The Design and Development of a Potent and Selective Novel Diprolyl Derivative That Binds to the N-Domain of Angiotensin-I Converting Enzyme.,Journal of Medicinal Chemistry

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The Design and Development of a Potent and Selective Novel Diprolyl Derivative That Binds to the N-Domain of Angiotensin-I Converting Enzyme.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-12-21 , DOI: 10.1021/acs.jmedchem.7b01478
Stephen Fienberg ₁ , Gyles E Cozier ₂ , K Ravi Acharya ₂ , Kelly Chibale _{1,

3,

4} , Edward D Sturrock _{3,

5}

Affiliation

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 P2 position (compound 16) displayed potent inhibition (Ki = 11.45 nM) and was 84-fold more selective toward the N-domain. A high-resolution crystal structure of compound 16 in complex with the N-domain revealed the molecular basis for the observed selectivity.

中文翻译：

与血管紧张素-I转换酶N域结合的强效选择性新型二脯氨酰基衍生物的设计和开发。

血管紧张素-I转化酶（ACE）是由两个催化域（N-和C-）组成的锌金属蛋白酶。多数临床ACE抑制剂（ACEi）已显示出非选择性抑制两个结构域的功能，从而导致诸如咳嗽和血管性水肿等不良反应。选择性抑制单个结构域可能会降低这些作用，并可能除高血压外还治疗纤维化。检查了来自GVK Biosciences数据库的ACEi，寻找可能的N结构域选择性结合模式。从该组中，使用对接模拟对二甲苯基化学系列进行建模。该系列是基于涉及包含已知可赋予N域选择性的残基的关键靶点相互作用而扩展的。总共合成了七种二吡咯基化合物，并测试了其对N域选择性ACE的抑制作用。一种在P2位置带有天冬氨酸的化合物（化合物16）显示出有效的抑制作用（Ki = 11.45 nM），并且对N结构域的选择性高84倍。与N结构域复合的化合物16的高分辨率晶体结构揭示了观察到的选择性的分子基础。

更新日期：2017-12-21

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