De Vita Simona, Chini Maria Giovanna, Lauro Gianluigi, Bifulco Giuseppe
Department of Pharmacy, University of Salerno Via Giovanni Paolo II 132 Fisciano 84084 Italy
Department of Biosciences and Territory, University of Molise C.da Fonte Lappone 86090 Pesche (IS) Italy.
RSC Adv. 2020 Nov 10;10(67):40867-40875. doi: 10.1039/d0ra09010g. eCollection 2020 Nov 9.
The recent release of the main protein structures belonging to SARS CoV-2, responsible for the coronavirus disease-19 (COVID-19), strongly pushed for identifying valuable drug treatments. With this aim, we show a repurposing study on FDA-approved drugs applying a new computational protocol and introducing a novel parameter called IVS. Starting with a virtual screening against three SARS CoV-2 targets (main protease, papain-like protease, spike protein), the top-ranked molecules were reassessed combining the Inverse Virtual Screening novel approach and MM-GBSA calculations. Applying this protocol, a list of drugs was identified against the three investigated targets. Also, the top-ranked selected compounds on each target (rutin main protease, velpatasvir papain-like protease, lomitapide spike protein) were further tested with molecular dynamics simulations to confirm the promising binding modes, obtaining encouraging results such as high stability of the complex during the simulation and a good protein-ligand interaction network involving some important residues of each target. Moreover, the recent outcomes highlighting the inhibitory activity of quercetin, a natural compound strictly related to rutin, on the SARS-CoV-2 main protease, strengthened the applicability of the proposed workflow.
最近公布的导致冠状病毒病-19（COVID-19）的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）主要蛋白质结构，有力地推动了对有价值药物治疗方法的识别。出于这一目的，我们展示了一项针对美国食品药品监督管理局（FDA）批准药物的重新利用研究，应用了一种新的计算方案并引入了一个名为IVS的新参数。从针对三个SARS-CoV-2靶点（主要蛋白酶、木瓜样蛋白酶、刺突蛋白）的虚拟筛选开始，结合逆虚拟筛选新方法和MM-GBSA计算对排名靠前的分子进行重新评估。应用该方案，确定了针对三个研究靶点的一系列药物。此外，对每个靶点上排名靠前的选定化合物（芦丁针对主要蛋白酶、维帕他韦针对木瓜样蛋白酶、洛美他派针对刺突蛋白）进一步进行分子动力学模拟测试，以确认有前景的结合模式，获得了令人鼓舞的结果，如模拟过程中复合物的高稳定性以及涉及每个靶点一些重要残基的良好蛋白质-配体相互作用网络。此外，最近的研究结果突出了与芦丁密切相关的天然化合物槲皮素对SARS-CoV-2主要蛋白酶的抑制活性，加强了所提出工作流程的适用性。
