Structure-based drug design:: the discovery of novel nonpeptide orally active inhibitors of human renin
Structure-based drug design:: the discovery of novel nonpeptide orally active inhibitors of human renin
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DOI：
10.1016/s1074-5521(00)00134-4
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发表时间：
2000-07-01
影响因子：
--
通讯作者：
Grütter, MG
中科院分区：
文献类型：
--
作者：
Rahuel, J;Rasetti, V;Grütter, MG
背景：天冬氨酸蛋白酶肾素在血压调节中起着重要的生理作用。它催化血管紧张素原转化为激素血管紧张素II的第一步。在过去，已经开发出了有效的肾素肽抑制剂，但这些化合物都没有进入临床试验。我们的主要目标是开发新的非肽类抑制剂。基于现有的结构信息有关的肾素-底物相互作用，我们合成的抑制剂中的肽部分被取代的亲脂性部分，相互作用的大疏水性S1/S3-结合口袋中renin.Results：结合计算方法的药物化学优化过程中的肾素抑制剂复合物的晶体结构分析。结构分析表明，新设计的抑制剂结合预测的S1/S3口袋。此外，然而，这些化合物与迄今未识别的酶的大的、独特的子口袋相互作用，该子口袋从S3结合位点向酶的疏水性戈尔延伸。与该S3（sp）亚口袋的结合对于高结合亲和力是必不可少的。这种前所未有的结合模式指导的药物设计过程中，大多数疏水性相互作用内subsite S3（SP）进行了optimized.Conclusions：我们的设计方法导致化合物具有高的体外亲和力和特异性的肾素，良好的生物利用度和优良的口服疗效，在降低血压的灵长类动物。因此，这些肾素抑制剂是用于治疗高血压和相关心血管疾病的潜在治疗剂。
Background: The aspartic proteinase renin plays an important physiological role in the regulation of blood pressure. It catalyses the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compounds has made it to the end of clinical trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin.Results: Crystal structure analysis of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chemistry optimisation process. Structure analysis revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addition, however, these compounds interact with a hitherto unrecognised large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic Gore of the enzyme. Binding to this S3(sp) sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3(sp) were optimised.Conclusions: Our design approach led to compounds with high in vitro affinity and specificity for renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.