Buitrón-González Ivonne, Aguilera-Durán Giovanny, Romo-Mancillas Antonio
Laboratorio de Diseño Asistido por Computadora y Síntesis de Fármacos, Facultad de Química, Universidad Autónoma de Querétaro, Centro Universitario, Querétaro 76010, Mexico.
Results Chem. 2021 Jan;3:100094. doi: 10.1016/j.rechem.2020.100094. Epub 2020 Dec 28.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that leads to coronavirus disease (COVID-19) has put public health at risk in 2020. The spike protein (SP) in SARS-CoV-2 is primarily responsible for the attachment and entry of the virus into the cell, which binds to the angiotensin-converting enzyme 2 (ACE2). Owing to the lack of an effective therapy, drug repositioning is an opportunity to search for molecules with pharmacological potential for the treatment of COVID-19. In this study, three candidates with the potential to destabilize the SP-ACE2 complex are reported. Through molecular docking, 147 drugs were evaluated and their possible binding sites in the interface region of the SP-ACE2 complex and the SP of SARS-CoV-2 were identified. The five best candidate molecules were selected for molecular dynamics studies to observe changes in interactions between SP-ACE2 and ligands with the SP-ACE2 complex. Using umbrella sampling molecular dynamics simulations, the binding energy of SP with ACE2 (-29.58 kcal/mol) without ligands, and in complex with amprenavir (-20.13 kcal/mol), enalaprilat (-23.84 kcal/mol), and plerixafor (-19.72 kcal/mol) were calculated. These drugs are potential candidates for the treatment of COVID-19 as they destabilize the SP-ACE2 complex; the binding energy of SP is decreased in the presence of these drugs and may prevent the virus from entering the cell. Plerixafor is the drug with the greatest potential to destabilize the SP-ACE2 complex, followed by amprenavir and enalaprilat; thus, these three drugs are proposed for future in vitro and in vivo evaluations.
导致冠状病毒病（COVID-19）的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）在2020年给公众健康带来了风险。SARS-CoV-2中的刺突蛋白（SP）主要负责病毒与细胞的附着和进入，它与血管紧张素转换酶2（ACE2）结合。由于缺乏有效的治疗方法，药物重新定位是寻找具有治疗COVID-19药理学潜力分子的一个机会。在本研究中，报告了三种有可能破坏SP-ACE2复合物稳定性的候选药物。通过分子对接，评估了147种药物，并确定了它们在SP-ACE2复合物界面区域和SARS-CoV-2的SP中的可能结合位点。选择了五个最佳候选分子进行分子动力学研究，以观察SP-ACE2与配体和SP-ACE2复合物之间相互作用的变化。使用伞形采样分子动力学模拟，计算了无配体时SP与ACE2的结合能（-29.58千卡/摩尔），以及与安普那韦（-20.13千卡/摩尔）、依那普利拉（-23.84千卡/摩尔）和普乐沙福（-19.72千卡/摩尔）形成复合物时的结合能。这些药物是治疗COVID-19的潜在候选药物，因为它们会破坏SP-ACE2复合物的稳定性；在这些药物存在的情况下，SP的结合能降低，可能会阻止病毒进入细胞。普乐沙福是破坏SP-ACE2复合物稳定性潜力最大的药物，其次是安普那韦和依那普利拉；因此，建议对这三种药物进行未来的体外和体内评估。
