Enhancing Drug Residence Time by Shielding of Intra-Protein Hydrogen Bonds: A Case Study on CCR2 Antagonists
ACS medicinal chemistry letters(2019)
摘要
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.
更多查看译文
关键词
CCR2,GPCR,water networks,drug residence time,buried hydrogen bonds
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要