Predicting Regioselectivity of AO, CYP, FMO, and UGT Metabolism Using Quantum Mechanical Simulations and Machine Learning.

Unexpected metabolism in modification and conjugation phases can lead to the failure of many late-stage drug candidates or even withdrawal of approved drugs. Thus, it is critical to predict the sites of metabolism (SoM) for enzymes, which interact with drug-like molecules, in the early stages of the research. This study presents methods for predicting the isoform-specific metabolism for human AOs, FMOs, and UGTs and general CYP metabolism for preclinical species. The models use semi-empirical quantum mechanical simulations, validated using experimentally obtained data and DFT calculations, to estimate the reactivity of each SoM in the context of the whole molecule. Ligand-based models, trained and tested using high-quality regioselectivity data, combine the reactivity of the potential SoM with the orientation and steric effects of the binding pockets of the different enzyme isoforms. The resulting models achieve κ values of up to 0.94 and AUC of up to 0.92.