Pharmacoinformatics and molecular dynamics simulation studies reveal potential covalent and FDA-approved inhibitors of SARS-CoV-2 main protease 3CLpro
Pharmacoinformatics and molecular dynamics simulation studies reveal potential covalent and FDA-approved inhibitors of SARS-CoV-2 main protease 3CLpro
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DOI：
10.1080/07391102.2020.1782768
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发表时间：
2020-06-23
影响因子：
4.4
通讯作者：
Salo-Ahen, Outi M. H.
中科院分区：
文献类型：
--
作者：
Alamri, Mubarak A.;ul Qamar, Muhammad Tahir;Salo-Ahen, Outi M. H.
SARS-CoV-2被确认为导致2019冠状病毒病（COVID-19）全球大流行的原因。3-糜蛋白酶样蛋白酶（3CLpro）是病毒复制的必需酶，是对抗SARS-CoV和MERS-CoV的有效靶标。在这项工作中，我们提出了一个基于结构的研究，以确定潜在的共价抑制剂含有各种化学弹头。基于不同的反应类型筛选靶向Asinex聚焦共价（AFCL）文库，并鉴定潜在的共价抑制剂。此外，我们筛选了FDA批准的蛋白酶抑制剂，以寻找针对SARS-CoV-2 3CLpro的候选物。鉴定了许多具有显著共价对接分数的化合物。这些化合物能够与Cys 145的反应性硫醇基团建立共价键（C-S），并与衬于底物结合位点的残基形成有利的相互作用。此外，来自FDA批准的蛋白酶抑制剂的paritaprevir和simeprevir被鉴定为SARS-CoV-2 3CLpro的潜在抑制剂。通过分子动力学模拟，对化合物与SARS-CoV-2 3CLpro的结合机制和动力学稳定性进行了表征。已鉴定的化合物是潜在的抑制剂，值得进一步开发为COVID-19药物。重要的是，FDA批准的抗丙型肝炎病毒（HCV）药物paritaprevir和simeprevir可以准备进行临床试验，以治疗感染患者并帮助遏制COVID-19。作者：Ramaswamy H. Sarma
The SARS-CoV-2 was confirmed to cause the global pandemic of coronavirus disease 2019 (COVID-19). The 3-chymotrypsin-like protease (3CLpro), an essential enzyme for viral replication, is a valid target to combat SARS-CoV and MERS-CoV. In this work, we present a structure-based study to identify potential covalent inhibitors containing a variety of chemical warheads. The targeted Asinex Focused Covalent (AFCL) library was screened based on different reaction types and potential covalent inhibitors were identified. In addition, we screened FDA-approved protease inhibitors to find candidates to be repurposed against SARS-CoV-2 3CLpro. A number of compounds with significant covalent docking scores were identified. These compounds were able to establish a covalent bond (C-S) with the reactive thiol group of Cys145 and to form favorable interactions with residues lining the substrate-binding site. Moreover, paritaprevir and simeprevir from FDA-approved protease inhibitors were identified as potential inhibitors of SARS-CoV-2 3CLpro. The mechanism and dynamic stability of binding between the identified compounds and SARS-CoV-2 3CLpro were characterized by molecular dynamics (MD) simulations. The identified compounds are potential inhibitors worthy of further development as COVID-19 drugs. Importantly, the identified FDA-approved anti-hepatitis-C virus (HCV) drugs paritaprevir and simeprevir could be ready for clinical trials to treat infected patients and help curb COVID-19. Communicated by Ramaswamy H. Sarma