Barlow Nicholas, Vanga Sudarsana Reddy, Sävmarker Jonas, Sandström Anja, Burns Peta, Hallberg Anders, Åqvist Johan, Gutiérrez-de-Terán Hugo, Hallberg Mathias, Larhed Mats, Chai Siew Yeen, Thompson Philip E
Department of Medicinal Chemistry , BMC , Uppsala University , P.O. Box 574 , SE-751 23 Uppsala , Sweden.
Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences , Parkville , Victoria 3052 , Australia . Email:
RSC Med Chem. 2020 Jan 8;11(2):234-244. doi: 10.1039/c9md00485h. eCollection 2020 Feb 1.
Macrocyclic analogues of the linear hexapeptide, angiotensin IV (AngIV) have proved to be potent inhibitors of insulin-regulated aminopeptidase (IRAP, oxytocinase, EC 3.4.11.3). Along with higher affinity, macrocycles may also offer better metabolic stability, membrane permeability and selectivity, however predicting the outcome of particular cycle modifications is challenging. Here we describe the development of a series of macrocyclic IRAP inhibitors with either disulphide, olefin metathesis or lactam bridges and variations of ring size and other functionality. The binding mode of these compounds is proposed based on molecular dynamics analysis. Estimation of binding affinities (Δ) and relative binding free energies (ΔΔ) with the linear interaction energy (LIE) method and free energy perturbation (FEP) method showed good general agreement with the observed inhibitory potency. Experimental and calculated data highlight the cumulative importance of an intact N-terminal peptide, the specific nature of the macrocycle, the phenolic oxygen and the C-terminal functionality.
线性六肽血管紧张素IV（AngIV）的大环类似物已被证明是胰岛素调节氨肽酶（IRAP，催产素酶，EC 3.4.11.3）的有效抑制剂。除了具有更高的亲和力外，大环化合物还可能具有更好的代谢稳定性、膜通透性和选择性，然而预测特定环修饰的结果具有挑战性。在此，我们描述了一系列具有二硫键、烯烃复分解或内酰胺桥以及环大小和其他官能团变化的大环IRAP抑制剂的开发。基于分子动力学分析提出了这些化合物的结合模式。用线性相互作用能（LIE）方法和自由能微扰（FEP）方法估计结合亲和力（Δ）和相对结合自由能（ΔΔ），结果与观察到的抑制效力显示出良好的总体一致性。实验和计算数据突出了完整N端肽、大环的特定性质、酚氧和C端官能团的累积重要性。
