An attempt to incorporate effect of direct interaction between a ligand and explicit water molecules into MM/3D-RISM

Endpoint methods using continuum-solvent models are widely used to estimate protein-ligand affinity. A recently developed method, MM/3D-RISM, estimates the solvation energy using statistical mechanics by 3D-RISM. This method is theoretically expected to accurately describe solvation effects and to also be less dependent on protein-ligand systems. In this study, we examined the performance of MM/3D-RISM for a set of α-thrombin inhibitors with a non-congeneric series of ligands, containing three diverse chemical scaffolds. The standard MM/3D-RISM showed a weak correlation (R²  = 0.191) but correctly estimated affinity for two of the three scaffolds. However, the simplest inhibitor, benzamidine, was not ranked appropriately. From visual inspection of inhibitor-binding modes, an attempt was made to incorporate the direct interaction between a ligand and water molecules into MM/3D-RISM. A model (Model-1) dealing with directly interacting water molecules (Wat) as an independent component of a protein (R)-ligand (L) complex-formation, that is, R + L + Wat → R-L-Wat, showed a better linearity (R²  = 0.422) than that of the standard MM/3D-RISM model and achieved a good ranking of all three scaffolds of α-thrombin inhibitors. Additionally, an attempt was made to model avidin-biotin system with a congeneric series of inhibitors, and results showed that both the standard MM/3D-RISM model (R²  = 0.839) and Model-1 (R²  = 0.695) satisfactorily estimated the affinity.