Repurposing approved drugs as inhibitors of SARS-CoV-2 S-protein from molecular modeling and virtual screening
Repurposing approved drugs as inhibitors of SARS-CoV-2 S-protein from molecular modeling and virtual screening
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DOI：
10.1080/07391102.2020.1772885
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发表时间：
2020-06-01
影响因子：
4.4
通讯作者：
Costa, Luciano T.
中科院分区：
文献类型：
--
作者：
de Oliveira, Osmair Vital;Rocha, Gerd B.;Costa, Luciano T.
在此，分子建模技术的主要目标是从药物数据库中获得候选药物作为抗SARS-CoV-2的潜在靶点。这种新型冠状病毒自2019年底爆发以来一直是COVID-19疫情的罪魁祸首，由于没有针对这种疾病的疫苗，因此成为一个挑战。本研究的第一步是将分离的S-蛋白溶解在水中进行分子动力学（MD）模拟，观察到S-蛋白的受体结合结构域（RBD）分别以54.3度和43.0度的角度从“上”到“下”构象的转变。RBD区域由于其增强的表面积而更多地暴露于溶剂和可能的药物。从平衡的MD结构，使用含有9091种FDA批准的药物的文库通过对接计算进行虚拟筛选。其中，24个得分最高的配体（14个传统的草药分离物和10个已批准的药物）的结合能低于-8.1千卡/摩尔被选为潜在的候选人，以抑制SARS-CoV-2 S-蛋白，防止人类细胞感染和复制。例如，伊维菌素药物（目前在我们的候选名单中）最近被成功地用于控制病毒的体外复制。MD模拟进行了三个最好的配体@ S-蛋白复合物和结合能计算使用MM/PBSA方法。总的来说，它强调了一个重要的战略，一些关键的残留物和化学基团，可以考虑在COVID-19爆发的临床试验。
Herein, molecular modeling techniques were used with the main goal to obtain candidates from a drug database as potential targets to be used against SARS-CoV-2. This novel coronavirus, responsible by the COVID-19 outbreak since the end of 2019, became a challenge since there is not vaccine for this disease. The first step in this investigation was to solvate the isolated S-protein in water for molecular dynamics (MD) simulation, being observed a transition from "up" to "down" conformation of receptor-binding domain (RBD) of the S-protein with angle of 54.3 and 43.0 degrees, respectively. The RBD region was more exposed to the solvent and to the possible drugs due to its enhanced surface area. From the equilibrated MD structure, virtual screening by docking calculations were performed using a library contained 9091 FDA approved drugs. Among them, 24 best-scored ligands (14 traditional herbal isolate and 10 approved drugs) with the binding energy below -8.1 kcal/mol were selected as potential candidates to inhibit the SARS-CoV-2 S-protein, preventing the human cell infection and their replication. For instance, the ivermectin drug (present in our list of promise candidates) was recently used successful to control viral replicationin vitro.MD simulations were performed for the three best ligands@S-protein complexes and the binding energies were calculated using the MM/PBSA approach. Overall, it is highlighted an important strategy, some key residues, and chemical groups which may be considered on clinical trials for COVID-19 outbreak.