Inhibition of papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is projected to terminate its replication. Hence, these proteases represent viable therapeutic targets. Sixty-one flavonoids with reported activities against other RNA viruses were selected and docked in PLpro and 3CLpro. Flavonoids with better binding energies compared to reference inhibitors (lopinavir and ritonavir) in their interaction with PLpro and 3CLpro were selected for drug-likeness and ADMET analysis. The best representative flavonoid for each protease from the ADMET filtering analysis was subjected to molecular dynamics simulations (MDS) and clustering analysis of the trajectory files. Licorice, ugonin M, procyanidin, silymarin, and gallocatechin gallate had better binding energies (-11.8, -10.1, -9.8, -9.7 and -9.6 kcal/mol respectively) with PLpro compared to lopinavir and ritonavir (-9.1 and -8.5 kcal/mol respectively). Also, isonymphaeol B, baicalin, abyssinone II, tomentin A, and apigetrin had better binding energies (-8.7, -8.3, -8.2, -8.1, and -8.1 kcal/mol respectively) with 3CLpro compared to lopinavir and ritonavir (-7.3 and -7.1 kcal/mol respectively). These flavonoids interacted with the proteases via hydrogen and non-hydrogen bonding. Of these flavonoids, silymarin and isonymphaeol B demonstrated most favourable combination of attributes in terms of binding energies, compliance with Lipinski rule for drug-likeness and favourable pharmacokinetics in silico. These two flavonoids exhibited appreciable degree of structural stability, maintaining strong interaction with residues in the different representative clusters selected during the MDS run. Silymarin and isonymphaeol B are proposed for further studies as compounds with potential activities against SARS-CoV-2. • Flavonoids displayed varying affinities for PLpro and 3CLpro of SARS-CoV-2 • They interacted via hydrogen and non-hydrogen bonds; nine and twenty-seven flavonoids had better binding affinities for PLpro and 3CLpro respectively than lopinavir and ritonavir • Silymarin and isonymphaeol B demonstrated most favourable combination of attributes in terms of binding energies, compliance with Lipinski rule for drug-likeness and favourable pharmacokinetics. • Silymarin and isonymphaeol B exhibited appreciable degree of structural stability, maintaining strong interaction with residues in the different representative clusters selected during the MDS run.

中文翻译：

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选定的黄酮类化合物对 SARS-CoV-2 的木瓜蛋白酶和 3-糜蛋白酶样蛋白酶的抑制潜力的药物信息学研究

抑制严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的木瓜蛋白酶 (PLpro) 和 3-糜蛋白酶样蛋白酶 (3CLpro) 预计会终止其复制。因此，这些蛋白酶代​​表了可行的治疗靶点。选择了 61 种具有抗其他 RNA 病毒活性的类黄酮，并将其停靠在 PLpro 和 3CLpro 中。与参考抑制剂（洛匹那韦和利托那韦）相比，在它们与 PLpro 和 3CLpro 的相互作用中具有更好结合能的黄酮类化合物被选择用于药物相似性和 ADMET 分析。对来自 ADMET 过滤分析的每种蛋白酶的最佳代表性黄酮类化合物进行分子动力学模拟 (MDS) 和轨迹文件的聚类分析。甘草、乌戈宁 M、原花青素、水飞蓟素和没食子酸没食子酸具有更好的结合能 (-11.8, -10.1、-9.8、-9.7 和 -9.6 kcal/mol），PLp​​ro 与洛匹那韦和利托那韦（分别为 -9.1 和 -8.5 kcal/mol）相比。此外，与洛匹那韦和利托那韦（-7.3和-7.1 kcal/mol）。这些类黄酮通过氢键和非氢键与蛋白酶相互作用。在这些黄酮类化合物中，水飞蓟素和异烟酚 B 在结合能、药物相似性的 Lipinski 规则和良好的计算机药代动力学方面表现出最有利的属性组合。这两种黄酮类化合物表现出相当程度的结构稳定性，与 MDS 运行期间选择的不同代表性簇中的残基保持强烈的相互作用。水飞蓟素和异烟酚 B 被提议作为对 SARS-CoV-2 具有潜在活性的化合物进行进一步研究。• 类黄酮对 SARS-CoV-2 的 PLpro 和 3CLpro 显示出不同的亲和力 • 它们通过氢键和非氢键相互作用；9 种和 27 种黄酮类化合物对 PLpro 和 3CLpro 的结合亲和力分别优于洛匹那韦和利托那韦 • 水飞蓟素和异烟酚 B 在结合能、药物相似性符合 Lipinski 规则和有利的药代动力学方面表现出最有利的属性组合。• 水飞蓟素和异樟脑 B 表现出明显的结构稳定性，