The two-domain dipeptidylcarboxypeptidase Angiotensin-I-converting enzyme (EC 3.4.15.1; ACE) plays an important physiological role in blood pressure regulation via the reninangiotensin and kallikrein-kinin systems by converting angiotensin I to the potent vasoconstrictor angiotensin II, and by cleaving a number of other substrates including the vasodilator bradykinin and the anti-inflammatory peptide N-acetyl-SDKP. Therefore, the design of ACE inhibitors is within the priorities of modern medical sciences for treating hypertension, heart failures, myocardial infarction, and other related diseases. Despite the success of ACE inhibitors for the treatment of hypertension and congestive heart failure, they have some adverse effects, which could be attenuated by selective domain inhibition. Crystal structures of both ACE domains (nACE and cACE) reported over the last decades could facilitate the rational drug design of selective inhibitors. In this review, we refer to the history of the discovery of ACE inhibitors, which has been strongly related to the development of molecular modeling methods. We stated that the design of novel selective ACE inhibitors is a challenge for current researchers which requires a thorough understanding of the structure of both ACE domains and the help of molecular modeling methodologies. Finally, we performed a theoretical design of potential selective derivatives of trandolaprilat, a drug approved to treat critical conditions of hypertension, to illustrate how to use molecular modeling methods such as de novo design, docking, Molecular Dynamics (MD) simulations, and free energy calculations for creating novel potential drugs with specific interactions inside nACE and cACE binding sites.

两结构域二肽基羧肽酶血管紧张素-I转换酶（EC 3.4.15.1; ACE）通过将血管紧张素I转化为有效的血管收缩剂血管紧张素II并通过裂解，通过肾素血管紧张素和激肽释放酶激肽系统在血压调节中发挥重要的生理作用。许多其他底物，包括血管舒张缓激肽和抗炎肽N-乙酰基-SDKP。因此，ACE抑制剂的设计在现代医学中优先考虑，可用于治疗高血压，心力衰竭，心肌梗塞和其他相关疾病。尽管ACE抑制剂在治疗高血压和充血性心力衰竭方面取得了成功，但它们仍具有一些不良反应，这些不良反应可以通过选择性域抑制来减轻。过去几十年来报道的两个ACE域（nACE和cACE）的晶体结构均可促进选择性抑制剂的合理药物设计。在这篇综述中，我们参考了ACE抑制剂的发现历史，该发现与分子建模方法的发展密切相关。我们指出，新型选择性ACE抑制剂的设计对当前的研究人员是一个挑战，需要对ACE域的结构和分子建模方法的帮助有透彻的了解。最后，我们进行了trandolaprilat的潜在选择性衍生物的理论设计，tradolaprilat是一种被批准用于治疗高血压的严重疾病的药物，旨在说明如何使用分子建模方法，例如从头设计，对接，分子动力学（MD）模拟，