利用基于结构的对接方法开发有效的G蛋白偶联受体激酶（GRK）2和5抑制剂。
Utilizing a structure-based docking approach to develop potent G protein-coupled receptor kinase (GRK) 2 and 5 inhibitors.
作者信息
Waldschmidt Helen V, Bouley Renee, Kirchhoff Paul D, Lee Pil, Tesmer John J G, Larsen Scott D
机构信息
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States.
Department of Pharmacology and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States.
出版信息
Bioorg Med Chem Lett. 2018 May 15;28(9):1507-1515. doi: 10.1016/j.bmcl.2018.03.082. Epub 2018 Mar 30.
Abstract
G protein-coupled receptor (GPCR) kinases (GRKs) regulate the desensitization and internalization of GPCRs. Two of these, GRK2 and GRK5, are upregulated in heart failure and are promising targets for heart failure treatment. Although there have been several reports of potent and selective inhibitors of GRK2 there are few for GRK5. Herein, we describe a ligand docking approach utilizing the crystal structures of the GRK2-Gβγ·GSK180736A and GRK5·CCG215022 complexes to search for amide substituents predicted to confer GRK2 and/or GRK5 potency and selectivity. From this campaign, we successfully generated two new potent GRK5 inhibitors, although neither exhibited selectivity over GRK2.
摘要
G蛋白偶联受体（GPCR）激酶（GRK）调节GPCR的脱敏和内化。其中，GRK2和GRK5在心力衰竭中上调，是心力衰竭治疗的有希望的靶点。尽管已经有几篇关于GRK2的强效和选择性抑制剂的报道，但针对GRK5的报道却很少。在此，我们描述了一种配体对接方法，利用GRK2-Gβγ·GSK180736A和GRK5·CCG215022复合物的晶体结构来寻找预测可赋予GRK2和/或GRK5效力和选择性的酰胺取代基。通过这次研究，我们成功地生成了两种新的强效GRK5抑制剂，尽管它们对GRK2均无选择性。
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