Coronavirus disease 2019 (COVID-19) is a new pandemic characterized by quick spreading and illness of the respiratory system. To date, there is no specific therapy for Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Flavonoids, especially rutin, have attracted considerable interest as a prospective SARS-CoV-2 main protease (M^pro) inhibitor. In this study, a database containing 2017 flavone analogs was prepared and screened against SARS-CoV-2 M^pro using the molecular docking technique. According to the results, 371 flavone analogs exhibited good potency towards M^pro with docking scores less than −9.0 kcal/mol. Molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM/GBSA) binding energy calculations, were performed for the top potent analogs in complex with M^pro. Compared to rutin, PubChem-129-716-607 and PubChem-885-071-27 showed better binding affinities against SARS-CoV-2 M^pro over 150 ns MD course with ΔG_binding values of −69.0 and −68.1 kcal/mol, respectively. Structural and energetic analyses demonstrated high stability of the identified analogs inside the SARS-CoV-2 M^pro active site over 150 ns MD simulations. The oral bioavailabilities of probable SARS-CoV-2 M^pro inhibitors were underpinned using drug-likeness parameters. A comparison of the binding affinities demonstrated that the MM/GBSA binding energies of the identified flavone analogs were approximately three and two times less than those of lopinavir and baicalein, respectively. In conclusion, PubChem-129-716-607 and PubChem-885-071-27 are promising anti-COVID-19 drug candidates that warrant further clinical investigations.

2019 年冠状病毒病 (COVID-19) 是一种新的流行病，其特征是快速传播和呼吸系统疾病。迄今为止，尚无针对严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的特效疗法。类黄酮，尤其是芦丁，作为一种潜在的 SARS-CoV-2 主要蛋白酶 (M ^pro ) 抑制剂引起了人们的极大兴趣。在本研究中，使用分子对接技术制备了包含 2017 年黄酮类似物的数据库，并针对 SARS-CoV-2 M ^pro进行了筛选。结果显示，371 种黄酮类似物对 M ^pro表现出良好的效力，对接分数低于 -9.0 kcal/mol。对与 M ^pro复合物中最有效的类似物进行分子动力学 (MD) 模拟，然后进行分子力学广义玻恩表面积 (MM/GBSA) 结合能计算。与芦丁相比，PubChem-129-716-607 和 PubChem-885-071-27 在 150 ns MD 过程中对 SARS-CoV-2 M ^pro显示出更好的结合亲和力，Δ G_结合值为 -69.0 和 -68.1 kcal/mol ， 分别。结构和能量分析表明，在 150 ns MD 模拟中，SARS-CoV-2 M^前活性位点内已识别的类似物具有高度稳定性。可能的 SARS-CoV-2 M^前抑制剂的口服生物利用度是通过药物相似参数来确定的。结合亲和力的比较表明，所鉴定的黄酮类似物的 MM/GBSA 结合能分别比洛匹那韦和黄芩素的结合能低约三倍和两倍。 总之，PubChem-129-716-607 和 PubChem-885-071-27 是有前景的抗 COVID-19 候选药物，值得进一步的临床研究。