| Classification of cytochrome P450 inhibitors with respect to binding free energy and pIC50 using common molecular descriptors. | |
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MedLine Citation:
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PMID: 19777996 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Virtual screening of chemical libraries following experimental assays of drug candidates is a common procedure in structure based drug discovery. However, the relationship between binding free energies and biological activities (pIC50) of drug candidates is still an unsolved issue that limits the efficiency and speed of drug development processes. In this study, the relationship between them is investigated based on a common molecular descriptor set for human cytochrome P450 enzymes (CYPs). CYPs play an important role in drug-drug interactions, drug metabolism, and toxicity. Therefore, in silico prediction of CYP inhibition by drug candidates is one of the major considerations in drug discovery. The combination of partial least-squares regression (PLSR) and a variety of classification algorithms were employed by considering this relationship as a classification problem. Our results indicate that PLSR with classification is a powerful tool to predict more than one output such as binding free energy and pIC50 simultaneously. PLSR with mixed-integer linear programming based hyperboxes predicts the binding free energy and pIC50 with a mean accuracy of 87.18% (min: 81.67% max: 97.05%) and 88.09% (min: 79.83% max: 92.90%), respectively, for the cytochrome p450 superfamily using the common 6 molecular descriptors with a 10-fold cross-validation. |
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Authors:
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Onur Dagliyan; I Halil Kavakli; Metin Turkay |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of chemical information and modeling Volume: 49 ISSN: 1549-960X ISO Abbreviation: - Publication Date: 2009 Oct |
Date Detail:
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Created Date: 2009-10-26 Completed Date: 2009-12-24 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101230060 Medline TA: J Chem Inf Model Country: United States |
Other Details:
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Languages: eng Pagination: 2403-11 Citation Subset: IM |
Affiliation:
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Department of Chemical and Biological Engineering, College of Engineering and Center for Computational Biology and Bioinformatics, Ko?? University, Rumelifeneri yolu, Sariyer, Istanbul, 34450 Turkey. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Algorithms Cytochrome P-450 Enzyme System / antagonists & inhibitors*, chemistry, metabolism* Drug Discovery Enzyme Inhibitors / classification, metabolism*, pharmacology* Humans Inhibitory Concentration 50 Least-Squares Analysis Molecular Dynamics Simulation Protein Binding Protein Conformation Thermodynamics* |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 9035-51-2/Cytochrome P-450 Enzyme System |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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