{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T11:53:49Z","timestamp":1780055629379,"version":"3.54.0"},"reference-count":112,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T00:00:00Z","timestamp":1697500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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\u2013protein binding properties and analyze the protein\u2013protein 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\u2013protein 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.<\/jats:p>","DOI":"10.3390\/ph16101479","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T08:08:33Z","timestamp":1697530113000},"page":"1479","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Anti-Viral Activity of Bioactive Molecules of Silymarin against COVID-19 via In Silico Studies"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2567-029X","authenticated-orcid":false,"given":"Chunye","family":"Zhang","sequence":"first","affiliation":[{"name":"Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Sui","sequence":"additional","affiliation":[{"name":"School of Life Science, Shanxi Normal University, Linfen 041004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9695-2492","authenticated-orcid":false,"given":"Shuai","family":"Liu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4895-5864","authenticated-orcid":false,"given":"Ming","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Missouri, Columbia, MO 65212, USA"},{"name":"NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (2020). 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