Abstract

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

摘要

SARS-CoV-2 已被证实导致 2019 年冠状病毒病（COVID-19）全球大流行。3-胰凝乳蛋白酶样蛋白酶 (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，我们提出了一项基于结构的研究，以确定含有各种化学弹头的潜在共价抑制剂。根据不同反应类型筛选靶向 Asinex Focused Covalent (AFCL) 文库，并鉴定出潜在的共价抑制剂。此外，我们筛选了 FDA 批准的蛋白酶抑制剂，以寻找可重新用于对抗 SARS-CoV-2 3CLpro 的候选药物。鉴定出许多具有显着共价对接分数的化合物。这些化合物能够与 Cys145 的反应性硫醇基团建立共价键 (C-S)，并与底物结合位点内的残基形成有利的相互作用。此外，FDA 批准的蛋白酶抑制剂中的 paritaprevir 和 simeprevir 被确定为 SARS-CoV-2 3CLpro 的潜在抑制剂。通过分子动力学 (MD) 模拟来表征所鉴定的化合物与 SARS-CoV-2 3CLpro 之间的结合机制和动态稳定性。鉴定出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，已确定的 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。

拉马斯瓦米·萨尔马 (Ramaswamy H. Sarma) 通讯