Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1–7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor’s active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor’s critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future.

血管紧张素转换酶2（ACE2）是一种与膜结合的锌金属肽酶，可产生血管扩张肽血管紧张素1-7，因此在心脏病中起保护作用。由于SARS-CoV-2通过ACE2介导的机制进入允许的细胞，因此被认为是控制COVID-19爆发的重要治疗靶点。目前的计算机这项研究试图改变现有药物的用途，以用作靶向人ACE2的前瞻性病毒进入抑制剂。最初，使用分子对接针对受体筛选了临床上批准的7,173个配体的药物库，然后进行了能量最小化和对接的配体的核对。最后，检查了潜在的粘合剂，以确保具有不同支架的分子与金属辅因子和受体活性位点的关键残基保持良好接触。计算结果表明，lividomycin，burixafor，quisinostat，fluprofylline，pemetrexed，spirofylline，edotecarin和diniprofylline有望成为可重新定位的候选药物，以稳定ACE2的封闭（受底物/抑制剂结合）构象。从而改变了SARS-CoV-2识别的受体关键外部残基的相对位置。这项研究是相关科学文献中罕见的寻找潜在ACE2抑制剂的研究。实际上，可以将未经修饰的药物引入目前正在进行的对抗COVID-19的治疗性武器库中，或者它们的支架可以作为在不久的将来设计新型ACE2抑制剂的丰富骨架。