The Design and Development of a Potent and Selective Novel Diprolyl Derivative That Binds to the N-Domain of Angiotensin-I Converting Enzyme.
The Design and Development of a Potent and Selective Novel Diprolyl Derivative That Binds to the N-Domain of Angiotensin-I Converting Enzyme.
复制标题
设计和开发一种有效且选择性的新型二丙酰衍生物，可与血管紧张素-I 转换酶的 N 结构域结合。
DOI：
10.1021/acs.jmedchem.7b01478
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发表时间：
2018
影响因子：
7.3
通讯作者：
Fienberg S
中科院分区：
文献类型：
--
作者：
Fienberg S
血管紧张素-I转化酶（ACE）是一种锌金属蛋白酶，由两个催化结构域（N-和C-）组成。大多数临床ACE抑制剂（ACEi）已被证明非选择性地抑制这两个结构域，导致不良反应，如咳嗽和血管性水肿。选择性抑制单个结构域可能会减少这些作用，并可能治疗纤维化以及高血压。检查来自GVK Biosciences数据库的ACEi的可能的N-结构域选择性结合模式。从这一组中，使用对接模拟来建模二脯氨酰化学系列。基于涉及已知赋予N结构域选择性的残基的关键靶相互作用，扩展了该系列。总共合成了七种二脯氨酰化合物，并测试了N结构域选择性ACE抑制。一种在P2位具有天冬氨酸的化合物（化合物16）显示出有效的抑制（Ki= 11.45 nM），并且对N结构域的选择性高84倍。化合物16与N-结构域复合的高分辨率晶体结构揭示了所观察到的选择性的分子基础。
Angiotensin-I converting enzyme (ACE) is a zinc metalloprotease consisting of two catalytic domains (N- and C-). Most clinical ACE inhibitor(s) (ACEi) have been shown to inhibit both domains nonselectively, resulting in adverse effects such as cough and angioedema. Selectively inhibiting the individual domains is likely to reduce these effects and potentially treat fibrosis in addition to hypertension. ACEi from the GVK Biosciences database were inspected for possible N-domain selective binding patterns. From this set, a diprolyl chemical series was modeled using docking simulations. The series was expanded based on key target interactions involving residues known to impart N-domain selectivity. In total, seven diprolyl compounds were synthesized and tested for N-domain selective ACE inhibition. One compound with an aspartic acid in the P2position (compound16) displayed potent inhibition (Ki= 11.45 nM) and was 84-fold more selective toward the N-domain. A high-resolution crystal structure of compound16in complex with the N-domain revealed the molecular basis for the observed selectivity.