Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays


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.

DOI: 10.1038/srep16749

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@inproceedings{Shen2015DiscoveryON, title={Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays}, author={Mingyun Shen and Sheng Tian and Peichen Pan and Huiyong Sun and Dan Li and Youyong Li and Hefeng Zhou and Chuwen Li and Simon Ming-yuen Lee and Tingjun Hou}, booktitle={Scientific reports}, year={2015} }