Modulating hydrogen-bond basicity within the context of protein-ligand binding: A case study with thrombin inhibitors that reveals a dominating role for desolvation
The role of H-bond basicity in SAR studies was explored in thrombin inhibitors. H-bond basicity/strength was systematically modulated via bioisosterism. Improved strength of H-bonds to the protein did not improve binding affinity. Decreased strength of H-bonds to water of desolvation lead to better inhibitors. Bioisosteric replacements were found to produce synergism in SAR modifications.