XenoSite: Accurately Predicting CYP-Mediated Sites of Metabolism with Neural Networks
- 13 November 2013
- journal article
- Published by American Chemical Society (ACS) in Journal of Chemical Information and Modeling
- Vol. 53 (12), 3373-3383
- https://doi.org/10.1021/ci400518g
Abstract
Understanding how xenobiotic molecules are metabolized is important because it influences the safety, efficacy, and dose of medicines and how they can be modified to improve these properties. The cytochrome P450s (CYPs) are proteins responsible for metabolizing 90% of drugs on the market, and many computational methods can predict which atomic sites of a molecule—sites of metabolism (SOMs)—are modified during CYP-mediated metabolism. This study improves on prior methods of predicting CYP-mediated SOMs by using new descriptors and machine learning based on neural networks. The new method, XenoSite, is faster to train and more accurate by as much as 4% or 5% for some isozymes. Furthermore, some “incorrect” predictions made by XenoSite were subsequently validated as correct predictions by revaluation of the source literature. Moreover, XenoSite output is interpretable as a probability, which reflects both the confidence of the model that a particular atom is metabolized and the statistical likelihood that its prediction for that atom is correct.Keywords
This publication has 20 references indexed in Scilit:
- DR-Predictor: Incorporating Flexible Docking with Specialized Electronic Reactivity and Machine Learning Techniques to Predict CYP-Mediated Sites of MetabolismJournal of Chemical Information and Modeling, 2013
- Exposition and reactivity optimization to predict sites of metabolism in chemicalsDrug Discovery Today: Technologies, 2013
- RS-Predictor Models Augmented with SMARTCyp Reactivities: Robust Metabolic Regioselectivity Predictions for Nine CYP IsozymesJournal of Chemical Information and Modeling, 2012
- Computational Prediction of Metabolism: Sites, Products, SAR, P450 Enzyme Dynamics, and MechanismsJournal of Chemical Information and Modeling, 2012
- RS-Predictor: A New Tool for Predicting Sites of Cytochrome P450-Mediated Metabolism Applied to CYP 3A4Journal of Chemical Information and Modeling, 2011
- SMARTCyp: A 2D Method for Prediction of Cytochrome P450-Mediated Drug MetabolismACS Medicinal Chemistry Letters, 2010
- Cytochrome P450s and other enzymes in drug metabolism and toxicityThe AAPS Journal, 2006
- Clinical importance of the cytochromes P450The Lancet, 2002
- Metabolism of dexfenfluramine in human liver microsomes and by recombinant enzymes: role of CYP2D6 and 1A2Pharmacogenetics, 1998
- Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: Analysis of instances of therapeutic misadventureJournal of Hepatology, 1995