Abstract

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global health emergency. Repurposing of approved pharmaceutical drugs for COVID-19 treatment represents an attractive approach to quickly identify promising drug candidates. SARS-CoV-2 main protease (M^pro) is responsible for the maturation of viral functional proteins making it a key antiviral target. Based on the recently revealed crystal structures of SARS-CoV-2 M^pro, we herein describe a multi-stage virtual screening protocol including pharmacophore screening, molecular docking and protein-ligand interaction fingerprints (PLIF) post-docking filtration for efficient enrichment of potent SARS-CoV-2 M^pro inhibitors. Potential hits, along with a cocrystallized control were further studied via molecular dynamics. A 150-ns production trajectory was followed by RMSD, free energy calculation, and H-bond analysis for each compound. The applied virtual screening protocol led to identification of five FDA-approved drugs with promising binding modes to key subsites of the substrate-binding pocket of SARS-CoV-2 M^pro. The identified compounds belong to different pharmaceutical classes, including several protease inhibitors, antineoplastic agents and a natural flavonoid. The drug candidates discovered in this study present a potential extension of the recently reported SARS-CoV-2 M^pro inhibitors that have been identified using other virtual screening protocols and may be repurposed for COVID-19 treatment.

摘要

由严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起的 2019 年冠状病毒病 (COVID-19) 是一种持续的全球卫生紧急情况。将已批准的药物重新用于 COVID-19 治疗是一种快速识别有希望的候选药物的有吸引力的方法。SARS-CoV-2 主要蛋白酶 (M ^pro ) 负责病毒功能蛋白的成熟，使其成为关键的抗病毒靶点。基于最近揭示的 SARS-CoV-2 M ^pro晶体结构，我们在此描述了一种多阶段虚拟筛选方案，包括药效团筛选、分子对接和蛋白质-配体相互作用指纹 (PLIF) 对接后过滤，以有效富集强效SARS-CoV-2 M ^pro抑制剂。通过分子动力学进一步研究了潜在的命中以及共结晶对照。150 ns 的生产轨迹之后是每种化合物的 RMSD、自由能计算和 H 键分析。应用的虚拟筛选方案导致鉴定出五种 FDA 批准的药物，这些药物具有与 SARS-CoV-2 M ^pro底物结合袋的关键亚位点有希望的结合模式。鉴定出的化合物属于不同的药物类别，包括几种蛋白酶抑制剂、抗肿瘤剂和一种天然类黄酮。本研究中发现的候选药物是最近报道的 SARS-CoV-2 M ^{pro的潜在扩展}已使用其他虚拟筛查方案确定并可能重新用于 COVID-19 治疗的抑制剂。