Shen Mingyun, Tian Sheng, Pan Peichen, Sun Huiyong, Li Dan, Li Youyong, Zhou Hefeng, Li Chuwen, Lee Simon Ming-Yuen, Hou Tingjun
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Institute of Functional Nano &Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China.
Sci Rep. 2015 Nov 16;5:16749. doi: 10.1038/srep16749.
Rho-associated kinases (ROCKs) have been regarded as promising drug targets for the treatment of cardiovascular diseases, nervous system diseases and cancers. In this study, a novel integrated virtual screening protocol by combining molecular docking and pharmacophore mapping based on multiple ROCK1 crystal structures was utilized to screen the ChemBridge database for discovering potential inhibitors of ROCK1. Among the 38 tested compounds, seven of them exhibited significant inhibitory activities of ROCK1 (IC50 < 10 μM) and the most potent one (compound TS-f22) with the novel scaffold of 4-Phenyl-1H-pyrrolo [2,3-b] pyridine had an IC50 of 480 nM. Then, the structure-activity relationships of 41 analogues of TS-f22 were examined. Two potent inhibitors were proven effective in inhibiting the phosphorylation of the downstream target in the ROCK signaling pathway in vitro and protecting atorvastatin-induced cerebral hemorrhage in vivo. The high hit rate (28.95%) suggested that the integrated virtual screening strategy was quite reliable and could be used as a powerful tool for identifying promising active compounds for targets of interest.
Rho相关激酶（ROCKs）被认为是治疗心血管疾病、神经系统疾病和癌症的有前景的药物靶点。在本研究中，基于多个ROCK1晶体结构，利用分子对接和药效团映射相结合的新型综合虚拟筛选方案，对ChemBridge数据库进行筛选，以发现ROCK1的潜在抑制剂。在38种测试化合物中，有7种表现出对ROCK1的显著抑制活性（IC50＜10μM），最有效的一种（化合物TS-f22）具有4-苯基-1H-吡咯并[2,3-b]吡啶的新型骨架，IC50为480 nM。然后，研究了TS-f22的41种类似物的构效关系。两种强效抑制剂在体外被证明能有效抑制ROCK信号通路中下游靶点的磷酸化，并在体内保护阿托伐他汀诱导的脑出血。高命中率（28.95%）表明，综合虚拟筛选策略相当可靠，可作为一种强大的工具，用于识别感兴趣靶点的有前景的活性化合物。
