Kesar Seema, Paliwal Sarvesh, Mishra Pooja, Madan Kirtika, Chauhan Monika, Chauhan Neha, Verma Kanika, Sharma Swapnil
Department of Pharmacy, Banasthali Vidyapith, P. O. Banasthali-304022, Rajasthan, India.
ACS Med Chem Lett. 2020 Aug 4;11(9):1694-1703. doi: 10.1021/acsmedchemlett.0c00126. eCollection 2020 Sep 10.
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 Rho-kinase enzyme-based assay, followed by rat aortic vasodilatory assay. All three compounds showed good biological activity as predicted by the model and confirmed by the docking studies.
小GTPase蛋白Rho激酶（ROCK）在高血压发病机制中起重要作用。抑制ROCK II会引发导致血管平滑肌舒张的生化变化，最终产生有效的降压活性。在寻找有效的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）和一个疏水基团（HY）。该药效团用于虚拟筛选，从美国国立癌症研究所（NCI）数据库中检索到的命中物根据拟合值、估计值和违反Lipinski规则的情况进行排序。在与Rho激酶活性位点中的氨基酸进行对接研究时，还观察到了命中物的潜在特征相互作用。基于上述筛选，选择了三个命中物（NSC 2488、NSC 2888和NSC 4231），并进行基于Rho激酶酶的测定，随后进行大鼠主动脉舒张试验。所有三种化合物均表现出如模型预测并经对接研究所证实的良好生物活性。
