. In this chapter, available data on mechanisms of action, structure-activity relationships, and immunity mechanisms for class I microcins and related compounds are discussed.

  15. Categorical apparatus of individual marketing

    Directory of Open Access Journals (Sweden)

    I.L. Reshetnikova

    2013-12-01

    Full Text Available The aim of the article. The aim of the article is to clarify the essence of individual marketing and its interconnection with relationship marketing, CRM, direct marketing and database marketing based on a study of the marketing genesis and the evolution of the process of individual communication between buyer and seller. We consider relationship marketing as the most general notion that involves individual marketing, CRM, direct marketing and database marketing. Relationship marketing is to be viewed as establishing long-term relationships between seller and buyer on mutually beneficial basis. The emergence of information technologies and their widespread use in business has a significant impact on relationship marketing and led to the concept of CRM. The results of the analysis. We consider CRM as business strategy which is based on information technologies and designed to provide long-term, mutually beneficial relationships with customers through client-oriented approach and the creation of high customer value to the product and company. CRM and CRM-systems that are designed to work with customers' databases and are operating with huge volumes of information for marketing purposes have contributed to the realization of the principles of individual marketing. Conceptual approaches to the definition of the concepts of «individual marketing» and CRM allow us to identify common and distinctive features as well as the interdependency between them. It is appropriate to talk about CRM as the concept which is broader than individual marketing. CRM focuses on relationships with customers, and the main objective of it is to establish long-term relationships for mutual benefit, while individual marketing needs to be supported by resources and technologies to create a specific product that is able to meet the particular individual needs of customers. It should be noted that the practical implementation of the principles of CRM is possible when using an

  16. Space Structure and Clustering of Categorical Data.

    Science.gov (United States)

    Qian, Yuhua; Li, Feijiang; Liang, Jiye; Liu, Bing; Dang, Chuangyin

    2016-10-01

    Learning from categorical data plays a fundamental role in such areas as pattern recognition, machine learning, data mining, and knowledge discovery. To effectively discover the group structure inherent in a set of categorical objects, many categorical clustering algorithms have been developed in the literature, among which k -modes-type algorithms are very representative because of their good performance. Nevertheless, there is still much room for improving their clustering performance in comparison with the clustering algorithms for the numeric data. This may arise from the fact that the categorical data lack a clear space structure as that of the numeric data. To address this issue, we propose, in this paper, a novel data-representation scheme for the categorical data, which maps a set of categorical objects into a Euclidean space. Based on the data-representation scheme, a general framework for space structure based categorical clustering algorithms (SBC) is designed. This framework together with the applications of two kinds of dissimilarities leads two versions of the SBC-type algorithms. To verify the performance of the SBC-type algorithms, we employ as references four representative algorithms of the k -modes-type algorithms. Experiments show that the proposed SBC-type algorithms significantly outperform the k -modes-type algorithms.

  17. Population Code Dynamics in Categorical Perception.

    Science.gov (United States)

    Tajima, Chihiro I; Tajima, Satohiro; Koida, Kowa; Komatsu, Hidehiko; Aihara, Kazuyuki; Suzuki, Hideyuki

    2016-03-03

    Categorical perception is a ubiquitous function in sensory information processing, and is reported to have important influences on the recognition of presented and/or memorized stimuli. However, such complex interactions among categorical perception and other aspects of sensory processing have not been explained well in a unified manner. Here, we propose a recurrent neural network model to process categorical information of stimuli, which approximately realizes a hierarchical Bayesian estimation on stimuli. The model accounts for a wide variety of neurophysiological and cognitive phenomena in a consistent framework. In particular, the reported complexity of categorical effects, including (i) task-dependent modulation of neural response, (ii) clustering of neural population representation, (iii) temporal evolution of perceptual color memory, and (iv) a non-uniform discrimination threshold, are explained as different aspects of a single model. Moreover, we directly examine key model behaviors in the monkey visual cortex by analyzing neural population dynamics during categorization and discrimination of color stimuli. We find that the categorical task causes temporally-evolving biases in the neuronal population representations toward the focal colors, which supports the proposed model. These results suggest that categorical perception can be achieved by recurrent neural dynamics that approximates optimal probabilistic inference in the changing environment.

  18. Antitumor Agents 286. Design, Synthesis and Structure-Activity Relationships of 3′R,4′R-Disubstituted-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DSP) Analogs as Potent Chemosensitizers to Overcome Multidrug Resistance

    Science.gov (United States)

    Zhou, Ting; Shi, Qian; Bastow, Kenneth F.; Lee, Kuo-Hsiung

    2010-01-01

    In this study, various 3′R,4′R-disubstituted-2′,2′-dimethydihydropyrano[2,3-f]chromone (DSP) derivatives were discovered as potent chemosensitizers in the treatment of multidrug resistant cancer cells. Twenty-four DSP analogs (5–28) were synthesized and evaluated against a multi-drug resistant (MDR) cell line (KB-Vin) with and without vincristine (VCR). All DSP analogs exhibited low intrinsic cytotoxicity. However, in combination treatment, most DSPs reversed resistance to VCR and lowered the GI50 value of VCR by 12–349-fold. At a concentration of 1μg/mL, three compounds, 11, 14 and 21, fully reversed resistance to VCR in KB-Vin cancer cells, a twofold increase compared to verapamil, a first generation chemosensitizer. Detailed structure-activity relationship (SAR) conclusions were established based on 3′ and 4′ substitutions. Moreover, a preliminary mechanism study indicated that the chemosensitizing activity of DSP analogs results from inhibition of P-glycoprotein (P-gp) over-expressed in MDR cancer cells.1 PMID:21082774

  19. Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254).

    Science.gov (United States)

    Turlington, Mark; Noetzel, Meredith J; Chun, Aspen; Zhou, Ya; Gogliotti, Rocco D; Nguyen, Elizabeth D; Gregory, Karen J; Vinson, Paige N; Rook, Jerri M; Gogi, Kiran K; Xiang, Zixiu; Bridges, Thomas M; Daniels, J Scott; Jones, Carrie; Niswender, Colleen M; Meiler, Jens; Conn, P Jeffrey; Lindsley, Craig W; Stauffer, Shaun R

    2013-10-24

    Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlu5 PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure-activity relationship of allosteric agonism was examined within an acetylenic series of mGlu5 PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, a low glutamate fold-shift allosteric ligand (maximum fold-shift ~ 3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM 38t (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlu5 PAMs.

  20. Using backpropagation artificial neural network to study the structure-activity relationship between aromatics compounds and rat LD50%BP人工神经网络用于芳香族化合物结构参数和大鼠LD50构效关系研究

    Institute of Scientific and Technical Information of China (English)

    黄德生; 刘延令; 金一和

    2001-01-01

    Objective Using BP Artificial Neural Network to study the Structure-Activity relationship between aromatics compounds and rat LD50, improved precision of toxicity prediction. Methods Firstly, Principal-Components-Analysis was adopted, then used BP ANN net-structure, and applied LM arithumetic as iteration method to train the network. Result We have discussed the relationship betwenn the structure parameter of 120 varieties of aromatics compound and rat LD50, and optimized the parameter design of the net to avoid over-fitting. I found that three-layer BP ANN which using log-sigmoid function, (i.e.) f(x)=1/1(+exp(-x)) as network transfer function got better fitting power. When the number of the hidden layer node is 13, the sum-square error is 0.36 which is far less than linear models. While the outer prediction precision of multiplayer BP ANN is higher than linear model in evidence, SSE=4.63. Conclusion We can consider that the classify power of multiplayer BP ANN is superior to linear nodels. Multilayer BP ANN can be use to predict toxicity of aromatics compounds, this method is better than traditional methods.%对结构参数采用主成分变换,再利用BP人工神经网络,采用LM算法作为迭代方法训练网络,预测检验集化合物的LD50。结果显示,BP人工神经网络可以用于定量毒性构效关系研究,含隐层的BP人工神经网络拟合能力明显优于传统方法,消除过度拟合后的多层BP网络预测能力也好于传统方法,可以用于预测。

  1. Efficiency of the categorization of the public procurement contracts

    Directory of Open Access Journals (Sweden)

    Edwin Tachlian

    2010-12-01

    Full Text Available The French public procurement contracts at large, including the public markets - public Works or services contracts – the delegation public service, public-private partnership contract or even the administrative emphyteutic lease are close as these contracts aims to procure a good or service to a public entity. But these contracts are classified and specialized, as France does not know a single and generic type of contract for its relation between the administration and the private sector. This categorization is rigid and complex. It is thus extremely difficult in France to create new forms of contract, due to the fact that each contract must enter into a predefined and pre-existing category. If the strict supervision of contracts of public seems dictated by a desire to secure the relationship between the administration and its contractors, it may nevertheless be asked whether this principle of categorization does not be an additional cost to the contractors and the same administration.

  2. Categorization of exchange fluxes explains the four relational models

    CERN Document Server

    Favre, Maroussia

    2013-01-01

    The theory of Relational Models (RMs) posits four elementary models of relationships governing all human interactions, singly or in combination: Communal Sharing, Authority Ranking, Equality Matching, and Market Pricing. By considering two agents that can act in one out of three ways towards one another: give resource A, give resource B, or give nothing, we find four discrete categories of exchange fluxes that map unequivocally to the four RMs. This categorization shows that the RMs form an exhaustive set of all possible elementary exchanges. Hence, the fluxes categorization answers why there are just four RMs and explains their discreteness. By considering the costs associated with extracting resources, storing them and implementing each flux category, we are able to propose conditions under which each RM should evolve. We also logically deduce the singular nature of the Authority Ranking model. Our propositions are compatible with anthropological, ethnological and historical observations and can be tested a...

  3. The influence of landscape variation on landform categorization

    Directory of Open Access Journals (Sweden)

    Maia Williams

    2012-12-01

    Full Text Available This paper compares the landform vocabularies of residents from two regions in Portugal. Participants described both their own and the other, less familiar landscapes in response to video footage of the regions. The results indicate that participants used more detailed vocabularies to describe the known landscape compared to the less familiar study site, with detail triggered by individual place recognition. A relationship between landform lexica content and landscape type was observed in the relative placement of detail within each vocabulary. The observed drivers of categorization were the salient features of the landscape (elevation and land cover and utilitarian motivations (land use, context, and familiarity. The results offer support to the notion of non-universality in geographic object categorization.

  4. Web Page Categorization Using Artificial Neural Networks

    CERN Document Server

    Kamruzzaman, S M

    2010-01-01

    Web page categorization is one of the challenging tasks in the world of ever increasing web technologies. There are many ways of categorization of web pages based on different approach and features. This paper proposes a new dimension in the way of categorization of web pages using artificial neural network (ANN) through extracting the features automatically. Here eight major categories of web pages have been selected for categorization; these are business & economy, education, government, entertainment, sports, news & media, job search, and science. The whole process of the proposed system is done in three successive stages. In the first stage, the features are automatically extracted through analyzing the source of the web pages. The second stage includes fixing the input values of the neural network; all the values remain between 0 and 1. The variations in those values affect the output. Finally the third stage determines the class of a certain web page out of eight predefined classes. This stage i...

  5. Interference effects of categorization on decision making.

    Science.gov (United States)

    Wang, Zheng; Busemeyer, Jerome R

    2016-05-01

    Many decision making tasks in life involve a categorization process, but the effects of categorization on subsequent decision making has rarely been studied. This issue was explored in three experiments (N=721), in which participants were shown a face stimulus on each trial and performed variations of categorization-decision tasks. On C-D trials, they categorized the stimulus and then made an action decision; on X-D trials, they were told the category and then made an action decision; on D-alone trials, they only made an action decision. An interference effect emerged in some of the conditions, such that the probability of an action on the D-alone trials (i.e., when there was no explicit categorization before the decision) differed from the total probability of the same action on the C-D or X-D trials (i.e., when there was explicit categorization before the decision). Interference effects are important because they indicate a violation of the classical law of total probability, which is assumed by many cognitive models. Across all three experiments, a complex pattern of interference effects systematically occurred for different types of stimuli and for different types of categorization-decision tasks. These interference effects present a challenge for traditional cognitive models, such as Markov and signal detection models, but a quantum cognition model, called the belief-action entanglement (BAE) model, predicted that these results could occur. The BAE model employs the quantum principles of superposition and entanglement to explain the psychological mechanisms underlying the puzzling interference effects. The model can be applied to many important and practical categorization-decision situations in life.

  6. Data Reduction Method for Categorical Data Clustering

    OpenAIRE

    Sánchez Garreta, José Salvador; Rendón, Eréndira; García, Rene A.; Abundez, Itzel; Gutiérrez, Citlalih; Gasca, Eduardo

    2008-01-01

    Categorical data clustering constitutes an important part of data mining; its relevance has recently drawn attention from several researchers. As a step in data mining, however, clustering encounters the problem of large amount of data to be processed. This article offers a solution for categorical clustering algorithms when working with high volumes of data by means of a method that summarizes the database. This is done using a structure called CM-tree. In order to test our metho...

  7. Learning a Probabilistic Topology Discovering Model for Scene Categorization.

    Science.gov (United States)

    Zhang, Luming; Ji, Rongrong; Xia, Yingjie; Zhang, Ying; Li, Xuelong

    2015-08-01

    A recent advance in scene categorization prefers a topological based modeling to capture the existence and relationships among different scene components. To that effect, local features are typically used to handle photographing variances such as occlusions and clutters. However, in many cases, the local features alone cannot well capture the scene semantics since they are extracted from tiny regions (e.g., 4×4 patches) within an image. In this paper, we mine a discriminative topology and a low-redundant topology from the local descriptors under a probabilistic perspective, which are further integrated into a boosting framework for scene categorization. In particular, by decomposing a scene image into basic components, a graphlet model is used to describe their spatial interactions. Accordingly, scene categorization is formulated as an intergraphlet matching problem. The above procedure is further accelerated by introducing a probabilistic based representative topology selection scheme that makes the pairwise graphlet comparison trackable despite their exponentially increasing volumes. The selected graphlets are highly discriminative and independent, characterizing the topological characteristics of scene images. A weak learner is subsequently trained for each topology, which are boosted together to jointly describe the scene image. In our experiment, the visualized graphlets demonstrate that the mined topological patterns are representative to scene categories, and our proposed method beats state-of-the-art models on five popular scene data sets.

  8. CATEGORIZATION OF EVENT SEQUENCES FOR LICENSE APPLICATION

    Energy Technology Data Exchange (ETDEWEB)

    G.E. Ragan; P. Mecheret; D. Dexheimer

    2005-04-14

    The purposes of this analysis are: (1) Categorize (as Category 1, Category 2, or Beyond Category 2) internal event sequences that may occur before permanent closure of the repository at Yucca Mountain. (2) Categorize external event sequences that may occur before permanent closure of the repository at Yucca Mountain. This includes examining DBGM-1 seismic classifications and upgrading to DBGM-2, if appropriate, to ensure Beyond Category 2 categorization. (3) State the design and operational requirements that are invoked to make the categorization assignments valid. (4) Indicate the amount of material put at risk by Category 1 and Category 2 event sequences. (5) Estimate frequencies of Category 1 event sequences at the maximum capacity and receipt rate of the repository. (6) Distinguish occurrences associated with normal operations from event sequences. It is beyond the scope of the analysis to propose design requirements that may be required to control radiological exposure associated with normal operations. (7) Provide a convenient compilation of the results of the analysis in tabular form. The results of this analysis are used as inputs to the consequence analyses in an iterative design process that is depicted in Figure 1. Categorization of event sequences for permanent retrieval of waste from the repository is beyond the scope of this analysis. Cleanup activities that take place after an event sequence and other responses to abnormal events are also beyond the scope of the analysis.

  9. SYNTHESIS AND STRUCTURE-ACTIVITY STUDIES OF SUBSTITUENT 1-(O-CHLOROBENZOYL)-3-(PHENYL) THIOUREA LARVICIDES

    Institute of Scientific and Technical Information of China (English)

    陆忠娥; 孙大庆; 李凯

    1990-01-01

    In this paper, we synthesized nineteen substituent 1-(o-chloro-benzoyl)-3-(phenyl) thiourea derivatives and studied their structure activity relationship, We found that the compounds with electron-withdrawing group (F) would have higher insecticidal activity.

  10. Tough and tender: embodied categorization of gender.

    Science.gov (United States)

    Slepian, Michael L; Weisbuch, Max; Rule, Nicholas O; Ambady, Nalini

    2011-01-01

    Emerging evidence has shown that human thought can be embodied within physical sensations and actions. Indeed, abstract concepts such as morality, time, and interpersonal warmth can be based on metaphors that are grounded in bodily experiences (e.g., physical temperature can signal interpersonal warmth). We hypothesized that social-category knowledge is similarly embodied, and we tested this hypothesis by examining a sensory metaphor related to categorical judgments of gender. We chose the dimension of "toughness" (ranging from tough to tender), which is often used to characterize differences between males and females. Across two studies, the proprioceptive experience of toughness (vs. tenderness) was manipulated as participants categorized sex-ambiguous faces as male or female. Two different manipulations of proprioceptive toughness predictably biased the categorization of faces toward "male." These findings suggest that social-category knowledge is at least partially embodied.

  11. Prosodic boundary information modulates phonetic categorization.

    Science.gov (United States)

    Kim, Sahyang; Cho, Taehong

    2013-07-01

    Categorical perception experiments were performed on an English /b-p/ voice onset time (VOT) continuum with native (American English) and non-native (Korean) listeners to examine whether and how phonetic categorization is modulated by prosodic boundary and language experience. Results demonstrated perceptual shifting according to prosodic boundary strength: A longer VOT was required to identify a sound as /p/ after an intonational phrase than a word boundary, regardless of the listeners' language experience. This suggests that segmental perception is modulated by the listeners' computation of an abstract prosodic structure reflected in phonetic cues of phrase-final lengthening and domain-initial strengthening, which are common across languages.

  12. 24 CFR 58.35 - Categorical exclusions.

    Science.gov (United States)

    2010-04-01

    ... impact statement or environmental assessment and finding of no significant impact under NEPA is required... significant impact. Compliance with the other applicable Federal environmental laws and authorities listed in... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Categorical exclusions....

  13. How Experimental Trial Context Affects Perceptual Categorization

    Directory of Open Access Journals (Sweden)

    Thomas J Palmeri

    2015-02-01

    Full Text Available To understand object categorization, participants are tested in experiments often quite different from how people experience object categories in the real world. Learning and knowledge of categories is measured in discrete experimental trials, those trials may or may not provide feedback, trials appear one after another, after some fixed inter-trial interval, with hundreds of trials in a row, within experimental blocks with some structure dictated by the experimental design. In the real world, outside of certain educational and vocational contexts, opportunities to learn and use categories are intermixed over time with a whole multitude of intervening experiences. It is clear from any elementary understanding of human cognition that sequential effects matter, yet this understanding is often ignored, and categorization trials are often instead treated as independent events, immune to local trial context. In this perspective, we use some of our work to illustrate some of the consequences of the fact that categorization experiments have a particular trial structure. Experimental trial context can affect performance in category learning and categorization experiments in ways that can profoundly affect theoretical conclusions.

  14. Categorical properties of topological and differentiable stacks

    NARCIS (Netherlands)

    Carchedi, D.J.

    2011-01-01

    The focus of this PhD research is on the theory of topological and differentiable stacks. There are two main themes of this research. The first, is the creation of the theory of compactly generated stacks, which solve many categorical shortcomings of the theory of classical topological stacks. In pa

  15. Visual categorization with negative examples for free

    NARCIS (Netherlands)

    Li, X.; Snoek, C.G.M.

    2009-01-01

    Automatic visual categorization is critically dependent on labeled examples for supervised learning. As an alternative to traditional expert labeling, social-tagged multimedia is becoming a novel yet subjective and inaccurate source of learning examples. Different from existing work focusing on coll

  16. Neighborhood conflicts: the role of social categorization

    NARCIS (Netherlands)

    Ufkes, E.G.; Otten, S.; Zee, van der K. I.; Giebels, E.

    2012-01-01

    Purpose – In a multicultural context, this study aims to investigate the effect of ingroup versus outgroup categorization and stereotypes on residents' emotional and behavioral reactions in neighbor-to-neighbor conflicts. Based on the literature on the “black sheep effect”, the authors predicted tha

  17. Mechanism and the structure-activity relationship of umbelliferone and aesculetin with DNA%7-羟基香豆素及6,7-二羟基香豆素与DNA的作用机理及构效关系研究

    Institute of Scientific and Technical Information of China (English)

    张爱平; 杨锦艳; 郑茂东; 郝娟; 黄茜

    2011-01-01

    目的:研究7-羟基香豆素(umbelliferone,UMB)和6,7-二羟基香豆素(aesculetin,AES)与小牛胸腺DNA的作用机制,探讨其构效关系.方法:采用荧光光谱法研究UMB和AES与DNA的结合作用,并计算相关结合参数,利用紫外光谱、盐效应、I-猝灭、与单双链DNA作用、DNA热变性温度及黏度测定等方法确定UMB和AES与DNA的作用模式.结果:DNA对UMB和AES的荧光猝灭机制均为静态猝灭;UMB和AES与DNA的结合常数分别为2.13×104和5.27×102L·mol-1,作用力主要是氢键和范德华力.结论:UMB和AES与DNA的作用方式均为沟槽作用.%Objective: To investigate the mechanism and the structure-activity relationship of umbelliferone (UMB) and aesculetin (AES) with calf thymus DNA. Methods: Fluorescence spectroscopy was used to determine the interaction of UMB and AES with DNA and to calculate the binding parameters. The binding mode of UMB and AES with DNA were determined by UV-Vis spectra, salt effect, I quenching effect, the comparison of single and double stranded DNA bound to UMB and AES, DNA denaturation temperature and DNA viscosity measurement.Results: The mechanism of fluorescence quenching of UMB and AES with DNA were static quenching. The binding constants of UMB and AES with DNA were 2.34 × 104 and 5.27 × 102 L·mol-1, respectively. The main binding forces were hydrogen bond and van der Waals. Conclusion: Both UMB and AES interacted with calf thymus DNA in groove bindings.

  18. 基于氨基酸性质的EB病毒抗原MHC-I类分子限制性表位的定量构效关系建模%Quantitative structure-activity relationship modeling of MHC class-Ⅰrestrained antigenic epitope of Epstein-Barr virus based on the properties of amino acids

    Institute of Scientific and Technical Information of China (English)

    韩英子; 王远强; 胡勇; 纪永军; 路亚阔; 蓝君; 罗鸿; 林治华

    2013-01-01

    目的 建立EB病毒(EBBV)抗原表位的理论计算模型并用于其定量预测,为肿瘤免疫的多肽疫苗设计提供理论基础.方法 从表位数据库中收集33条EBV抗原表位,使用逐步回归(STR)方法筛选2个对平衡解离常数(KD)贡献较大的结构参数用于表位的结构表征,最后用多元线性回归(MLR)方法建立结构参数与KD的定量构效关系(QSAR)模型.结果 该模型具有较好的稳定性(R2=0.637,Q2=0.581)与预测能力(R2test=0.501).结论 此方法可确定表位中各个氨基酸的物理性质对于平衡解离常数的贡献,为表位设计与改造提供直接线索;STR和MLR相结合建模方法具有物化意义明确、易于解释及操作简便易行等优点.%Epstein-Barr virus (EBV) is highly associated with several neoplastic diseases. The development of vaccine based on the antigenic epitope is very important for immunotherapies of human cancers. It is necessary to construct theoretical model for quantitative prediction of epitope, because the identification and screen of epitope need long time and high cost through experiments. In this study, 33 epitopes from EBV had been collected from epitope database. Then, the properties with significant contribution for equilibrium dissociation constant (KD) were screened by the stepwise, which were used to characterize the epitopes. Finally, the quantitative structure-activity relationship model between structural variables and KD was constructed by multiple linear regressions (MLR). The QSAR model has good reliability (R2=0.637, Q2=0.581) and predictive ability (R2test=0.501), and can provide more clues for the design and modification of epitope. The QSAR model constructed by STR and MLR has some advantages, such as good reliability and predictive ability, definitive physiochemical meaning and easier operation, and it can guide the rational design and structural modification of epitope directly.

  19. Estudo da relação estrutura-atividade de saponinas hemolíticas e/ou imunoadjuvantes mediante uso de análise multivariada Study of the structure-activity relationship of adjuvant and/or hemolytic saponins by use of multivariate analysis

    Directory of Open Access Journals (Sweden)

    Samuel Kaiser

    2010-07-01

    Full Text Available Entre as diversas atividades biológicas relatadas para as saponinas, merecem destaque aquelas relacionadas ao aumento da resposta imune e a ruptura das membranas dos eritrócitos. No desenvolvimento de vacinas, ambas as propriedades exercem atividades antagônicas, contudo, as informações sobre as relações estrutura-atividade são relativamente escassas e, às vezes, conflitantes. O presente trabalho visa contribuir no estabelecimento das relações estruturais envolvidas com as atividades imunoadjuvante e hemolítica de saponinas triterpênicas. Para isso, foram selecionadas vinte saponinas de estrutura triterpênica, isoladas das espécies Aesculus hippocastanum, Dolichos lablab e Glycine max. A relação entre grupamentos substituintes do anel triterpênico e as atividades biológicas foi estudada mediante análise de agrupamentos e análise de componentes principais. Os resultados confirmam a importância da presença de açúcares em C-3 para a atividade hemolítica. Porém o efeito causado pela presença de uma hidroxila em C-16, de CH2OH em C-17, de uma acetila em C-22 e de um grupamento acila em C-21 sobre essa atividade parece ser mais acentuado. Já a presença de uma hidroxila em C-21, de uma metila em C-17 e de dois açúcares ligados à aglicona parece ser determinante para a atividade imunoadjuvante. Além disso, observa-se a existência de uma relação inversa entre as atividades hemolítica e imunoadjuvante.Among the various biological activities reported for saponins, those related with increase immune response and the destruction of the membrane of red blood cells deserve attention. In the development of vaccines, these properties exert antagonistic activities. However, the information about the structure-activity relationships is relatively scarce and sometimes contradictory. This paper aims to contribute to the establishment of structural relations involved with the hemolytic and adjuvant activities of triterpenic

  20. Phonetic categorization in auditory word perception.

    Science.gov (United States)

    Ganong, W F

    1980-02-01

    To investigate the interaction in speech perception of auditory information and lexical knowledge (in particular, knowledge of which phonetic sequences are words), acoustic continua varying in voice onset time were constructed so that for each acoustic continuum, one of the two possible phonetic categorizations made a word and the other did not. For example, one continuum ranged between the word dash and the nonword tash; another used the nonword dask and the word task. In two experiments, subjects showed a significant lexical effect--that is, a tendency to make phonetic categorizations that make words. This lexical effect was greater at the phoneme boundary (where auditory information is ambiguous) than at the ends of the condinua. Hence the lexical effect must arise at a stage of processing sensitive to both lexical knowledge and auditory information.

  1. Speech perception as complex auditory categorization

    Science.gov (United States)

    Holt, Lori L.

    2002-05-01

    Despite a long and rich history of categorization research in cognitive psychology, very little work has addressed the issue of complex auditory category formation. This is especially unfortunate because the general underlying cognitive and perceptual mechanisms that guide auditory category formation are of great importance to understanding speech perception. I will discuss a new methodological approach to examining complex auditory category formation that specifically addresses issues relevant to speech perception. This approach utilizes novel nonspeech sound stimuli to gain full experimental control over listeners' history of experience. As such, the course of learning is readily measurable. Results from this methodology indicate that the structure and formation of auditory categories are a function of the statistical input distributions of sound that listeners hear, aspects of the operating characteristics of the auditory system, and characteristics of the perceptual categorization system. These results have important implications for phonetic acquisition and speech perception.

  2. [Review and categorization of quinolone antibiotics].

    Science.gov (United States)

    Benes, Jirí

    2005-02-01

    No standard categorization of quinolone antibiotics into generations may be found in either Czech or world literature. The author recommends a categorization into four groups defined according to their spectrum of action and utilization: 1) preparations for the treatment of urinary tract infections; 2) systemically acting quinolones chiefly efficacious against Gram-negative bacteria; 3) so-called respiratory quinolones; and 4) quinolones with a very broad spectrum of action suitable for the treatment of very complicated infections. The author describes the chief characteristics of the most important quinolone antibiotics, including preparations either in their development stage or whose development has been prematurely interrupted because of adverse side-effects. The list includes all preparations that are or were temporarily registered in the Czech Republic.

  3. Multilingual Sentence Categorization according to Language

    CERN Document Server

    Giguet, E

    1995-01-01

    In this paper, we describe an approach to sentence categorization which has the originality to be based on natural properties of languages with no training set dependency. The implementation is fast, small, robust and textual errors tolerant. Tested for french, english, spanish and german discrimination, the system gives very interesting results, achieving in one test 99.4% correct assignments on real sentences. The resolution power is based on grammatical words (not the most common words) and alphabet. Having the grammatical words and the alphabet of each language at its disposal, the system computes for each of them its likelihood to be selected. The name of the language having the optimum likelihood will tag the sentence --- but non resolved ambiguities will be maintained. We will discuss the reasons which lead us to use these linguistic facts and present several directions to improve the system's classification performance. Categorization sentences with linguistic properties shows that difficult problems ...

  4. Other-Initiated Repair and Membership Categorization

    DEFF Research Database (Denmark)

    Egbert, Maria

    2004-01-01

    In continuation of recent discussions in JoP and elsewhere concerning the aptness of conversation analysis (‘‘CA’’) as a research methodology for ‘‘intercultural’’ interaction, this CA-study shows some procedures by which interactants overtly or covertly orient to regional or linguistic category...... membership where apparent trouble in hearing or understanding the talk are addressed (‘‘other- initiated repair’’ [Language 54 (2) (1977) 361]). These practices of membership categorizing are inferred from different kinds of structural elaborateness beyond the basic two-part repair sequence. CA is shown...... to provide analytic tools which are highly suitable to detecting and describing practices of membership categorizing along regional or linguistic lines both in so-called ‘‘native/native’’ and ‘‘native/nonnative’’ interaction....

  5. The Representation and Matching of Categorical Shape

    Science.gov (United States)

    2005-07-01

    with added flexibility for representing complex 3-D objects. Leibe and Schiele [23] propose a new database for comparing different methods for object cat...for object class recognition. In Workshop on Learning, Snowbird, Utah, 2004. [22] B. Leibe and B. Schiele . Analyzing appearance and contour based...and Bernt Schiele . Analyzing appearance and contour based methods for object categorization. In CVPR (2), pages 409–415, 2003. [24] T. Lindeberg. Edge

  6. Categorizing the Growth Strategies of Small Firms

    OpenAIRE

    Mika Westerlund; Seppo Leminen

    2012-01-01

    This study investigates the link between a small firm’s investment in R&D and its growth strategy. A firm’s growth strategy refers to the means by which the organization plans to achieve its objective to grow in volume and turnover. We categorize firm growth strategies into eight distinctive clusters: opportunity explorers, radical innovators, business developers, business expanders, profit makers, business rebuilders, stagnators, and downsizers. We argue that understanding a firm’s growth or...

  7. Identification and Categorization of Climate Change Risks

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yuehong; WU Shaohong; DAI Erfu; LIU Dengwei; YIN Yunhe

    2008-01-01

    The scientific evidence that climate is changing due to greenhouse gas emission is now incontestable,which may put many social,biological,and geophysical systems in the world at risk.In this paper,we first identified main risks induced from or aggravated by climate change.Then we categorized them applying a new risk categorization system brought forward by Renn in a framework of International Risk Governance Council.We proposed that "uncertainty" could be treated as the classification criteria.Based on this,we established a quantitative method with fuzzy set theory,in which "confidence" and "likelihood",the main quantitative terms for expressing uncertainties in IPCC,were used as the feature parameters to construct the fuzzy membership functions of four risk types.According to the maximum principle,most climate change risks identified were classified into the appropriate risk types.In the mean time,given that not all the quantitative terms are available,a qualitative approach was also adopted as a complementary classification method.Finally,we get the preliminary results of climate change risk categorization,which might lay the foundation for the future integrated risk management of climate change.

  8. Integrating image data into biomedical text categorization.

    Science.gov (United States)

    Shatkay, Hagit; Chen, Nawei; Blostein, Dorothea

    2006-07-15

    Categorization of biomedical articles is a central task for supporting various curation efforts. It can also form the basis for effective biomedical text mining. Automatic text classification in the biomedical domain is thus an active research area. Contests organized by the KDD Cup (2002) and the TREC Genomics track (since 2003) defined several annotation tasks that involved document classification, and provided training and test data sets. So far, these efforts focused on analyzing only the text content of documents. However, as was noted in the KDD'02 text mining contest-where figure-captions proved to be an invaluable feature for identifying documents of interest-images often provide curators with critical information. We examine the possibility of using information derived directly from image data, and of integrating it with text-based classification, for biomedical document categorization. We present a method for obtaining features from images and for using them-both alone and in combination with text-to perform the triage task introduced in the TREC Genomics track 2004. The task was to determine which documents are relevant to a given annotation task performed by the Mouse Genome Database curators. We show preliminary results, demonstrating that the method has a strong potential to enhance and complement traditional text-based categorization methods.

  9. Assessing Expertise in Quantum Mechanics using Categorization Task

    CERN Document Server

    Lin, Shih-Yin

    2016-01-01

    We discuss the categorization of 20 quantum mechanics problems by 6 physics professors and 22 undergraduate students from two honors-level quantum mechanics courses. Professors and students were asked to categorize the problems based upon similarity of solution. We also had individual discussions with professors who categorized the problems. Faculty members' categorizations were overall rated better than those of students by three faculty members who evaluated all of the categorizations. But the categories created by faculty members were more diverse compared to the uniformity of the categories they created when asked to categorize introductory mechanics problems.

  10. 三种查尔酮类化合物与人血清白蛋白相互作用及其构效关系研究%Study on the Interaction and Structure-activity Relationship between Three Chalcones and Human Serum Albumin

    Institute of Scientific and Technical Information of China (English)

    张爱平; 郝娟; 黄茜; 高晓亚; 文雯

    2013-01-01

    The interaction and structure-activity relationship of human serum albumin with chalcone, 4'-methoxychalcone and 4'-chlorochalcone were investigated by ultraviolet spectroscopy, fluorescence spectroscopy and synchronous fluorescence spectroscopy under the simulative human physiological conditions. The binding constants, the number of binding sites and the thermodynamic parameters were calculated and the effects of the three compounds on the conformation of HSA were studied. The results showed that the intrinsic fluorescence of HSA was significantly quenched by chalcone, 4 -methoxychalcone and 4- respectively. The mechanism of fluorescence quenching was mainly static quenching with non-radiation energy transfer. The 1:1 compound was formed between each chalcone and HSA. The binding parameters of chalcone,4'-methoxychalcone and 4'-chlorochalcone with HSA were as follows: the binding constants K were 2. 50×104,6. 97×103 and 2.77×103L?moL-1 ,the binding distances r were 3. 78,3. 93 and 4. 25 nm,respectively. The driving forces were mainly hydrogen bond and Vander Waals according to the thermodynamic parameters. The synchronous fluorescence spectra indicated that the binding sites of chalcone,4'-methoxychalcone and 4'-chlorochalcone with HSA were closer to tryptophan residues. The interaction of the three compounds with HSA could result in the decrease of tryptophan residues hydrophobicity and the change of HSA conformation. The results demonstrated that the different substituent in chalcones played an important role in the interaction between chalcones and HSA,and the order of the interaction strength between chalcones and HSA were chalcone >4'-methoxychalcone >4 -chlorochalcone.%在模拟人体生理条件下,采用紫外光谱法、荧光光谱法和同步荧光光谱法研究查尔酮、4′-甲氧基查尔酮和4′-氯查尔酮与人血清白蛋白(HSA)的相互作用及其构效关系.实验表明:三种查尔酮类化合物对HSA的荧光猝灭机制主

  11. Categorization:The major focus of cognitive linguistics

    Institute of Scientific and Technical Information of China (English)

    程丽群

    2009-01-01

    This paper is a part of literature review of categorization of cognitive linguistics.Based on the cognitive view,some comments on categorization theory are elaborated to provide theoretical evidence for our practical teaching.

  12. Categorization.The major focus of cogni tive linguistics

    Institute of Scientific and Technical Information of China (English)

    程丽群

    2009-01-01

    This paper is a part of literature review of categorization of cognitive linguistics:Based on the cognitive view,some comments on categorization theory are elaborated to provide theoretical evidence for our practical teaching.

  13. Clustering Categorical Data:A Cluster Ensemble Approach

    Institute of Scientific and Technical Information of China (English)

    He Zengyou(何增友); Xu Xiaofei; Deng Shengchun

    2003-01-01

    Clustering categorical data, an integral part of data mining,has attracted much attention recently. In this paper, the authors formally define the categorical data clustering problem as an optimization problem from the viewpoint of cluster ensemble, and apply cluster ensemble approach for clustering categorical data. Experimental results on real datasets show that better clustering accuracy can be obtained by comparing with existing categorical data clustering algorithms.

  14. Applied categorical and count data analysis

    CERN Document Server

    Tang, Wan; Tu, Xin M

    2012-01-01

    Introduction Discrete Outcomes Data Source Outline of the BookReview of Key Statistical ResultsSoftwareContingency Tables Inference for One-Way Frequency TableInference for 2 x 2 TableInference for 2 x r TablesInference for s x r TableMeasures of AssociationSets of Contingency Tables Confounding Effects Sets of 2 x 2 TablesSets of s x r TablesRegression Models for Categorical Response Logistic Regression for Binary ResponseInference about Model ParametersGoodness of FitGeneralized Linear ModelsRegression Models for Polytomous ResponseRegression Models for Count Response Poisson Regression Mode

  15. Introduction to Categories and Categorical Logic

    Science.gov (United States)

    Abramsky, S.; Tzevelekos, N.

    The aim of these notes is to provide a succinct, accessible introduction to some of the basic ideas of category theory and categorical logic. The notes are based on a lecture course given at Oxford over the past few years. They contain numerous exercises, and hopefully will prove useful for self-study by those seeking a first introduction to the subject, with fairly minimal prerequisites. The coverage is by no means comprehensive, but should provide a good basis for further study; a guide to further reading is included.

  16. Predictive Manufacturing: Classification of categorical data

    DEFF Research Database (Denmark)

    Khan, Abdul Rauf; Schiøler, Henrik; Kulahci, Murat;

    2017-01-01

    processes is high volume of information about the process dynamics. In this paper we present a methodology to deal with the categorical data streams from manufacturing processes, with an objective of predicting failures on the last stage of the process. A thorough examination of the behaviour...... and classification capabilities of our methodology (on different experimental settings) is done through a specially designed simulation experiment. Secondly, in order to demonstrate the applicability in a real life problem a data set from electronics component manufacturing is being analysed through our proposed...

  17. Categorizing the Growth Strategies of Small Firms

    Directory of Open Access Journals (Sweden)

    Mika Westerlund

    2012-05-01

    Full Text Available This study investigates the link between a small firm’s investment in R&D and its growth strategy. A firm’s growth strategy refers to the means by which the organization plans to achieve its objective to grow in volume and turnover. We categorize firm growth strategies into eight distinctive clusters: opportunity explorers, radical innovators, business developers, business expanders, profit makers, business rebuilders, stagnators, and downsizers. We argue that understanding a firm’s growth orientation provides a way to assess the returns of its R&D investments, because an organization’s intangible growth strategies and tangible inputs are connected.

  18. Tourist Satisfaction and Destination Loyalty intention: A Structural and Categorical Analysis

    OpenAIRE

    Guerreiro, M.; Mendes, J; J. A. Silva; Oom do Valle, P.

    2006-01-01

    This study explores the relationship between travel satisfaction and destination loyalty intention. The research was conducted with 486 tourists visiting Arade, a Portuguese tourist destination. Taking as the basis the use of structural equation modelling (SEM), the results substantiate the importance of tourism satisfaction as a determinant of destination loyalty. Also, a categorical principal components analysis (CATPCA) provides a detailed analysis of this cause-effect relationship by esta...

  19. Using Corpus Statistics to Remove Redundant Words in Text Categorization.

    Science.gov (United States)

    Yang, Yiming; Wilbur, John

    1996-01-01

    Studies aggressive automated word removal in text categorization in large databases based on corpus statistics to reduce the noise in free texts and to enhance the computational efficiency of categorization. Topics include stop word identification, categorization methods for comparison, tests on four document collections, and evaluation…

  20. The Curious Case of Orthographic Distinctiveness: Disruption of Categorical Processing

    Science.gov (United States)

    McDaniel, Mark A.; Cahill, Michael J.; Bugg, Julie M.

    2016-01-01

    How does orthographic distinctiveness affect recall of structured (categorized) word lists? On one theory, enhanced item-specific information (e.g., more distinct encoding) in concert with robust relational information (e.g., categorical information) optimally supports free recall. This predicts that for categorically structured lists,…

  1. Categorization of Quantum Mechanics Problems by Professors and Students

    Science.gov (United States)

    Lin, Shih-Yin; Singh, Chandralekha

    2010-01-01

    We discuss the categorization of 20 quantum mechanics problems by physics professors and undergraduate students from two honours-level quantum mechanics courses. Professors and students were asked to categorize the problems based upon similarity of solution. We also had individual discussions with professors who categorized the problems. Faculty…

  2. Behavioural evidence of a dissociation between voice gender categorization and phoneme categorization using auditory morphed stimuli

    Directory of Open Access Journals (Sweden)

    Cyril R Pernet

    2014-01-01

    Full Text Available Both voice gender and speech perception rely on neuronal populations located in the peri-sylvian areas. However, whilst functional imaging studies suggest a left versus right hemisphere and anterior versus posterior dissociation between voice and speech categorization, psycholinguistic studies on talker variability suggest that these two processes (voice and speech categorization share common mechanisms. In this study, we investigated the categorical perception of voice gender (male vs. female and phonemes (/pa/ vs. /ta/ using the same stimulus continua generated by morphing. This allowed the investigation of behavioural differences while controlling acoustic characteristics, since the same stimuli were used in both tasks. Despite a higher acoustic dissimilarity between items during the phoneme categorization task (a male and female voice producing the same phonemes than the gender task (the same person producing 2 phonemes, results showed that speech information is being processed much faster than voice information. In addition, f0 or timbre equalization did not affect RT, which disagrees with the classical psycholinguistic models in which voice information is stripped away or normalized to access phonetic content. Also, despite similar response (percentages and perceptual (d’ curves, a reverse correlation analysis on acoustic features revealed, as expected, that the formant frequencies of the consonant distinguished stimuli in the phoneme task, but that only the vowel formant frequencies distinguish stimuli in the gender task. The 2nd set of results thus also disagrees with models postulating that the same acoustic information is used for voice and speech. Altogether these results suggest that voice gender categorization and phoneme categorization are dissociated at an early stage on the basis of different enhanced acoustic features that are diagnostic to the task at hand.

  3. Meta-Analysis With a Continuous Covariate That Is Differentially Categorized Across Studies.

    Science.gov (United States)

    Perin, Jamie; Fischer Walker, Christa L; Black, Robert E; Aryee, Martin J

    2016-03-01

    We propose taking advantage of methodology for missing data to estimate relationships and adjust outcomes in a meta-analysis where a continuous covariate is differentially categorized across studies. The proposed method incorporates all available data in an implementation of the expectation-maximization algorithm. We use simulations to demonstrate that the proposed method eliminates bias that would arise by ignoring a covariate and generalizes the meta-analytical approach for incorporating covariates that are not uniformly categorized. The proposed method is illustrated in an application for estimating diarrhea incidence in children aged ≤59 months.

  4. Structure-Activity Association of Flavonoids in Lung Diseases

    Directory of Open Access Journals (Sweden)

    João Henrique G. Lago

    2014-03-01

    Full Text Available Flavonoids are polyphenolic compounds classified into flavonols, flavones, flavanones, isoflavones, catechins, anthocyanidins, and chalcones according to their chemical structures. They are abundantly found in Nature and over 8,000 flavonoids have from different sources, mainly plant materials, have been described. Recently reports have shown the valuable effects of flavonoids as antiviral, anti-allergic, antiplatelet, antitumor, antioxidant, and anti-inflammatory agents and interest in these compounds has been increasing since they can be helpful to human health. Several mechanisms of action are involved in the biological properties of flavonoids such as free radical scavenging, transition metal ion chelation, activation of survival genes and signaling pathways, regulation of mitochondrial function and modulation of inflammatory responses. The anti-inflammatory effects of flavonoids have been described in a number of studies in the literature, but not frequently associated to respiratory disease. Thus, this review aims to discuss the effects of different flavonoids in the control of lung inflammation in some disorders such as asthma, lung emphysema and acute respiratory distress syndrome and the possible mechanisms of action, as well as establish some structure-activity relationships between this biological potential and chemical profile of these compounds.

  5. What is automatized during perceptual categorization?

    Science.gov (United States)

    Roeder, Jessica L; Ashby, F Gregory

    2016-09-01

    An experiment is described that tested whether stimulus-response associations or an abstract rule are automatized during extensive practice at perceptual categorization. Twenty-seven participants each completed 12,300 trials of perceptual categorization, either on rule-based (RB) categories that could be learned explicitly or information-integration (II) categories that required procedural learning. Each participant practiced predominantly on a primary category structure, but every third session they switched to a secondary structure that used the same stimuli and responses. Half the stimuli retained their same response on the primary and secondary categories (the congruent stimuli) and half switched responses (the incongruent stimuli). Several results stood out. First, performance on the primary categories met the standard criteria of automaticity by the end of training. Second, for the primary categories in the RB condition, accuracy and response time (RT) were identical on congruent and incongruent stimuli. In contrast, for the primary II categories, accuracy was higher and RT was lower for congruent than for incongruent stimuli. These results are consistent with the hypothesis that rules are automatized in RB tasks, whereas stimulus-response associations are automatized in II tasks. A cognitive neuroscience theory is proposed that accounts for these results.

  6. Transfer learning for visual categorization: a survey.

    Science.gov (United States)

    Shao, Ling; Zhu, Fan; Li, Xuelong

    2015-05-01

    Regular machine learning and data mining techniques study the training data for future inferences under a major assumption that the future data are within the same feature space or have the same distribution as the training data. However, due to the limited availability of human labeled training data, training data that stay in the same feature space or have the same distribution as the future data cannot be guaranteed to be sufficient enough to avoid the over-fitting problem. In real-world applications, apart from data in the target domain, related data in a different domain can also be included to expand the availability of our prior knowledge about the target future data. Transfer learning addresses such cross-domain learning problems by extracting useful information from data in a related domain and transferring them for being used in target tasks. In recent years, with transfer learning being applied to visual categorization, some typical problems, e.g., view divergence in action recognition tasks and concept drifting in image classification tasks, can be efficiently solved. In this paper, we survey state-of-the-art transfer learning algorithms in visual categorization applications, such as object recognition, image classification, and human action recognition.

  7. Automatic Induction of Rule Based Text Categorization

    Directory of Open Access Journals (Sweden)

    D.Maghesh Kumar

    2010-12-01

    Full Text Available The automated categorization of texts into predefined categories has witnessed a booming interest in the last 10 years, due to the increased availability of documents in digital form and the ensuingneed to organize them. In the research community the dominant approach to this problem is based on machine learning techniques: a general inductive process automatically builds a classifier by learning, from a set of preclassified documents, the characteristics of the categories. This paper describes, a novel method for the automatic induction of rule-based text classifiers. This method supports a hypothesis language of the form "if T1, … or Tn occurs in document d, and none of T1+n,... Tn+m occurs in d, then classify d under category c," where each Ti is a conjunction of terms. This survey discusses the main approaches to text categorization that fall within the machine learning paradigm. Issues pertaining tothree different problems, namely, document representation, classifier construction, and classifier evaluation were discussed in detail.

  8. Combining dimensional and categorical representation of psychosis: the way forward for DSM-V and ICD-11?

    LENUS (Irish Health Repository)

    Demjaha, A

    2009-12-01

    There is good evidence that psychotic symptoms segregate into symptom dimensions. However, it is still unclear how these dimensions are associated with risk indicators and other clinical variables, and whether they have advantages over categorical diagnosis in clinical practice. We investigated symptom dimensions in a first-onset psychosis sample and examined their associations with risk indicators and clinical variables. We then examined the relationship of categorical diagnoses to the same variables.

  9. Categorical Perception of Lexical Tones in Mandarin-speaking Congenital Amusics

    Directory of Open Access Journals (Sweden)

    Wan Ting Huang

    2015-06-01

    Full Text Available Previous research suggests that within Mandarin-speaking congenital amusics, only a subgroup has behavioral lexical tone perception impairments (tone agnosia, whereas the rest of amusics do not. The purpose of the current study was to investigate the categorical nature of lexical tone perception in Mandarin-speaking amusics with and without behavioral lexical tone deficits. Three groups of listeners (controls, pure amusics and amusics with tone agnosia participated in tone identification and discrimination tasks. Indexes of the categorical perception of a physical continuum of fundamental frequencies ranging from a rising to level tone were measured. Specifically, the stimulus durations were manipulated at 100 and 200 ms. For both stimulus durations, all groups exhibited similar categorical boundaries. The pure amusics showed sharp identification slopes and significantly peaked discrimination functions similar to those of normal controls. However, such essential characteristics for the categorical perception of lexical tones were not observed in amusics with tone agnosia. An enlarged step-size from 20 Hz to 35 Hz was not able to produce any discrimination peaks in tone agnosics either. The current study revealed that only amusics with tone agnosia showed a lack of categorical tone perception, while the pure amusics demonstrated typical categorical perception of lexical tones, indicating that the deficit of pitch processing in music does not necessarily result in the deficit in the categorical perception of lexical tones. The different performance between congenital amusics with and without tone agnosia provides a new perspective on the proposition of the relationship between music and speech perception.

  10. Categorization of Quantum Mechanics Problems by Professors and Students

    CERN Document Server

    Lin, Shih-Yin

    2016-01-01

    We discuss the categorization of 20 quantum mechanics problems by physics professors and undergraduate students from two honors-level quantum mechanics courses. Professors and students were asked to categorize the problems based upon similarity of solution. We also had individual discussions with professors who categorized the problems. Faculty members' categorizations were overall rated higher than those of students by three faculty members who evaluated all of the categorizations. The categories created by faculty members were more diverse compared to the categories they created for a set of introductory mechanics problems. Some faculty members noted that the categorization of introductory physics problems often involves identifying fundamental principles relevant for the problem, whereas in upper-level undergraduate quantum mechanics problems, it mainly involves identifying concepts and procedures required to solve the problem. Moreover, physics faculty members who evaluated others' categorizations express...

  11. Biological and structure-activity evaluation of chalcone derivatives against bacteria and fungi

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Wender A.; Andrade, Carlos Kleber Z.; Napolitano, Hamilton B., E-mail: wender@unb.br, E-mail: ckleber@unb.br [Universidade de Brasilia (LaQMOS/UnB), DF (Brazil). Inst. de Quimica; Vencato, Ivo; Castro, Miriam R.C. de; Camargo, Ademir J. [Universidade Estadual de Goias (UEG), Anapolis, GO (Brazil). Ciencias Exatas e Tecnologicas; Lariucci, Carlito [Universidade Estadual de Goias (UEG), Goiania, GO (Brazil). Inst. de Fisica

    2013-01-15

    The present work describes the antibacterial and antifungal activities of several chalcones obtained by a straight Claisen-Schmidt aldol condensation determined by the minimal inhibitory concentration against different microorganisms (Gram-positive and Gram-negative bacteria and fungi). Solid state crystal structures of seven chalcones were determined by X-ray diffraction (XRD) analysis. Chemometric studies were carried out in order to identify a potential structure activity relationship. (author)

  12. Categorical Design Departure and Symbolic Enhancement

    DEFF Research Database (Denmark)

    Krabbe, Anders Dahl

    by showing how product form design can impact the selection of dominant technological designs within industries by enhancing the symbolic attributes of products. A longitudinal case study was carried out of the establishment of a new dominant technological architecture in the hearing aid industry....... It was found how categorically departing product designs can catalyze the selection of a new dominant technological architecture by establishing a ‘dominant aesthetic manifestation’ of superior symbolic value.......Previous research has tended to assume that the role of product form design in the early stages of technology lifecycles is to decrease the cognitive distance between the new product and previous designs within the given product category. This paper will contrast this tendency in the literature...

  13. Intuitionistic Fuzzy Graphs with Categorical Properties

    Directory of Open Access Journals (Sweden)

    Hossein Rashmanlou

    2015-09-01

    Full Text Available The main purpose of this paper is to show the rationality of some operations, defined or to be defined, on intuitionistic fuzzy graphs. Firstly, three kinds of new product operations (called direct product, lexicographic product, and strong product are defined in intuitionistic fuzzy graphs, and some important notions on intuitionistic fuzzy graphs are demonstrated by characterizing these notions and their level counterparts graphs such as intuitionistic fuzzy complete graph, cartesian product of intuitionistic fuzzy graphs, composition of intuitionistic fuzzy graphs, union of intuitionistic fuzzy graphs, and join of intuitionistic fuzzy graphs. As a result, a kind of representations of intuitionistic fuzzy graphs and intuitionistic fuzzy complete graphs are given. Next, categorical goodness of intuitionistic fuzzy graphs is illustrated by proving that the category of intuitionistic fuzzy graphs and homomorphisms between them is isomorphic-closed, complete, and co-complete.

  14. Introduction to Categories and Categorical Logic

    CERN Document Server

    Abramsky, Samson

    2011-01-01

    The aim of these notes is to provide a succinct, accessible introduction to some of the basic ideas of category theory and categorical logic. The notes are based on a lecture course given at Oxford over the past few years. They contain numerous exercises, and hopefully will prove useful for self-study by those seeking a first introduction to the subject, with fairly minimal prerequisites. The coverage is by no means comprehensive, but should provide a good basis for further study; a guide to further reading is included. The main prerequisite is a basic familiarity with the elements of discrete mathematics: sets, relations and functions. An Appendix contains a summary of what we will need, and it may be useful to review this first. In addition, some prior exposure to abstract algebra - vector spaces and linear maps, or groups and group homomorphisms - would be helpful.

  15. Towards a Categorical Account of Conditional Probability

    Directory of Open Access Journals (Sweden)

    Robert Furber

    2015-11-01

    Full Text Available This paper presents a categorical account of conditional probability, covering both the classical and the quantum case. Classical conditional probabilities are expressed as a certain "triangle-fill-in" condition, connecting marginal and joint probabilities, in the Kleisli category of the distribution monad. The conditional probabilities are induced by a map together with a predicate (the condition. The latter is a predicate in the logic of effect modules on this Kleisli category. This same approach can be transferred to the category of C*-algebras (with positive unital maps, whose predicate logic is also expressed in terms of effect modules. Conditional probabilities can again be expressed via a triangle-fill-in property. In the literature, there are several proposals for what quantum conditional probability should be, and also there are extra difficulties not present in the classical case. At this stage, we only describe quantum systems with classical parametrization.

  16. Neural network models of categorical perception.

    Science.gov (United States)

    Damper, R I; Harnad, S R

    2000-05-01

    Studies of the categorical perception (CP) of sensory continua have a long and rich history in psychophysics. In 1977, Macmillan, Kaplan, and Creelman introduced the use of signal detection theory to CP studies. Anderson and colleagues simultaneously proposed the first neural model for CP, yet this line of research has been less well explored. In this paper, we assess the ability of neural-network models of CP to predict the psychophysical performance of real observers with speech sounds and artificial/novel stimuli. We show that a variety of neural mechanisms are capable of generating the characteristics of CP. Hence, CP may not be a special model of perception but an emergent property of any sufficiently powerful general learning system.

  17. Person categorization and automatic racial stereotyping effects on weapon identification.

    Science.gov (United States)

    Jones, Christopher R; Fazio, Russell H

    2010-08-01

    Prior stereotyping research provides conflicting evidence regarding the importance of person categorization along a particular dimension for the automatic activation of a stereotype corresponding to that dimension. Experiment 1 replicated a racial stereotyping effect on object identification and examined whether it could be attenuated by encouraging categorization by age. Experiment 2 employed socially complex person stimuli and manipulated whether participants categorized spontaneously or by race. In Experiment 3, the distinctiveness of the racial dimension was manipulated by having Black females appear in the context of either Black males or White females. The results indicated that conditions fostering categorization by race consistently produced automatic racial stereotyping and that conditions fostering nonracial categorization can eliminate automatic racial stereotyping. Implications for the relation between automatic stereotype activation and dimension of categorization are discussed.

  18. Categorization of birds, mammals, and chimeras by pigeons.

    Science.gov (United States)

    Cook, Robert G; Wright, Anthony A; Drachman, Eric E

    2013-02-01

    Identifying critical features that control categorization of complex polymorphous pictures by animals remains a challenging and important problem. Toward this goal, experiments were conducted to isolate the properties controlling the categorization of two pictorial categories by pigeons. Pigeons were trained in a go/no-go task to categorize black and white line drawings of birds and mammals. They were then tested with a variety of familiar and novel exemplars of these categories to examine the features controlling this categorization. These tests suggested the pigeons were segregating and using the principal axis of orientation of the animal figures as the primary means of discriminating each category, although other categorical and item-specific cues were likely involved. This perceptual/cognitive reduction of the categorical stimulus space to a few visual features or dimensions is likely a characteristic of this species' processing of complex pictorial discrimination problems and is a critical property for theoretical accounts of this behavior.

  19. ARABIC TEXT CATEGORIZATION ALGORITHM USING VECTOR EVALUATION METHOD

    Directory of Open Access Journals (Sweden)

    Ashraf Odeh

    2014-12-01

    Full Text Available Text categorization is the process of grouping documents into categories based on their contents. This process is important to make information retrieval easier, and it became more important due to the huge textual information available online. The main problem in text categorization is how to improve the classification accuracy. Although Arabic text categorization is a new promising field, there are a few researches in this field. This paper proposes a new method for Arabic text categorization using vector evaluation. The proposed method uses a categorized Arabic documents corpus, and then the weights of the tested document's words are calculated to determine the document keywords which will be compared with the keywords of the corpus categorizes to determine the tested document's best category.

  20. Assessing Expertise in Introductory Physics Using Categorization Task

    CERN Document Server

    Mason, Andrew

    2016-01-01

    The ability to categorize problems based upon underlying principles, rather than surface features or contexts, is considered one of several proxy predictors of expertise in problem solving. With inspiration from the classic study by Chi, Feltovich, and Glaser, we assess the distribution of expertise among introductory physics students by asking three introductory physics classes, each with more than a hundred students, to categorize mechanics problems based upon similarity of solution. We compare their categorization with those of physics graduate students and faculty members. To evaluate the effect of problem context on students' ability to categorize, two sets of problems were developed for categorization. Some problems in one set included those available from the prior study by Chi et al. We find a large overlap between calculus-based introductory students and graduate students with regard to their categorizations that were assessed as "good." Our findings, which contrast with those of Chi et al., suggest ...

  1. A Prototype-Based Resonance Model of Rhythm Categorization

    Directory of Open Access Journals (Sweden)

    Rasmus Bååth

    2014-10-01

    Full Text Available Categorization of rhythmic patterns is prevalent in musical practice, an example of this being the transcription of (possibly not strictly metrical music into musical notation. In this article we implement a dynamical systems' model of rhythm categorization based on the resonance theory of rhythm perception developed by Large (2010. This model is used to simulate the categorical choices of participants in two experiments of Desain and Honing (2003. The model accurately replicates the experimental data. Our results support resonance theory as a viable model of rhythm perception and show that by viewing rhythm perception as a dynamical system it is possible to model central properties of rhythm categorization.

  2. A prototype-based resonance model of rhythm categorization.

    Science.gov (United States)

    Bååth, Rasmus; Lagerstedt, Erik; Gärdenfors, Peter

    2014-01-01

    Categorization of rhythmic patterns is prevalent in musical practice, an example of this being the transcription of (possibly not strictly metrical) music into musical notation. In this article we implement a dynamical systems' model of rhythm categorization based on the resonance theory of rhythm perception developed by Large (2010). This model is used to simulate the categorical choices of participants in two experiments of Desain and Honing (2003). The model accurately replicates the experimental data. Our results support resonance theory as a viable model of rhythm perception and show that by viewing rhythm perception as a dynamical system it is possible to model central properties of rhythm categorization.

  3. On $\\omega$-categorical groups and rings with NIP

    CERN Document Server

    Krupinski, Krzysztof

    2010-01-01

    We show that $\\omega$-categorical rings with NIP are nilpotent-by-finite. We prove that an $\\omega$-categorical group with NIP and fsg is nilpotent-by-finite. We also notice that an $\\omega$-categorical group with at least one strongly regular type is abelian. Moreover, we get that each $\\omega$-categorical, characteristically simple $p$-group with NIP has an infinite, definable abelian subgroup. Assuming additionally the existence of a non-algebraic, generically stable over $\\emptyset$ type, such a group is abelian.

  4. Residual abilities in age-related macular degeneration to process spatial frequencies during natural scene categorization.

    Science.gov (United States)

    Musel, Benoit; Hera, Ruxandra; Chokron, Sylvie; Alleysson, David; Chiquet, Christophe; Romanet, Jean-Paul; Guyader, Nathalie; Peyrin, Carole

    2011-11-01

    Age-related macular degeneration (AMD) is characterized by a central vision loss. We explored the relationship between the retinal lesions in AMD patients and the processing of spatial frequencies in natural scene categorization. Since the lesion on the retina is central, we expected preservation of low spatial frequency (LSF) processing and the impairment of high spatial frequency (HSF) processing. We conducted two experiments that differed in the set of scene stimuli used and their exposure duration. Twelve AMD patients and 12 healthy age-matched participants in Experiment 1 and 10 different AMD patients and 10 healthy age-matched participants in Experiment 2 performed categorization tasks of natural scenes (Indoors vs. Outdoors) filtered in LSF and HSF. Experiment 1 revealed that AMD patients made more no-responses to categorize HSF than LSF scenes, irrespective of the scene category. In addition, AMD patients had longer reaction times to categorize HSF than LSF scenes only for indoors. Healthy participants' performance was not differentially affected by spatial frequency content of the scenes. In Experiment 2, AMD patients demonstrated the same pattern of errors as in Experiment 1. Furthermore, AMD patients had longer reaction times to categorize HSF than LSF scenes, irrespective of the scene category. Again, spatial frequency processing was equivalent for healthy participants. The present findings point to a specific deficit in the processing of HSF information contained in photographs of natural scenes in AMD patients. The processing of LSF information is relatively preserved. Moreover, the fact that the deficit is more important when categorizing HSF indoors, may lead to new perspectives for rehabilitation procedures in AMD.

  5. Categorical representation of North American precipitation projections

    Science.gov (United States)

    Greene, Arthur M.; Seager, Richard

    2016-04-01

    We explore use of the familiar tercile framework of seasonal forecasting for the characterization of 21st-century precipitation projections over North America. Consistent with direct analyses of modeled precipitation change, in a superensemble of CMIP5 simulations an unambiguous pattern of shifted tercile population statistics develops as the globe warms. Expressed categorically, frequencies for the low (i.e., dry) tercile increase in the southwestern United States and southward into Mexico and decrease across the northern tier of North America, while counts for the high tercile shift in the opposite sense. We show that as the 21st-century proceeds, changes become statistically significant over wide regions in the pointwise sense, and also when considered as projections on model-specific climate change “fingerprints”. Background noise in the superensemble, against which significance is established, comprises both structural model uncertainty and natural climate variability. The robustness of these findings makes a compelling case for long-range planning for a dryer future in the American Southwest and southward, and wetter one to the north and especially northeast, while communication is facilitated by widespread user familiarity with the tercile format.

  6. Categorization of natural dynamic audiovisual scenes.

    Directory of Open Access Journals (Sweden)

    Olli Rummukainen

    Full Text Available This work analyzed the perceptual attributes of natural dynamic audiovisual scenes. We presented thirty participants with 19 natural scenes in a similarity categorization task, followed by a semi-structured interview. The scenes were reproduced with an immersive audiovisual display. Natural scene perception has been studied mainly with unimodal settings, which have identified motion as one of the most salient attributes related to visual scenes, and sound intensity along with pitch trajectories related to auditory scenes. However, controlled laboratory experiments with natural multimodal stimuli are still scarce. Our results show that humans pay attention to similar perceptual attributes in natural scenes, and a two-dimensional perceptual map of the stimulus scenes and perceptual attributes was obtained in this work. The exploratory results show the amount of movement, perceived noisiness, and eventfulness of the scene to be the most important perceptual attributes in naturalistically reproduced real-world urban environments. We found the scene gist properties openness and expansion to remain as important factors in scenes with no salient auditory or visual events. We propose that the study of scene perception should move forward to understand better the processes behind multimodal scene processing in real-world environments. We publish our stimulus scenes as spherical video recordings and sound field recordings in a publicly available database.

  7. Complex surveys analysis of categorical data

    CERN Document Server

    Mukhopadhyay, Parimal

    2016-01-01

    The primary objective of this book is to study some of the research topics in the area of analysis of complex surveys which have not been covered in any book yet. It discusses the analysis of categorical data using three models: a full model, a log-linear model and a logistic regression model. It is a valuable resource for survey statisticians and practitioners in the field of sociology, biology, economics, psychology and other areas who have to use these procedures in their day-to-day work. It is also useful for courses on sampling and complex surveys at the upper-undergraduate and graduate levels. The importance of sample surveys today cannot be overstated. From voters’ behaviour to fields such as industry, agriculture, economics, sociology, psychology, investigators generally resort to survey sampling to obtain an assessment of the behaviour of the population they are interested in. Many large-scale sample surveys collect data using complex survey designs like multistage stratified cluster designs. The o...

  8. Different options for noble gas categorization schemes

    Science.gov (United States)

    Kalinowski, Martin

    2010-05-01

    For noble gas monitoring it is crucial to support the decision makers who need to decide whether a decection may indicate a potential nuclear test. Several parameters are available that may help to distinguish a legitimate civilian source from a nuclear explosion. The most promising parameters are: (a) Anomaly observations with respect to the history of concentrations found at that site. (b) Isotopic activity ratios can be used to separate a nuclear reactor domain from the parameter space that is specific for nuclear explosions. (c) Correlation with source-receptor-sensitivities related to known civilian sources as determined by atmospheric transport simulations. A combination of these can be used to categorize an observation. So far, several initial ideas have been presented but the issue of noble gas categorisation has been postponed with the argument that further scientific studies and additional experience have to be awaited. This paper presents the principles of different options for noble gas categorisation and considers how they would meet the interests of different classes of member states. It discusses under different points of view what might be the best approach for the noble gas categorisation scheme.

  9. Classification/Categorization Model of Instruction for Learning Disabled Students.

    Science.gov (United States)

    Freund, Lisa A.

    1987-01-01

    Learning-disabled students deficient in classification and categorization require specific instruction in these skills. Use of a classification/categorization instructional model improved the questioning strategies of 60 learning-disabled students, aged 10 to 12. The use of similar models is discussed as a basis for instruction in science, social…

  10. Categorization of aortic aneurysm thrombus morphology by magnetic resonance imaging

    DEFF Research Database (Denmark)

    de la Motte, Louise; Pedersen, Mads Møller; Thomsen, Carsten;

    2013-01-01

    Magnetic resonance imaging (MRI) has been proposed for qualitative categorization of intraluminal thrombus morphology. We aimed to correlate the qualitative MRI categorization previously described to quantitative measurements of signal intensity and to compare morphological characteristics...... of intraluminal thrombus specimens to the appearance on magnetic resonance imaging....

  11. Categorical Representation of Facial Expressions in the Infant Brain

    Science.gov (United States)

    Leppanen, Jukka M.; Richmond, Jenny; Vogel-Farley, Vanessa K.; Moulson, Margaret C.; Nelson, Charles A.

    2009-01-01

    Categorical perception, demonstrated as reduced discrimination of within-category relative to between-category differences in stimuli, has been found in a variety of perceptual domains in adults. To examine the development of categorical perception in the domain of facial expression processing, we used behavioral and event-related potential (ERP)…

  12. Categorical Perception of Emotional Facial Expressions in Preschoolers

    Science.gov (United States)

    Cheal, Jenna L.; Rutherford, M. D.

    2011-01-01

    Adults perceive emotional facial expressions categorically. In this study, we explored categorical perception in 3.5-year-olds by creating a morphed continuum of emotional faces and tested preschoolers' discrimination and identification of them. In the discrimination task, participants indicated whether two examples from the continuum "felt the…

  13. Assessing expertise in introductory physics using categorization task

    Directory of Open Access Journals (Sweden)

    Andrew Mason

    2011-10-01

    Full Text Available The ability to categorize problems based upon underlying principles, rather than surface features or contexts, is considered one of several proxy predictors of expertise in problem solving. With inspiration from the classic study by Chi, Feltovich, and Glaser, we assess the distribution of expertise among introductory physics students by asking three introductory physics classes, each with more than a hundred students, to categorize mechanics problems based upon similarity of solution. We compare their categorization with those of physics graduate students and faculty members. To evaluate the effect of problem context on students’ ability to categorize, two sets of problems were developed for categorization. Some problems in one set included those available from the prior study by Chi et al. We find a large overlap between calculus-based introductory students and graduate students with regard to their categorizations that were assessed as “good.” Our findings, which contrast with those of Chi et al., suggest that there is a wide distribution of expertise in mechanics among introductory and graduate students. Although the categorization task is conceptual, introductory students in the calculus-based course performed better than those in the algebra-based course. Qualitative trends in categorization of problems are similar between the non-Chi problems and problems available from the Chi study used in our study although the Chi problems used are more difficult on average.

  14. ONTOLOGY INTEGRATION APPROACHES AND ITS IMPACT ON TEXT CATEGORIZATION

    Directory of Open Access Journals (Sweden)

    Hamid Machhour

    2013-05-01

    Full Text Available This article will introduce some approaches for improving text categorization models by integrating previously imported ontologies. From the Reuters Corpus Volume I (RCV1 dataset, some categories very similar in content and related to telecommunications, Internet and computer areas were selected for models experiments. Several domain ontologies, covering these areas were built and integrated to categorization models for their improvements.

  15. Categorization and Pathology of Persian Stylistic Researches

    Directory of Open Access Journals (Sweden)

    Maryam Dorpar

    2014-08-01

    Full Text Available Abstract In following article, surveys and researches about Persian style were categorized in two branches of historical and formalistic styles Mohammad Taghi Bahar founded stylistics as an autonomous knowledge by publishing his book, History of the evolution of Persian prose (1331, for teaching in University of Tehran. This book which has been influenced by verbal instructions of qajar dynasty’s scholars made the way generally has been followed by researchers in Persian stylistics up to now. However, researchers and critics have introduced various theories and approaches during last four decades.  Stagnation in Persian stylistic researches is the main problem which is considered in current article. The main questions are: What branch of stylistics should be the performed Persian stylistic researches? “what are the weak points of surveys” and “what should be done for getting rid of this stagnation?” The main objective of current article is taking steps for removing stagnation from Persian stylistics.  Malek osh-Shoara Bahar used periodization in studying prose styles and analyzed revolution of Persian prose in lexical aspect (obsolete words, Arabic words, synonyms, words repetition, morphological aspect (verbal prefixes, comparative adjective suffixes, syntactic aspect (precedence of verb over its belongings, omission of verbs and rhetorical aspect (simile and allegory, metonymy and metaphor, prolixity and periphrasis, riming prose and harmony. In fact he tried to show both health and strength and laxity and corruption period of prose. We call Bahar stylistics and all researches done in his way historical stylistics with traditional attitude. In this method, styles' consistency and evolution through history have been studied and preiodization of styles has been taken into account. Mentioned researches periodized styles, finding formal similarities and differences. Since, neglecting meaning and text functionality they have only paid

  16. Formalization of Human Categorization Process Using Interpolative Boolean Algebra

    Directory of Open Access Journals (Sweden)

    Vladimir Dobrić

    2015-01-01

    Full Text Available Since the ancient times, it has been assumed that categorization has the basic form of classical sets. This implies that the categorization process rests on the Boolean laws. In the second half of the twentieth century, the classical theory has been challenged in cognitive science. According to the prototype theory, objects belong to categories with intensities, while humans categorize objects by comparing them to prototypes of relevant categories. Such categorization process is governed by the principles of perceived world structure and cognitive economy. Approaching the prototype theory by using truth-functional fuzzy logic has been harshly criticized due to not satisfying the complementation laws. In this paper, the prototype theory is approached by using structure-functional fuzzy logic, the interpolative Boolean algebra. The proposed formalism is within the Boolean frame. Categories are represented as fuzzy sets of objects, while comparisons between objects and prototypes are formalized by using Boolean consistent fuzzy relations. Such relations are directly constructed from a Boolean consistent fuzzy partial order relation, which is treated by Boolean implication. The introduced formalism secures the principles of categorization showing that Boolean laws are fundamental in the categorization process. For illustration purposes, the artificial cognitive system which mimics human categorization activity is proposed.

  17. Color Vision and Hue Categorization in Young Human Infants

    Science.gov (United States)

    Bornstein, Marc H.; And Others

    1976-01-01

    The main objective of the present investigations was to determine whether or not young human infants see the physical spectrum in a categorical fashion as human adults and animals who possess color vision regularly do. (Author)

  18. A Goal-Directed Bayesian Framework for Categorization

    Science.gov (United States)

    Rigoli, Francesco; Pezzulo, Giovanni; Dolan, Raymond; Friston, Karl

    2017-01-01

    Categorization is a fundamental ability for efficient behavioral control. It allows organisms to remember the correct responses to categorical cues and not for every stimulus encountered (hence eluding computational cost or complexity), and to generalize appropriate responses to novel stimuli dependant on category assignment. Assuming the brain performs Bayesian inference, based on a generative model of the external world and future goals, we propose a computational model of categorization in which important properties emerge. These properties comprise the ability to infer latent causes of sensory experience, a hierarchical organization of latent causes, and an explicit inclusion of context and action representations. Crucially, these aspects derive from considering the environmental statistics that are relevant to achieve goals, and from the fundamental Bayesian principle that any generative model should be preferred over alternative models based on an accuracy-complexity trade-off. Our account is a step toward elucidating computational principles of categorization and its role within the Bayesian brain hypothesis.

  19. A CLUSTERING ALGORITHM FOR MIXED NUMERIC AND CATEGORICAL DATA

    Institute of Scientific and Technical Information of China (English)

    Ohn Mar San; Van-Nam Huynh; Yoshiteru Nakamori

    2003-01-01

    Most of the earlier work on clustering mainly focused on numeric data whose inherent geometric properties can be exploited to naturally define distance functions between data points. However, data mining applications frequently involve many datasets that also consists of mixed numeric and categorical attributes. In this paper we present a clustering algorithm which is based on the k-means algorithm. The algorithm clusters objects with numeric and categorical attributes in a way similar to k-means. The object similarity measure is derived from both numeric and categorical attributes. When applied to numeric data, the algorithm is identical to the k-means. The main result of this paper is to provide a method to update the "cluster centers" of clustering objects described by mixed numeric and categorical attributes in the clustering process to minimize the clustering cost function. The clustering performance of the algorithm is demonstrated with the two well known data sets, namely credit approval and abalone databases.

  20. SUPERVISED LEARNING METHODS FOR BANGLA WEB DOCUMENT CATEGORIZATION

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    Ashis Kumar Mandal

    2014-09-01

    Full Text Available This paper explores the use of machine learning approaches, or more specifically, four supervised learning Methods, namely Decision Tree(C 4.5, K-Nearest Neighbour (KNN, Naïve Bays (NB, and Support Vector Machine (SVM for categorization of Bangla web documents. This is a task of automatically sorting a set of documents into categories from a predefined set. Whereas a wide range of methods have been applied to English text categorization, relatively few studies have been conducted on Bangla language text categorization. Hence, we attempt to analyze the efficiency of those four methods for categorization of Bangla documents. In order to validate, Bangla corpus from various websites has been developed and used as examples for the experiment. For Bangla, empirical results support that all four methods produce satisfactory performance with SVM attaining good result in terms of high dimensional and relatively noisy document feature vectors.