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基于二元定量构效关系指导的针对严重急性呼吸综合征冠状病毒2主要蛋白酶的FDA批准药物及临床研究中的化合物的虚拟筛选

Binary-QSAR guided virtual screening of FDA approved drugs and compounds in clinical investigation against SARS-CoV-2 main protease.

作者信息

Oktay Lalehan, Erdemoğlu Ece, Tolu İlayda, Yumak Yeşim, Özcan Ayşenur, Acar Elif, Büyükkiliç Şehriban, Olkan Alpsu, Durdaği Serdar

机构信息

Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahçeşehir University, İstanbul Turkey.

School of Medicine, Mersin University, Mersin Turkey.

出版信息

Turk J Biol. 2021 Aug 30;45(4):459-468. doi: 10.3906/biy-2106-61. eCollection 2021.

Abstract

With the emergence of the new SARS-CoV-2 virus, drug repurposing studies have gained substantial importance. Combined with the efficacy of recent improvements in ligand- and target-based virtual screening approaches, virtual screening has become faster and more productive than ever. In the current study, an FDA library of approved drugs and compounds under clinical investigation were screened for their antiviral activity using the antiviral therapeutic activity binary QSAR model of the MetaCore/MetaDrug platform. Among 6733-compound collection, we found 370 compounds with a normalized therapeutic activity value greater than a cutoff of 0.75. Only these selected compounds were used for molecular docking studies against the SARS-CoV-2 main protease (M). After initial short (10 ns) molecular dynamics (MD) simulations with the top-50 docking scored compounds and following molecular mechanics generalized born surface area (MM/GBSA) calculations, top-10 compounds were subjected to longer (100 ns) MD simulations and end-point MM/GBSA estimations. Our virtual screening protocol yielded Cefuroxime pivoxetil, an ester prodrug of second-generation cephalosporin antibiotic Cefuroxime, as being a considerable molecule for drug repurposing against the SARS-CoV-2 M.

摘要

随着新型严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的出现,药物再利用研究变得至关重要。结合基于配体和靶点的虚拟筛选方法近期改进后的功效,虚拟筛选比以往任何时候都更快且更高效。在当前研究中,使用MetaCore/MetaDrug平台的抗病毒治疗活性二元定量构效关系(QSAR)模型,对美国食品药品监督管理局(FDA)批准药物库以及处于临床研究阶段的化合物进行抗病毒活性筛选。在6733种化合物集合中,我们发现370种化合物的标准化治疗活性值大于0.75的临界值。仅这些选定的化合物用于针对SARS-CoV-2主要蛋白酶(M)的分子对接研究。在用排名前50的对接得分化合物进行初始短时间(10纳秒)分子动力学(MD)模拟并随后进行分子力学广义玻恩表面积(MM/GBSA)计算后,排名前10的化合物进行更长时间(100纳秒)的MD模拟和终点MM/GBSA估计。我们的虚拟筛选方案得出头孢呋辛酯匹伐酯,一种第二代头孢菌素抗生素头孢呋辛的酯前药,是用于针对SARS-CoV-2 M进行药物再利用的重要分子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b21a/8573836/ffde0faa7068/turkjbio-45-459-fig001.jpg

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