The life challenging COVID-19 disease caused by the SARS-CoV-2 virus has greatly impacted smooth survival worldwide since its discovery in December 2019. Currently, it is one of the major threats to humanity. Moreover, any specific drug or vaccine unavailability against COVID-19 forces to discover a new drug on an urgent basis. Viral cycle inhibition could be one possible way to prevent the further genesis of this viral disease, which can be contributed by drug repurposing techniques or screening of small bioactive natural molecules against already validated targets of COVID-19. The main protease (M^pro) responsible for producing functional proteins from polyprotein is an important key step for SARS-CoV-2 virion replication. Natural product or herbal based formulations are an important platform for potential therapeutics and lead compounds in the drug discovery process. Therefore, here we have screened >53,500 bioactive natural molecules from six different natural product databases against M^pro (PDB ID: 6LU7) of COVID-19 through computational study. Further, the top three molecules were subjected to pharmacokinetics evaluation, which is an important factor that reduces the drug failure rate. Moreover, the top three screened molecules (C00014803, C00006660, ANLT0001) were further validated by a molecular dynamics study under a condition similar to the physiological one. Relative binding energy analysis of three lead molecules indicated that C00014803 possess highest binding affinity among all three hits. These extensive studies can be a significant foundation for developing a therapeutic agent against COVID-19 through vet lab studies.

由 SARS-CoV-2 病毒引起的危及生命的 COVID-19 疾病自 2019 年 12 月被发现以来，极大地影响了全球的顺利生存。目前，它是人类面临的主要威胁之一。此外，任何针对 COVID-19 的特定药物或疫苗都无法使用，这迫使人们迫切需要发现一种新药。病毒周期抑制可能是防止这种病毒性疾病进一步发生的一种可能方法，这可以通过药物再利用技术或针对已验证的 COVID-19 靶标筛选具有生物活性的天然小分子来实现。主要蛋白酶（M ^pro) 负责从多蛋白中产生功能蛋白是 SARS-CoV-2 病毒粒子复制的重要关键步骤。基于天然产品或草药的配方是药物发现过程中潜在疗法和先导化合物的重要平台。因此，在这里我们从六个不同的天然产物数据库中筛选出超过 53,500 种具有生物活性的天然分子来对抗 M ^pro(PDB ID: 6LU7) 的 COVID-19 通过计算研究。此外，对排名前三的分子进行了药代动力学评价，这是降低药物失败率的重要因素。此外，前三个筛选分子（C00014803、C00006660、ANLT0001）在类似于生理条件的条件下通过分子动力学研究进一步验证。三个先导分子的相对结合能分析表明 C00014803 在所有三个命中中具有最高的结合亲和力。这些广泛的研究可以成为通过兽医实验室研究开发针对 COVID-19 的治疗剂的重要基础。