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.
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Authors | Mingyun Shen, Sheng Tian, Peichen Pan, Huiyong Sun, Dan Li, Youyong Li, Hefeng Zhou, Chuwen Li, Simon Ming-Yuen Lee, Tingjun Hou |
Journal | Scientific reports
(Sci Rep)
Vol. 5
Pg. 16749
(Nov 16 2015)
ISSN: 2045-2322 [Electronic] England |
PMID | 26568382
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Actin Depolymerizing Factors
- Amides
- Protein Kinase Inhibitors
- Pyridines
- Pyrroles
- Y 27632
- Atorvastatin
- ROCK1 protein, human
- rho-Associated Kinases
- pyrrolo(2, 3-b)pyridine
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Topics |
- Actin Depolymerizing Factors
(metabolism)
- Amides
(chemistry, metabolism)
- Animals
- Atorvastatin
(pharmacology)
- Binding Sites
- Cerebral Hemorrhage
(chemically induced, prevention & control)
- Databases, Chemical
- Databases, Protein
- Disease Models, Animal
- Enzyme Activation
(drug effects)
- Human Umbilical Vein Endothelial Cells
- Humans
- Inhibitory Concentration 50
- Molecular Docking Simulation
- Phosphorylation
(drug effects)
- Protein Kinase Inhibitors
(chemistry, pharmacology, therapeutic use)
- Protein Structure, Tertiary
- Pyridines
(chemistry, metabolism, therapeutic use)
- Pyrroles
(chemistry, metabolism, therapeutic use)
- Signal Transduction
(drug effects)
- Structure-Activity Relationship
- Zebrafish
- rho-Associated Kinases
(antagonists & inhibitors, metabolism)
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