通过屏蔽蛋白质内氢键提高药物驻留时间：以CCR2拮抗剂为例的研究。
Enhancing Drug Residence Time by Shielding of Intra-Protein Hydrogen Bonds: A Case Study on CCR2 Antagonists.
作者信息
Magarkar Aniket, Schnapp Gisela, Apel Anna-Katharina, Seeliger Daniel, Tautermann Christofer S
机构信息
Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, D-88397 Biberach a.d. Riss, Germany.
出版信息
ACS Med Chem Lett. 2019 Feb 7;10(3):324-328. doi: 10.1021/acsmedchemlett.8b00590. eCollection 2019 Mar 14.
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 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.
给定配体的目标驻留时间（RT）是药物设计过程中必须优化的重要参数之一。众所周知，使受体-配体氢键（H键）相互作用免受水的影响是增加配体RT的因素之一。在此基础上，我们在此报告，屏蔽赋予结合口袋刚性且不直接参与药物-受体相互作用的蛋白质内部H键，可强烈影响CCR2拮抗剂的RT。基于我们最近解析的CCR2结构以及分子动力学（MD）模拟，我们表明该配体及结构相关配体的RT直接取决于Tyr120-Glu291 H键免受水的影响。如果该H键被溶剂化，它常常会断裂，使结合口袋变得灵活并导致RT缩短。
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