Combined use of the hepatitis C drugs and amentoflavone could interfere with binding of the spike glycoprotein of SARS-CoV-2 to ACE2: the results of a molecular simulation study

The worldwide rapid spread of the COVID-19 disease necessitates the search for fast and effective treatments. The repurposing of existing drugs seems to be the best solution in this situation. In this study, the molecular docking method was used to test 248 drugs against the receptor-binding domain (RBD) of spike glycoprotein of SARS-CoV-2, which is responsible for viral entry into the host cell. Among the top-ranked ligands are drugs that are used for hepatitis C virus (HCV) treatments (paritaprevir, ledipasvir, simeprevir) and a natural biflavonoid amentoflavone. The binding sites of the HCV drugs and amentoflavone are different. Therefore, the ternary complexes of the HCV drug, amentoflavone, and RBD can be created. For the 5 top-ranked ligands, the validating molecular dynamics simulations of binary and ternary complexes with RBD were performed. According to the MMPBSA-binding free energies, the HCV drugs ledipasvir and paritaprevir (in a neutral form) are the most efficient binders of the RBD when used in combination with amentoflavone. Communicated by Ramaswamy H. Sarma新型冠状病毒肺炎（COVID-19）在全球范围内快速蔓延，亟需探索快速有效的治疗手段。在此背景下，现有药物的重定位似乎是最佳解决方案。本研究采用分子对接方法，针对介导病毒侵入宿主细胞的新型冠状病毒（SARS-CoV-2）刺突糖蛋白的受体结合域（receptor-binding domain, RBD），对248种药物开展了筛选测试。筛选出的排名靠前的配体包括用于丙型肝炎病毒（hepatitis C virus, HCV）治疗的帕利瑞韦（paritaprevir）、莱迪帕韦（ledipasvir）、西米普韦（simeprevir），以及天然双黄酮类化合物扁柏双黄酮（amentoflavone）。上述丙型肝炎治疗药物与扁柏双黄酮的结合位点存在差异，因此可构建丙型肝炎治疗药物、扁柏双黄酮与RBD的三元复合物。针对排名前五的配体，本研究对其与RBD形成的二元及三元复合物开展了验证性分子动力学模拟。基于分子力学泊松-玻尔兹曼表面积（MMPBSA）计算的结合自由能结果显示，当与扁柏双黄酮联用时，中性形式的丙型肝炎治疗药物莱迪帕韦与帕利瑞韦是与RBD结合效率最高的配体。由Ramaswamy H. Sarma转交