ABSTRACT

COVID-19 is the most unanticipated incidence of 2020 affecting the human population worldwide. Currently, it is utmost important to produce novel small molecule anti-SARS-CoV-2 drugs urgently that can save human lives globally. Based on the earlier SARS-CoV and MERS-CoV infection along with the general characters of coronaviral replication, a number of drug molecules have been proposed. However, one of the major limitations is the lack of experimental observations with different drug molecules. In this article, 70 diverse chemicals having experimental SARS-CoV-2 3CL^proinhibitory activity were accounted for robust classification-based QSAR analysis statistically validated with 4 different methodologies to recognize the crucial structural features responsible for imparting the activity. Results obtained from all these methodologies supported and validated each other. Important observations obtained from these analyses were also justified with the ligand-bound crystal structure of SARS-CoV-2 3CL^pro enzyme. Our results suggest that molecules should contain a 2-oxopyrrolidine scaffold as well as a methylene (hydroxy) sulphonic acid warhead in proper orientation to achieve higher inhibitory potency against SARS-CoV-2 3CL^pro. Outcomes of our study may be able to design and discover highly effective SARS-CoV-2 3CL^pro inhibitors as potential anticoronaviral therapy to crusade against COVID-19.

摘要

COVID-19 是 2020 年影响全球人口的最出乎意料的发病率。当前，迫切需要生产可以在全球范围内挽救人类生命的新型小分子抗 SARS-CoV-2 药物。基于早期的 SARS-CoV 和 MERS-CoV 感染以及冠状病毒复制的一般特征，已经提出了许多药物分子。然而，主要限制之一是缺乏对不同药物分子的实验观察。在这篇文章中，70 种不同的化学物质具有实验性 SARS-CoV-2 3CL ^pro抑制活性被解释为稳健的基于分类的 QSAR 分析，使用 4 种不同的方法进行统计验证，以识别负责赋予活性的关键结构特征。从所有这些方法中获得的结果相互支​​持和验证。从这些分析中获得的重要观察结果也与 SARS-CoV-2 3CL ^pro酶的配体结合晶体结构相一致。我们的结果表明，分子应该包含一个 2-氧代吡咯烷支架以及一个适当方向的亚甲基（羟基）磺酸弹头，以实现对 SARS-CoV-2 3CL ^{pro 的}更高抑制效力。我们的研究结果可能能够设计和发现高效的 SARS-CoV-2 3CL ^pro 抑制剂作为潜在的抗冠状病毒疗法来对抗 COVID-19。