The COVID-19 outbreak has been devastating, with hundreds of millions of infections and millions of deaths reported worldwide. In response, the application of structure–activity relationships (SAR) upon experimentally validated inhibitors of SARS-CoV-2 main protease (M^pro) may provide an avenue for the identification of new lead compounds active against COVID-19. Upon the basis of information gleaned from a combination of reported crystal structures and the docking of experimentally validated inhibitors, four “rules” for designing potent M^pro inhibitors have been proposed. The aim here is to guide medicinal chemists toward the most probable hits and to provide guidance on repurposing available structures as M^pro inhibitors. Experimental examination of our own previously reported inhibitors using the four “rules” identified a potential lead compound, the cathepsin inhibitor GB111-NH₂, that was 2.3 times more potent than SARS-CoV-2 M^pro inhibitor N3.

中文翻译：

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设计 SARS-CoV-2 主要蛋白酶 (Mpro) 抑制剂的引物

COVID-19 的爆发是毁灭性的，全球报告了数亿人感染、数百万人死亡。因此，将构效关系 (SAR) 应用到经过实验验证的 SARS-CoV-2 主要蛋白酶 (M ^pro ) 抑制剂上，可能为鉴定具有抗 COVID-19 活性的新先导化合物提供一条途径。根据从已报道的晶体结构和经过实验验证的抑制剂的对接中收集的信息，提出了设计有效的 M ^{pro抑制剂的四个“规则”。这里的目的是指导药物化学家寻找最可能的命中，并为重新利用可用结构作为 M pro}抑制剂提供指导。使用四个“规则”对我们之前报道的抑制剂进行实验检查，发现了一种潜在的先导化合物，即组织蛋白酶抑制剂 GB111 -NH ₂ ^{，其效力比 SARS-CoV-2 M前}抑制剂N3强 2.3 倍。