Predicting routes of phase I and II metabolism based on quantum mechanics and machine learning

In this study, we describe the development and validation of a 'WhichEnzyme' model that accurately predicts the enzyme families most likely to be responsible for a drug-like molecule's metabolism. Furthermore, we combine this model with our previously published regioselectivity models for Cytochromes P450, Aldehyde Oxidases, Flavin-containing Monooxygenases, UDP-glucuronosyltransferases and Sulfotransferases - the most important Phase I and Phase II drug metabolising enzymes - and a 'WhichP450' model that predicts the Cytochrome P450 isoform(s) responsible for a compound's metabolism. The regioselectivity models are based on a mechanistic understanding of these enzymes' actions, and use quantum mechanical simulations with machine learning methods to accurately predict sites of metabolism and the resulting metabolites. We train heuristic based on the outputs of the 'WhichEnzyme', 'WhichP450', and regioselectivity models to determine the most likely routes of metabolism and metabolites to be observed experimentally. Finally, we demonstrate that this combination delivers high sensitivity in identifying experimentally reported metabolites and higher precision than other methods for predicting in vivo metabolite profiles.PMID:37966132 | DOI:10.1080/00498254.2023.2284251

Source: Xenobiotica - November 15, 2023 Category: Research Authors: Mario Öeren Peter A Hunt Charlotte E Wharrick Hamed Tabatabaei Ghomi Matthew D Segall Source Type: research