title: Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays.
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 (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.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.|Institute of Functional Nano &Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Mingyun
authors.initials: M
authors.lastname: Shen
authors.affiliation: Institute of Functional Nano &Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Tian
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Peichen
authors.initials: P
authors.lastname: Pan
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Huiyong
authors.initials: H
authors.lastname: Sun
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Functional Nano &Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Youyong
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory for Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, MO 999078, China.
authors.forename: Hefeng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: State Key Laboratory for Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, MO 999078, China.
authors.forename: Chuwen
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory for Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, MO 999078, China.
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.|State Key Lab of CAD&CG, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000577:Amides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin / Q000494:pharmacology; D001665:Binding Sites; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D062126:Databases, Chemical; D030562:Databases, Protein; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D015027:Zebrafish; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D000577:Amides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; C108830:Y 27632; D000069059:Atorvastatin; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; C486292:pyrrolo(2, 3-b)pyridine