Abstract

Regarding the urgency of therapeutic measures for coronavirus disease 2019 (COVID-19) pandemic, the use of available drugs with FDA approval is preferred because of the less time and cost required for their development. In silico drug repurposing is an accurate way to speed up the screening of the existing FDA-approved drugs to find a therapeutic option for COVID-19. The similarity in SARS-CoV-2 and HIV-1 fusion mechanism to host cells can be a key point for Inhibit SARS-CoV-2 entry into host cells by HIV fusion inhibitors. Accordingly, in this study, an HIV-1 fusion inhibitor called Enfuvirtide (Enf) was selected. The affinity and essential residues involving in the Enf binding to the S2 protein of SARS-CoV-2, HIV-1 gp41 protein and angiotensin-converting enzyme 2 (ACE-2) as a negative control, was evaluated using molecular docking. Eventually, Enf-S2 and Enf-gp41 protein complexes were simulated by molecular dynamics (MD) in terms of binding affinity and stability. Based on the most important criteria such as docking score, cluster size, energy and dissociation constant, the strongest interaction was observed between Enf with the S2 protein. In addition, MD results confirmed that Enf-S2 protein interaction was remarkably stable and caused the S2 protein residues to undergo the fewest fluctuations. In conclusion, it can be stated that Enf can act as a strong SARS-CoV-2 fusion inhibitor and demonstrates the potential to enter the clinical trial phase of COVID-19.

Communicated by Ramaswamy H. Sarma

摘要

关于2019年冠状病毒病（COVID-19）大流行的治疗措施的紧迫性，首选使用经过FDA批准的可用药物，因为其开发所需的时间和成本更少。电脑改变药物用途是加快筛选现有FDA批准的药物以找到COVID-19的治疗选择的准确方法。SARS-CoV-2和HIV-1融合机制与宿主细胞的相似性可能是抑制SARS-CoV-2被HIV融合抑制剂进入宿主细胞的关键点。因此，在这项研究中，选择了一种称为Enfuvirtide（Enf）的HIV-1融合抑制剂。使用分子对接评估了Enf结合SARS-CoV-2的S2蛋白，HIV-1 gp41蛋白和血管紧张素转化酶2（ACE-2）的亲和力和必需残基作为阴性对照。最终，通过分子动力学（MD）在结合亲和力和稳定性方面模拟了Enf-S2和Enf-gp41蛋白复合物。根据最重要的标准，例如对接得分，簇大小，能量和解离常数，Enf与S2蛋白之间的相互作用最强。此外，MD结果证实Enf-S2蛋白相互作用非常稳定，并导致S2蛋白残基的波动最小。总之，可以说Enf可以作为强效SARS-CoV-2融合抑制剂发挥作用，并证明有可能进入COVID-19的临床试验阶段。

由Ramaswamy H.Sarma沟通