Enhancing CYP450-Ligand Binding Predictions: A Comparative Analysis of Ligand-Based and Hybrid Machine Learning Models

Predicting cytochrome P450 (CYP450) ligand binding is critical in early-stage drug discovery, as CYP450-mediated metabolism profoundly influences drug efficacy, safety, and adverse reaction risks. However, experimental determination of CYP450-ligand interactions remains resource- and time-intensive, underscoring the need for robust computational alternatives. While ligand-based methods are commonly employed, they often fail to fully account for structural intricacies governing protein-ligand interactions. To address this gap, we developed a hybrid machine learning framework integrating ligand descriptors, protein descriptors, and protein-ligand interaction descriptors, that include molecular docking-derived parameters, rescoring function components from multiple algorithms and structural interaction fingerprints (SIFt). Evaluated on CYP1A2 and CYP17A1 isoforms, our model demonstrated superior predictive accuracy in cross-validation compared to stand-alone molecular docking and ligand-based approaches. Furthermore, benchmarking against state-of-the-art tools —SwissADME and ADMETlab 3.0 — revealed enhanced performance in binding prediction. This work establishes a versatile framework for advancing computational tools to prioritize CYP450 binding assessments during drug discovery.