Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine.
Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine.
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DOI：
10.1021/acs.jmedchem.7b00112
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发表时间：
2017-04-13
影响因子：
7.3
通讯作者：
Larsen SD
中科院分区：
文献类型：
--
作者：
Waldschmidt HV;Homan KT;Cato MC;Cruz-Rodríguez O;Cannavo A;Wilson MW;Song J;Cheung JY;Koch WJ;Tesmer JJ;Larsen SD
在心力衰竭中，β-肾上腺素能受体 (βAR) 变得脱敏并与异三聚体 G 蛋白解偶联。这一过程由 G 蛋白偶联受体激酶 (GRK) 启动，其中一些在衰竭心脏中表达上调，使其成为理想的治疗靶点。血清素再摄取抑制剂帕罗西汀先前被鉴定为 GRK2 抑制剂。利用基于结构的药物设计方法，我们修改了帕罗西汀以生成小型化合物库。该系列包括一种高效、选择性的 GRK2 抑制剂 14as，针对 GRK2 的 IC50 为 30 nM，选择性比其他 GRK 和激酶高 230 倍以上。此外，14as 在心肌细胞收缩力测定中显示出比帕罗西汀提高 100 倍，并且血浆浓度高于其 IC50 超过 7 小时。其中三种抑制剂（包括 14as）另外与 GRK2 形成复合物结晶，以深入了解这些抑制剂的效力和选择性的结构决定因素。
In heart failure, the β-adrenergic receptors (βARs) become desensitized and uncoupled from heterotrimeric G proteins. This process is initiated by G protein-coupled receptor kinases (GRKs), some of which are upregulated in the failing heart making them desirable therapeutic targets. The serotonin reuptake inhibitor paroxetine was previously identified as a GRK2 inhibitor. Utilizing a structure based drug design approach we modified paroxetine to generate a small compound library. Included in this series is a highly potent and selective GRK2 inhibitor, 14as, with an IC50 of 30 nM against GRK2 and greater than 230-fold selectivity over other GRKs and kinases. Furthermore, 14as showed a 100-fold improvement in cardiomyocyte contractility assays over paroxetine and a plasma concentration higher than its IC50 for over seven hours. Three of these inhibitors, including 14as, were additionally crystallized in complex with GRK2 to give insights into the structural determinants of potency and selectivity of these inhibitors.
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DOI：
10.2741/3898
发表时间：
2011-06-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
--
作者：
Huang ZM;Gold JI;Koch WJ
通讯作者：
Koch WJ
影响因子：
9.3
作者：
Hullmann J;Traynham CJ;Coleman RC;Koch WJ
通讯作者：
Koch WJ
影响因子：
4.8
作者：
Homan, Kristoff T.;Waldschmidt, Helen V.;Tesmer, John J. G.
通讯作者：
Tesmer, John J. G.
影响因子：
4.8
作者：
Komolov, Konstantin E.;Bhardwaj, Anshul;Benovic, Jeffrey L.
通讯作者：
Benovic, Jeffrey L.
影响因子：
17.1
作者：
Schumacher SM;Gao E;Zhu W;Chen X;Chuprun JK;Feldman AM;Tesmer JJ;Koch WJ
通讯作者：
Koch WJ