Ace revisited: a new target for structure-based drug design.
Ace revisited: a new target for structure-based drug design.
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DOI：
10.1038/nrd1227
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发表时间：
2003-11
期刊：
影响因子：
--
通讯作者：
Ehlers MR
中科院分区：
文献类型：
--
作者：
Acharya KR;Sturrock ED;Riordan JF;Ehlers MR
血管紧张素转换酶（ACE）是一种氯离子依赖性的金属酶，催化许多调节性寡肽的羧基端水解裂解二肽。ACE是调节血压、体液平衡、肾和血管功能的肾素-血管紧张素系统的核心。因此，它是心血管治疗的主要目标。ACE抑制剂（例如，卡托普利、依那普利拉和赖诺普利）已上市20多年。ACE抑制剂治疗的副作用包括咳嗽和血管性水肿。ACE包含N-和C-结构域，每个结构域含有具有不同底物和活化性质的活性位点。结构域选择性抑制剂的设计可能会产生新的药物，提高安全性和有效性-这一努力将促进最近确定的三维结构的ACE。C结构域似乎主要负责血压的调节。数据表明，C结构域选择性抑制剂的副作用比目前的抑制剂要轻，目前的抑制剂通常靶向N结构域和C结构域。与C结构域相反，N结构域似乎对控制血压的肽具有相对较低的亲和力。它优先水解至少三种其他生理上重要的肽，因此N结构域的靶向抑制可能具有新的治疗应用。目前，血管紧张素转换酶（ACE）抑制剂被广泛用于心血管疾病，包括高血压，心力衰竭，心脏病发作和肾衰竭，并已合并超过60亿美元的年销售额。然而，这些ACE抑制剂是在20世纪70年代末和80年代初开发的，其使用受到常见副作用的阻碍。此外，我们现在知道ACE实际上由两部分组成（称为N-和C-域），它们具有不同的功能。因此，设计特异性结构域选择性ACE抑制剂有望生产出更安全、更有效的下一代药物。在这里，我们讨论了目前的抑制剂的结构特点，并概述了如何下一代ACE抑制剂可以设计使用的三维分子结构的人睾丸ACE。ACE结构为合理的药物设计提供了一个独特的机会，基于使用现有抑制剂作为支架的计算机建模和迭代先导优化的组合来驱动合成化学。
Angiotensin-converting enzyme (ACE) is a chloride-dependent metalloenzyme that catalyses the hydrolytic cleavage of dipeptides from the carboxyl terminus of many regulatory oligopeptides. ACE is central to the renin–angiotensin system that regulates blood pressure, fluid homeostasis, and renal and vascular function. It is therefore a major target for cardiovascular therapies. ACE inhibitors (for example, captopril, enalaprilat and lisinopril) have been on the market for more than 20 years. Side effects of treatment with ACE inhibitors include cough and angioedema. ACE comprises an N- and a C-domain, each containing an active site with distinct substrates and activation properties. The design of domain-selective inhibitors might produce new drugs with improved safety and efficacy — this endeavour will be facilitated by the recent determination of the three-dimensional structure of ACE. The C-domain seems to be primarily responsible for the regulation of blood pressure. Data indicate that C-domain-selective inhibitors will have less severe side effects than current-generation inhibitors, which generally target both the N- and C-domains. In contrast to the C-domain, the N-domain seems to have relatively low affinity for the peptides that control blood pressure. It preferentially hydrolyses at least three other physiologically important peptides, so targeted inhibition of the N-domain might have novel therapeutic applications. Current-generation angiotensin-converting enzyme (ACE) inhibitors are widely used for cardiovascular diseases, including high blood pressure, heart failure, heart attack and kidney failure, and have combined annual sales in excess of US $6 billion. However, the use of these ACE inhibitors, which were developed in the late 1970s and early 1980s, is hampered by common side effects. Moreover, we now know that ACE actually consists of two parts (called the N- and C-domains) that have different functions. Therefore, the design of specific domain-selective ACE inhibitors is expected to produce next-generation drugs that might be safer and more effective. Here we discuss the structural features of current inhibitors and outline how next-generation ACE inhibitors could be designed by using the three-dimensional molecular structure of human testis ACE. The ACE structure provides a unique opportunity for rational drug design, based on a combination of in silico modelling using existing inhibitors as scaffolds and iterative lead optimization to drive the synthetic chemistry.
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