BioModeling and bioInformatics, Eindhoven University of Technology, PO Box 513, Eindhoven 5600 MB, The Netherlands.
J Med Chem. 2010 Feb 25;53(4):1712-25. doi: 10.1021/jm901356d.
Reducing aldosterone action is beneficial in various major diseases such as heart failure. Currently, this is achieved with mineralocorticoid receptor antagonists, however, aldosterone synthase (CYP11B2) inhibitors may offer a promising alternative. In this study, we used three-dimensional modeling of CYP11B2 to model the binding modes of the natural substrate 18-hydroxycorticosterone and the recently published CYP11B2 inhibitor R-fadrozole as a rational guide to design 44 structurally simple and achiral 1-benzyl-1H-imidazoles. Their syntheses, in vitro inhibitor potencies, and in silico docking are described. Some promising CYP11B2 inhibitors were identified, with our novel lead MOERAS115 (4-((5-phenyl-1H-imidazol-1-yl)methyl)benzonitrile) displaying an IC(50) for CYP11B2 of 1.7 nM, and a CYP11B2 (versus CYP11B1) selectivity of 16.5, comparable to R-fadrozole (IC(50) for CYP11B2 6.0 nM, selectivity 19.8). Molecular docking of the inhibitors in the models enabled us to generate posthoc hypotheses on their binding modes, providing a valuable basis for future studies and further design of CYP11B2 inhibitors.
降低醛固酮的作用在心力衰竭等各种重大疾病中是有益的。目前，这是通过使用盐皮质激素受体拮抗剂来实现的，然而，醛固酮合酶（CYP11B2）抑制剂可能提供一种很有前途的替代方法。在这项研究中，我们使用 CYP11B2 的三维建模来模拟天然底物 18-羟基皮质酮和最近发表的 CYP11B2 抑制剂 R-fadrozole 的结合模式，作为合理设计 44 种结构简单、无手性的 1-苄基-1H-咪唑的指导。描述了它们的合成、体外抑制剂效力和计算机对接。确定了一些有前途的 CYP11B2 抑制剂，我们的新型先导化合物 MOERAS115（4-((5-苯基-1H-咪唑-1-基)甲基)苯甲腈）对 CYP11B2 的 IC50 为 1.7 nM，对 CYP11B2（与 CYP11B1 相比）的选择性为 16.5，与 R-fadrozole（CYP11B2 的 IC50 为 6.0 nM，选择性为 19.8）相当。抑制剂在模型中的分子对接使我们能够对其结合模式生成事后假设，为未来的研究和进一步设计 CYP11B2 抑制剂提供了有价值的基础。
