Knowledge-Based Scoring Functions in Drug Design: 3. A Two-Dimensional Knowledge-Based Hydrogen-Bonding Potential for the Prediction of Protein–Ligand Interactions

Hydrogen bonding is a key contributor to the molecular recognition between ligands and their host molecules in biological systems. Here we develop a novel orientation-dependent hydrogen bonding potential based on the geometric characteristics of hydrogen bonds observed in 44,585 protein–ligand complexes. We find a close correspondence between the empirical knowledge and the energy landscape inferred from the distribution of HBs. A scoring function based on the resultant hydrogen-bonding potentials discriminates native protein–ligand structures from incorrectly docked decoys with remarkable predictive power.