IDSite: An Accurate Approach to Predict P450-Mediated Drug Metabolism
- 2 September 2011
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Chemical Theory and Computation
- Vol. 7 (11), 3829-3845
- https://doi.org/10.1021/ct200462q
Abstract
Accurate prediction of drug metabolism is crucial for drug design. Since a large majority of drugs’ metabolism involves P450 enzymes, we herein describe a computational approach, IDSite, to predict P450-mediated drug metabolism. To model induced-fit effects, IDSite samples the conformational space with flexible docking in Glide followed by two refinement stages using the Protein Local Optimization Program (PLOP). Sites of metabolism (SOMs) are predicted according to a physical-based score that evaluates the potential of atoms to react with the catalytic iron center. As a preliminary test, we present in this paper the prediction of hydroxylation and O-dealkylation sites mediated by CYP2D6 using two different models: a physical-based simulation model and a modification of this model in which a small number of parameters are fit to a training set. Without fitting any parameters to experimental data, the physical IDSite scoring recovers 83% of the experimental observations for 56 compounds with a very low false positive rate. With only four fitted parameters, the fitted IDSite was trained with a subset of 36 compounds and successfully applied to the other 20 compounds, recovering 94% of the experimental observations with high sensitivity and specificity for both sets.Keywords
This publication has 54 references indexed in Scilit:
- The VSGB 2.0 model: A next generation energy model for high resolution protein structure modelingProteins-Structure Function and Bioinformatics, 2011
- RS-Predictor: A New Tool for Predicting Sites of Cytochrome P450-Mediated Metabolism Applied to CYP 3A4Journal of Chemical Information and Modeling, 2011
- Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450Proceedings of the National Academy of Sciences, 2011
- QM/MM Simulation on P450 BM3 Enzyme Catalysis MechanismJournal of Chemical Theory and Computation, 2009
- Quantitative DFT Modeling of the Enantiomeric Excess for Dioxirane-Catalyzed EpoxidationsJournal of the American Chemical Society, 2009
- Diversity in the Oxidation of Substrates by Cytochrome P450 2D6: Lack of an Obligatory Role of Aspartate 301−Substrate Electrostatic BondingBiochemistry, 2002
- Pharmacokinetic-Pharmacodynamic Consequences and Clinical Relevance of Cytochrome P450 3A4 InhibitionClinical Pharmacokinetics, 2000
- Clinically Relevant Pharmacology of Selective Serotonin Reuptake InhibitorsClinical Pharmacokinetics, 1997
- Metabolism of methoxyphenamine and 2-methoxyamphetamine in P4502D6-transfected cells and cell preparationsXenobiotica, 1995
- Reversible multiple time scale molecular dynamicsThe Journal of Chemical Physics, 1992