Limits...
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 concentration-dependent inhibition of ROCK1 activities for Y27632 and TS-f22.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4645114&req=5

f3: The concentration-dependent inhibition of ROCK1 activities for Y27632 and TS-f22.

Mentions: First, these compounds were evaluated in triplicate on three individual times at the concentration of 41.67 ug/ml. The results showed that 11 compounds had more than 50% inhibition activities of ROCK1. The hit rate was 28.95%, suggesting that the integrated VS strategy was quite reliable and accurate. Then, the IC50 values of these 11 compounds were determined on three individual times with 8-point dilutions. As shown in Table 1 and Fig. 3, seven compounds had the IC50 values lower than 10 μM and compound TS-f22 exhibited the most potent activity with IC50 = 480 nM. The chemical structures of the 11 promising ROCK1 inhibitors were shown in Fig. 4. In our previous study, 12 potent ROCK1 inhibitors (IC50 values between 7 and 28 μM) were discovered from 174 tested compounds given by molecular docking based on a single crystal structure of ROCK132. That is to say, the hit rate reported in our previous study was only 6.90%, which was quite lower than that (28.95%) reported in this study.


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 concentration-dependent inhibition of ROCK1 activities for Y27632 and TS-f22.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: The concentration-dependent inhibition of ROCK1 activities for Y27632 and TS-f22.
Mentions: First, these compounds were evaluated in triplicate on three individual times at the concentration of 41.67 ug/ml. The results showed that 11 compounds had more than 50% inhibition activities of ROCK1. The hit rate was 28.95%, suggesting that the integrated VS strategy was quite reliable and accurate. Then, the IC50 values of these 11 compounds were determined on three individual times with 8-point dilutions. As shown in Table 1 and Fig. 3, seven compounds had the IC50 values lower than 10 μM and compound TS-f22 exhibited the most potent activity with IC50 = 480 nM. The chemical structures of the 11 promising ROCK1 inhibitors were shown in Fig. 4. In our previous study, 12 potent ROCK1 inhibitors (IC50 values between 7 and 28 μM) were discovered from 174 tested compounds given by molecular docking based on a single crystal structure of ROCK132. That is to say, the hit rate reported in our previous study was only 6.90%, which was quite lower than that (28.95%) reported in this study.

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