Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
J Biomol Struct Dyn. 2022;40(24):13747-13758. doi: 10.1080/07391102.2021.1994013. Epub 2021 Oct 28.
COVID-19 caused by SARS-CoV-2 has emerged as a potential threat to human life, especially to people suffering from chronic diseases. In this study, we investigated the ability of selected FDA-approved drugs to inhibit TACE (tumor necrosis factor α converting enzyme), which is responsible for the shedding of membrane-bound ACE2 (angiotensin-converting enzyme2) receptors into soluble ACE2. The inhibition of TACE would lead to an increased population of membrane-bound ACE2, which would facilitate ACE2-Spike protein interaction and viral entry. A total of 50 drugs prescribed in treating various chronic diseases in Saudi Arabia were screened by performing molecular docking using AutoDock4.2. Based on docking energy (≤ -9.00 kcal mol), four drugs (Celecoxib, Glipizide, Lapatinib, and Sitagliptin) were identified as potential inhibitors of TACE, with binding affinities up to 10-10 . Analysis of the molecular docking suggests that these drugs were bound to TACE's catalytic domain and interact with the key residues such as His405, Glu406, and His415, which are involved in active site Zn ion chelation. Molecular dynamics simulation was performed to confirm the stability of TACE-drugs complexes. RMSD (root mean square deviation), RMSF (root mean square fluctuation), Rg (radius of gyration), and SASA (solvent accessible surface area) were within the acceptable limits. Free energy calculations using Prime-MM/GBSA suggest that Celecoxib formed the most stable complex with TACE, followed by Glipizide, Sitagliptin, and Lapatinib. The finding of this study suggests a mechanism for drugs to aggravate SARS-CoV-2 infection and hence high mortality in patients suffering from chronic diseases.Communicated by Ramaswamy H. Sarma.
由 SARS-CoV-2 引起的 COVID-19 已经成为对人类生命的潜在威胁，特别是对患有慢性疾病的人。在这项研究中，我们研究了选定的经美国食品和药物管理局批准的药物抑制 TACE（肿瘤坏死因子α转换酶）的能力，TACE 负责将膜结合的 ACE2（血管紧张素转换酶 2）受体脱落为可溶性 ACE2。TACE 的抑制作用会导致膜结合的 ACE2 数量增加，这将促进 ACE2-刺突蛋白相互作用和病毒进入。使用 AutoDock4.2 进行分子对接，对沙特阿拉伯治疗各种慢性疾病的 50 种药物进行了筛选。根据对接能（≤-9.00kcal/mol），确定了 4 种药物（塞来昔布、格列吡嗪、拉帕替尼和西他列汀）为 TACE 的潜在抑制剂，其结合亲和力高达 10-10。分子对接分析表明，这些药物与 TACE 的催化结构域结合，并与关键残基（如 His405、Glu406 和 His415）相互作用，这些残基参与活性部位 Zn 离子螯合。进行了分子动力学模拟以确认 TACE-药物复合物的稳定性。RMSD（均方根偏差）、RMSF（均方根波动）、Rg（回转半径）和 SASA（溶剂可及表面积）均在可接受范围内。使用 Prime-MM/GBSA 进行自由能计算表明，塞来昔布与 TACE 形成最稳定的复合物，其次是格列吡嗪、西他列汀和拉帕替尼。这项研究的结果表明，药物可能通过一种机制加重 SARS-CoV-2 感染，从而导致患有慢性疾病的患者死亡率升高。由 Ramaswamy H. Sarma 交流。
