PUBLICATION
Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays
- Authors
- Shen, M., Tian, S., Pan, P., Sun, H., Li, D., Li, Y., Zhou, H., Li, C., Lee, S.M., Hou, T.
- ID
- ZDB-PUB-170214-80
- Date
- 2015
- Source
- Scientific Reports 5: 16749 (Journal)
- Registered Authors
- Keywords
- High-throughput screening, Structure-based drug design
- MeSH Terms
-
- Actin Depolymerizing Factors/metabolism
- Amides/chemistry
- Amides/metabolism
- Animals
- Atorvastatin/pharmacology
- Binding Sites
- Cerebral Hemorrhage/chemically induced
- Cerebral Hemorrhage/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*
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- Protein Structure, Tertiary
- Pyridines/chemistry*
- Pyridines/metabolism
- Pyridines/therapeutic use
- Pyrroles/chemistry*
- Pyrroles/metabolism
- Pyrroles/therapeutic use
- Signal Transduction/drug effects
- Structure-Activity Relationship
- Zebrafish
- rho-Associated Kinases/antagonists & inhibitors*
- rho-Associated Kinases/metabolism
- PubMed
- 26568382 Full text @ Sci. Rep.
Citation
Shen, M., Tian, S., Pan, P., Sun, H., Li, D., Li, Y., Zhou, H., Li, C., Lee, S.M., Hou, T. (2015) Discovery of Novel ROCK1 Inhibitors via Integrated Virtual Screening Strategy and Bioassays. Scientific Reports. 5:16749.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping