Small GTPase protein Rho-kinase (ROCK) plays an important role in the pathogenesis of hypertension. Inhibition of ROCK II brings about the biochemical changes leading to vascular smooth muscles relaxation, finally resulting into potent antihypertensive activity. In the quest for potent ROCK-II inhibitors, a ligand-based pharmacophore containing four essential chemical features, namely two hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD), and one hydrophobe (HY), was developed and rigorously validated. The pharmacophore was used for virtual screening, and hits retrieved from the National Cancer Institute (NCI) database were sorted on the basis of fit value, estimate value, and Lipinski’s violation. Potential feature interaction of hits was also observed during docking studies with the amino acids present in the active site of Rho-kinase. Based on the above screening, three hits (NSC 2488, NSC 2888, and NSC 4231) were chosen and subjected to in vitro Rho-kinase enzyme-based assay, followed by ex vivo rat aortic vasodilatory assay. All three compounds showed good biological activity as predicted by the model and confirmed by the docking studies.

中文翻译：

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具有血管舒张活性的新型 Rho-激酶-II 抑制剂的鉴定。

小 GTPase 蛋白 Rho 激酶 (ROCK) 在高血压的发病机制中起重要作用。ROCK II 的抑制导致血管平滑肌松弛的生化变化，最终产生有效的抗高血压活性。在寻求有效的 ROCK-II 抑制剂的过程中，开发并严格验证了一种基于配体的药效团，其中包含四个基本化学特征，即两个氢键受体 (HBA)、一个氢键供体 (HBD) 和一个疏水基 (HY) . 药效团用于虚拟筛选，从国家癌症研究所 (NCI) 数据库中检索到的匹配项根据拟合值、估计值和利平斯基违规进行排序。在与 Rho 激酶活性位点中存在的氨基酸进行对接研究期间，还观察到了命中的潜在特征相互作用。基于 Rho 激酶的体外试验，然后是离体大鼠主动脉血管舒张试验。正如模型预测的那样，所有三种化合物都显示出良好的生物活性，并通过对接研究证实。