James H. Notwell; Michael W. Wood

Abstract

While investigating methods to predict small molecule potencies, we found random forests or support vector machines paired with extended-connectivity fingerprints (ECFP) consistently outperformed recently developed methods. A detailed investigation into regression algorithms and molecular fingerprints revealed gradient-boosted decision trees, particularly CatBoost, in conjunction with a combination of ECFP, Avalon, and ErG fingerprints, as well as 200 molecular properties, to be most effective. Incorporating a graph neural network fingerprint further enhanced performance. We successfully validated our model across 22 Therapeutics Data Commons ADMET benchmarks. Our findings underscore the significance of richer molecular representations for accurate property prediction.