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

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.