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

Shen M, Tian S, Pan P, Sun H, Li D, Li Y, Zhou H, Li C, Lee SM, Hou T - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.

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.

No MeSH data available.


Related in: MedlinePlus

The similarity scores of Assemblies for the top 500 molecules ranked by the Glide docking scores based on eight crystal structures of ROCK1-ligand complexes.
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f2: The similarity scores of Assemblies for the top 500 molecules ranked by the Glide docking scores based on eight crystal structures of ROCK1-ligand complexes.

Mentions: As reported in our previous study42, eight out of nine crystal complexes of ROCK1 satisfied the requirements of “docking power” (RMSD ≤ 2.0 Å) and “distinguishing power” (P-value ≤ 10−20) by using either Glide SP or XP scoring. The top 500 hits ranked by the Glide docking scores based on eight different crystal structures of ROCK1 were compared based on the similarity scores of Assemblies. As shown in Fig. 2, the similarity score of the top 500 hits for any two different ROCK1-ligand crystal structures was lower than 0.15, suggesting that the top-scored hits given by molecular docking based on different crystal structures were quite different (Table S1 in Supporting Information). In other words, the potential inhibitors predicted by docking-based VS were dependent on the conformations of the target. Therefore, in this study, the NBC technique was employed to integrate the predictions from molecular docking and pharmacophore mapping based on eight crystal structures of ROCK1-ligand complexes. Compared with the classifiers only based on the docking scores or fit values derived from any single protein structure, the Bayesian classifiers based on the docking scores and fit values derived from eight ROCK1-ligand crystal structures performed much better. For the dataset with the known inhibitors and non-inhibitors of ROCK1, the best Bayesian classifier could achieve a sensitivity of 0.826, a specificity of 0.875, a global accuracy of 0.873 and an AUC value of 0.938 based on the docking scores and fit values derived from eight ROCK1-ligand crystal structures. Then, the best Bayesian classifier was utilized to screen the ChemBridge database for identifying potential inhibitors of ROCK1, and 38 potential inhibitors of ROCK1 were identified and purchased for ROCK1 inhibitory activity assay.


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

Shen M, Tian S, Pan P, Sun H, Li D, Li Y, Zhou H, Li C, Lee SM, Hou T - Sci Rep (2015)

The similarity scores of Assemblies for the top 500 molecules ranked by the Glide docking scores based on eight crystal structures of ROCK1-ligand complexes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4645114&req=5

f2: The similarity scores of Assemblies for the top 500 molecules ranked by the Glide docking scores based on eight crystal structures of ROCK1-ligand complexes.
Mentions: As reported in our previous study42, eight out of nine crystal complexes of ROCK1 satisfied the requirements of “docking power” (RMSD ≤ 2.0 Å) and “distinguishing power” (P-value ≤ 10−20) by using either Glide SP or XP scoring. The top 500 hits ranked by the Glide docking scores based on eight different crystal structures of ROCK1 were compared based on the similarity scores of Assemblies. As shown in Fig. 2, the similarity score of the top 500 hits for any two different ROCK1-ligand crystal structures was lower than 0.15, suggesting that the top-scored hits given by molecular docking based on different crystal structures were quite different (Table S1 in Supporting Information). In other words, the potential inhibitors predicted by docking-based VS were dependent on the conformations of the target. Therefore, in this study, the NBC technique was employed to integrate the predictions from molecular docking and pharmacophore mapping based on eight crystal structures of ROCK1-ligand complexes. Compared with the classifiers only based on the docking scores or fit values derived from any single protein structure, the Bayesian classifiers based on the docking scores and fit values derived from eight ROCK1-ligand crystal structures performed much better. For the dataset with the known inhibitors and non-inhibitors of ROCK1, the best Bayesian classifier could achieve a sensitivity of 0.826, a specificity of 0.875, a global accuracy of 0.873 and an AUC value of 0.938 based on the docking scores and fit values derived from eight ROCK1-ligand crystal structures. Then, the best Bayesian classifier was utilized to screen the ChemBridge database for identifying potential inhibitors of ROCK1, and 38 potential inhibitors of ROCK1 were identified and purchased for ROCK1 inhibitory activity assay.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.

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.

No MeSH data available.


Related in: MedlinePlus