严重急性呼吸道综合症-冠状病毒-2(SARS-CoV-2)感染推动了2019年全球冠状病毒病(COVID-19)大流行,造成巨大的人命损失和对经济发展的负面影响。迫切需要探索抗病毒的潜在药物,如SARS-CoV-2。水飞蓟素,从水飞蓟中提取的草药来源的多酚类黄酮的混合物,具有有效的抗氧化能力,抗凋亡,和抗炎特性。越来越多的研究表明水飞蓟素对病毒的杀伤活性,如登革热病毒,基孔肯雅病毒,和丙型肝炎病毒。然而,水飞蓟素的抗COVID-19机制尚不清楚.在这项研究中,应用多种学科方法和方法来评估水飞蓟素作为抗SARS-CoV-2感染的抗病毒剂的潜在机制。在硅方法中,如分子对接,网络药理学,结合生物信息学方法来评估配体-蛋白质结合特性并分析蛋白质-蛋白质相互作用网络。DAVID数据库用于分析基因功能,例如京都基因和基因组百科全书(KEGG)途径和基因本体论(GO)富集。TCMSP和GeneCards用于鉴定药物靶基因和COVID-19相关基因。我们的结果表明水飞蓟素化合物,如水飞蓟宾A/B和水飞蓟宾,显示了针对SARS-CoV-2感染的三重功能,包括与人血管紧张素转换酶2(ACE2)直接结合以抑制SARS-CoV-2进入宿主细胞,直接与病毒蛋白RdRp和解旋酶结合以抑制病毒复制和增殖,调节宿主的免疫反应,间接抑制病毒感染。具体来说,筛选出水飞蓟素分子在免疫调节中的作用靶点,例如促炎细胞因子TNF和IL-6以及细胞生长因子VEGFA和EGF。此外,研究了药物-靶蛋白相互作用的分子机制,包括人ACE2和病毒蛋白中药物分子的结合袋,氢键的形成,疏水相互作用,和其他药物-蛋白质配体相互作用。最后,候选分子的药物相似性结果通过了药物筛选标准.总的来说,本研究阐明了水飞蓟素分子抗SARS-CoV-2感染的分子机制。
The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection drove the global coronavirus disease 2019 (COVID-19) pandemic, causing a huge loss of human life and a negative impact on economic development. It is an urgent necessity to explore potential drugs against viruses, such as SARS-CoV-2. Silymarin, a mixture of herb-derived polyphenolic flavonoids extracted from the milk thistle, possesses potent antioxidative, anti-apoptotic, and anti-inflammatory properties. Accumulating research studies have demonstrated the killing activity of silymarin against viruses, such as dengue virus, chikungunya virus, and hepatitis C virus. However, the anti-COVID-19 mechanisms of silymarin remain unclear. In this study, multiple disciplinary approaches and methodologies were applied to evaluate the potential mechanisms of silymarin as an anti-viral agent against SARS-CoV-2 infection. In silico approaches such as molecular docking, network pharmacology, and bioinformatic methods were incorporated to assess the ligand-protein binding properties and analyze the protein-protein interaction network. The DAVID database was used to analyze gene functions, such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment. TCMSP and GeneCards were used to identify drug target genes and COVID-19-related genes. Our results revealed that silymarin compounds, such as silybin A/B and silymonin, displayed triplicate functions against SARS-CoV-2 infection, including directly binding with human angiotensin-converting enzyme 2 (ACE2) to inhibit SARS-CoV-2 entry into the host cells, directly binding with viral proteins RdRp and helicase to inhibit viral replication and proliferation, and regulating host immune response to indirectly inhibit viral infection. Specifically, the targets of silymarin molecules in immune regulation were screened out, such as proinflammatory cytokines TNF and IL-6 and cell growth factors VEGFA and EGF. In addition, the molecular mechanism of drug-target protein interaction was investigated, including the binding pockets of drug molecules in human ACE2 and viral proteins, the formation of hydrogen bonds, hydrophobic interactions, and other drug-protein ligand interactions. Finally, the drug-likeness results of candidate molecules passed the criteria for drug screening. Overall, this study demonstrates the molecular mechanism of silymarin molecules against SARS-CoV-2 infection.