Tommasi Sara, Zanato Chiara, Lewis Benjamin C, Nair Pramod C, Dall'Angelo Sergio, Zanda Matteo, Mangoni Arduino A
Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
Org Biomol Chem. 2015 Dec 14;13(46):11315-30. doi: 10.1039/c5ob01843a. Epub 2015 Sep 30.
Dimethylarginine dimethylaminohydrolase (DDAH) is a key enzyme involved in the metabolism of asymmetric dimethylarginine (ADMA) and N-monomethyl arginine (NMMA), which are endogenous inhibitors of the nitric oxide synthase (NOS) family of enzymes. Two isoforms of DDAH have been identified in humans, DDAH-1 and DDAH-2. DDAH-1 inhibition represents a promising strategy to limit the overproduction of NO in pathological states without affecting the homeostatic role of this important messenger molecule. Here we describe the design and synthesis of 12 novel DDAH-1 inhibitors and report their derived kinetic parameters, IC50 and Ki. Arginine analogue 10a, characterized by an acylsulfonamide isosteric replacement of the carboxylate, showed a 13-fold greater inhibitory potential relative to the known DDAH-1 inhibitor, L-257. Compound 10a was utilized to study the putative binding interactions of human DDAH-1 inhibition using molecular dynamics simulations. The latter suggests that several stabilizing interactions occur in the DDAH-1 active-site, providing structural insights for the enhanced inhibitory potential demonstrated by in vitro inhibition studies.
二甲基精氨酸二甲胺水解酶（DDAH）是参与不对称二甲基精氨酸（ADMA）和N-单甲基精氨酸（NMMA）代谢的关键酶，这两种物质是一氧化氮合酶（NOS）家族酶的内源性抑制剂。在人类中已鉴定出两种DDAH同工型，即DDAH-1和DDAH-2。抑制DDAH-1是一种很有前景的策略，可在不影响这种重要信使分子的稳态作用的情况下，限制病理状态下NO的过量产生。在此，我们描述了12种新型DDAH-1抑制剂的设计与合成，并报告了它们的动力学参数、半数抑制浓度（IC50）和抑制常数（Ki）。精氨酸类似物10a，其特征在于用酰基磺酰胺等排体取代羧酸盐，相对于已知的DDAH-1抑制剂L-257，其抑制潜力高13倍。利用化合物10a通过分子动力学模拟研究了人DDAH-1抑制的假定结合相互作用。后者表明在DDAH-1活性位点发生了几种稳定相互作用，为体外抑制研究所显示的增强抑制潜力提供了结构见解。
