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Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays
Mingyun Shen1,3; Sheng Tian3; Peichen Pan1; Huiyong Sun1; Dan Li1; Youyong Li3; Hefeng Zhou4; Chuwen Li4; Simon Ming-Yuen Lee4; Tingjun Hou1,2
2015-11-16
Source PublicationScientific Reports
ISSN20452322
Volume5
Abstract

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 (IC < 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 IC of 480nM. 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.

DOI10.1038/srep16749
URLView the original
Language英语
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000364659900001
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Cited Times [WOS]:14   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China
2.State Key Lab of CAD&CG, Zhejiang University, Hangzhou, 310058, Zhejiang, China
3.Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, China
4.State Key Laboratory for Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, MO 999078, China
Recommended Citation
GB/T 7714
Mingyun Shen,Sheng Tian,Peichen Pan,et al. Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays[J]. Scientific Reports,2015,5.
APA Mingyun Shen.,Sheng Tian.,Peichen Pan.,Huiyong Sun.,Dan Li.,...&Tingjun Hou.(2015).Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays.Scientific Reports,5.
MLA Mingyun Shen,et al."Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays".Scientific Reports 5(2015).
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