MetScore: Site of Metabolism Prediction Beyond Cytochrome P450 Enzymes.

The metabolism of xenobiotics by humans and other organisms is a complex process involving numerous enzymes that catalyze phase I (functionalization) and phase II (conjugation) reactions. Herein we introduce MetScore, a machine learning model that can predict both phase I and phase II reaction sites of drugs in a single prediction run. We developed cheminformatics workflows to filter and process reactions to obtain suitable phase I and phase II data sets for model training. Employing a recently developed molecular representation based on quantum chemical partial charges, we constructed random forest machine learning models for phase I and phase II reactions. After combining these models with our previous cytochrome P450 model and calibrating the combination against Bayer in-house data, we obtained the MetScore model that shows good performance, with Matthews correlation coefficients of 0.61 and 0.76 for diverse phase I and phase II reaction types, respectively. We validated its potential applicability to lead optimization campaigns for a new and independent data set compiled from recent publications. The results of this study demonstrate the usefulness of quantum-chemistry-derived molecular representations for reactivity prediction.