药效团
虚拟筛选
对接(动物)
化学
β肾上腺素能受体激酶
计算生物学
药理学
数量结构-活动关系
激酶
受体
生物化学
生物
立体化学
G蛋白偶联受体
医学
护理部
作者
Wenling Ye,Suqing Yang,Liu‐Xia Zhang,Zhen‐Ke Deng,Wen‐Qun Li,Jinwei Zhang,Lin Zhang,Yong‐Huan Yun,Alex F. Chen,Dongsheng Cao
标识
DOI:10.1016/j.chemolab.2018.12.015
摘要
Heart failure (HF) has become an important social problem that seriously threatens human health due to its high morbidity and mortality. G Protein-Coupled Receptors Kinase 2 (GRK2), as a novel target of heart failure, is overexpressed in the pathogenesis and progression of HF. In this study, we conducted a multistep virtual screening process from the ZINC database to discover potential GRK2 inhibitors. First, by using 6 known GRK2 inhibitors with high bioactivity and diverse structures as the template molecules, 7499 compounds were obtained from ligand-based similarity screening by 4 types of fingerprints. Subsequently, these hits were further screened by three quantitative structure-activity relationship (QSAR) models, which were built by 197 known GRK2 compounds and represented by two-dimensional MOE descriptors (MOE2D), molecular fragments (MACCS) and 2- dimensional pharmacophore (CATS) based on random forest algorithm, respectively. These hit compounds were then filtered by three molecular docking packages (MOE, GOLD and GLIDE) to improve the docking accuracy for avoid losing candidate compounds. The compounds with high docking scores were selected for the evaluation of absorption, distribution, metabolism, excretion, and toxicity (ADMET). Finally, 17 compounds were identified the binding affinity to GRK2 by using SPR assay, three of which were considered as novel GRK2 inhibitors, and their binding modes with GRK2 active sites were analyzed. As new potential GRK2 inhibitors, COM5(KD = 0.172 μM) and COM17(KD = 0.595 μM) with the KD value less than 1 μM could be directly used in the next study, while the remaining hit COM4 (KD = 4.72 μM) whose KD over 1 μM can be optimized into the required low nanomole range for further study.
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