Identification of Potential Inhibitors of 3CL Protease of SARS-CoV-2 From ZINC Database by Molecular Docking-Based Virtual Screening.
Identification of Potential Inhibitors of 3CL Protease of SARS-CoV-2 From ZINC Database by Molecular Docking-Based Virtual Screening.
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DOI：
10.3389/fmolb.2020.603037
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发表时间：
2020
影响因子：
5
通讯作者：
Murugaiyah V
中科院分区：
文献类型：
--
作者：
Abdusalam AAA;Murugaiyah V
在武汉首次发现的2019年快速暴发冠状病毒病(新冠肺炎)，中国是由一种新型严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)引起的。3CL蛋白酶(3CLpro)是SARS-CoV-2的主要蛋白酶，负责病毒的复制，因此被认为是一个有吸引力的药物靶点，因为到目前为止还没有针对这种病毒的特异和有效的疫苗。在本文中，我们报道了基于分子对接的虚拟筛选(VS)，使用AutoDock Vina对从锌数据库中获得的2000个化合物和FDA批准的10个3CLPro上的抗病毒和抗疟疾化合物进行虚拟筛选，以寻找潜在的抑制剂。筛选结果表明，前4个化合物ZINC32960814、ZINC12006217、ZINC03231196和ZINC33173588在3CLPro结合口袋具有较高的亲和力。结合自由能(FEB)分别为−12.3、−11.9、−11.7和−11.2kcal/m ol；AutoDock Vina评分分别为−12.61、−12.32、−12.01和-11.92kcal/m o l。这些结果比共结晶配体N3更好，后者的FEB为−7.5kcal/mol和FDA批准的药物。鉴定的四个化合物与3CLPro的催化二联体残基之间存在着不同但稳定的相互作用。综上所述，利用VS和分子对接方法成功地从锌数据库中鉴定了新的3CLPro抑制剂，满足Lipinski规则5，并且与目的蛋白具有低Feb和功能分子相互作用。这些结果表明，所鉴定的化合物可能是潜在的先导化合物，作为新冠肺炎3CLPro的抑制剂，值得进一步评估和开发。
The rapid outbreak of Coronavirus Disease 2019 (COVID-19) that was first identified in Wuhan, China is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The 3CL protease (3CLpro) is the main protease of the SARS-CoV-2, which is responsible for the viral replication and therefore considered as an attractive drug target since to date there is no specific and effective vaccine available against this virus. In this paper, we reported molecular docking-based virtual screening (VS) of 2000 compounds obtained from the ZINC database and 10 FDA-approved (antiviral and anti-malaria) on 3CLpro using AutoDock Vina to find potential inhibitors. The screening results showed that the top four compounds, namely ZINC32960814, ZINC12006217, ZINC03231196, and ZINC33173588 exhibited high affinity at the 3CLpro binding pocket. Their free energy of binding (FEB) were −12.3, −11.9, −11.7, and −11.2 kcal/mol while AutoDock Vina scores were −12.61, −12.32, −12.01, and -11.92 kcal/mol, respectively. These results were better than the co-crystallized ligand N3, whereby its FEB was −7.5 kcal/mol and FDA-approved drugs. Different but stable interactions were obtained between the four identified compounds with the catalytic dyad residues of the 3CLpro. In conclusion, novel 3CLpro inhibitors from the ZINC database were successfully identified using VS and molecular docking approach, fulfilling the Lipinski rule of five, and having low FEB and functional molecular interactions with the target protein. The findings suggests that the identified compounds may serve as potential leads that act as COVID-19 3CLpro inhibitors, worthy for further evaluation and development.
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DOI：
10.1038/nrmicro.2016.81
发表时间：
2016-08
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
de Wit E;van Doremalen N;Falzarano D;Munster VJ
通讯作者：
Munster VJ
DOI：
10.1038/nrmicro2147
发表时间：
2009-06
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1007/978-1-4939-7000-1_26
发表时间：
2017
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Burley SK;Berman HM;Kleywegt GJ;Markley JL;Nakamura H;Velankar S
通讯作者：
Velankar S
影响因子：
4.7
作者：
Gralinski, Lisa E.;Menachery, Vineet D.
通讯作者：
Menachery, Vineet D.
影响因子：
7.3
作者：
Fornabaio, M;Spyrakis, F;Kellogg, GE
通讯作者：
Kellogg, GE