Decision tree‐based identification of important molecular fragments for protein‐ligand binding

Abstract Fragment‐based drug design is an emerging technology in pharmaceutical research and development. One of the key aspects of this technology is the identification and quantitative characterization of molecular fragments. This study presents a strategy for identifying important molecular fragments based on molecular fingerprints and decision tree algorithms and verifies its feasibility in predicting protein‐ligand binding affinity. Specifically, the three‐dimensional (3D) structures of protein‐ligand complexes are encoded using extended‐connectivity fingerprints (ECFP), and three decision tree models, namely Random Forest, XGBoost, and LightGBM, are used to quantitatively characterize the feature importance, thereby extracting important molecular fragments with high reliability. Few‐shot learning reveals that the extracted molecular fragments contribute significantly and consistently to the binding affinity even with a small sample size. Despite the absence of location and distance information for molecular fragments in ECFP, 3D visualization, in combination with the reverse ECFP process, shows that the majority of the extracted fragments are located at the binding interface of the protein and the ligand. This alignment with the distance constraints critical for binding affinity further supports the reliability of the strategy for identifying important molecular fragments.