Recent advances in the prediction of non‐ CYP450 ‐mediated drug metabolism

Computational models of drug metabolism prediction have focused mainly on cytochrome P450 enzymes, because drug–drug interactions, reactive metabolite formation, hepatotoxicity, idiosyncratic adverse drug interactions, and/or loss of efficacy of many drugs were the results of interactions with CYP450s. Metabolic regioselectivity and isoform specificity prediction models for CYP450‐catalyzed reactions have reached approximately 95% accuracy. Thus, a new drug candidate is less likely to show unexpected metabolic profile due to metabolism via CYP450 pathways. For such candidates, secondary metabolic Phase I and II enzymes are likely to play an expected (or unexpected) role in drug metabolism. The importance of flavin monooxygenases (FMOs), aldehyde and alcohol dehydrogenase, monoamine oxidase from the Phase I and UDP‐glucuronosyltransferase (UGT), sulfotransferase, glutathione S‐transferase, and methyltransferase from Phase II has increased and United States Food and Drug Administration guidelines on NDA have specific recommendations for in vitro and in vivo testing against these enzymes. Thus, there is an urgent requirement of reliable predictive models for drug metabolism catalyzed by these enzymes. In this review, we have classified drug metabolism prediction models (site of metabolism, isoform specificity, and kinetic parameter) for these enzymes into Phase I and II. When such models are unavailable, we discuss the Quantitative Structure Activity Relationship (QSAR), pharmacophore, docking, dynamics, and reactivity studies performed for the prediction of substrates and inhibitors. Recently published models for FMO and UGT are discussed. The need for comprehensive, widely applicable, sequential primary and secondary metabolite prediction is highlighted. Potential difficulties and future prospectives in the development of such models are discussed. WIREs Comput Mol Sci 2017, 7:e1323. doi: 10.1002/wcms.1323

This article is categorized under:

• Structure and Mechanism > Reaction Mechanisms and Catalysis
• Computer and Information Science > Chemoinformatics
• Software > Molecular Modeling