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The target residence time (RT) for a given ligand is one of the important parameters that have to be optimized during drug design. It is well established that shielding the receptor-ligand hydrogen bond (H-bond) interactions from water has been one of the factors in increasing ligand RT. Building on this foundation, here we report that shielding an intra-protein H-bond, which confers rigidity to the binding pocket and which is not directly involved in drug-receptor interactions, can strongly influence RT for CCR2 antagonists. Based on our recently solved CCR2 structure with MK-0812 and molecular dynamics (MD) simulations, we show that the RT for this and structurally related ligands is directly dependent on the shielding of the Tyr120-Glu291 H-bond from the water. If solvated this H-bond is often broken, making the binding pocket flexible and leading to shorter RT.

Enhancing Drug Residence Time by Shielding of Intra-Protein Hydrogen Bonds: A Case Study on CCR2 Antagonists