biostudies-literatureHernandez-Rodriguez XSECIHTIFundación IMSS A.C.2809https://www.ebi.ac.uk/biostudies/studies/S-EPMC12736355biostudies-literatureUnknown13(12)SARS-CoV-2 continues to evolve into immune-evasive variants, and although vaccination remains the cornerstone of prevention, the search for antiviral molecules targeting conserved viral enzymes remains essential. The RNA-dependent RNA polymerase (NSP12) is a central component of coronavirus replication, and natural polyphenols have been recurrently proposed as modulators of viral polymerases. Among these compounds, Fisetin has been reported to interact with multiple viral and cellular pathways, yet its direct antiviral activity against SARS-CoV-2 remained largely unexplored. Here, we first analyzed the interaction of Fisetin with the catalytic and NiRAN domains of NSP12 using molecular docking and molecular dynamics simulations, revealing stable and energetically favorable binding throughoMicroorganismsFisetin as an Antiviral Agent Targeting the RNA-Dependent RNA Polymerase of SARS-CoV-2: Computational Prediction and In Vitro Experimental Validation.PMC12736355R-2024-785-073CBF-2025-I-1331De Jesus-Gonzalez LACastaneda-Delgado JEOsuna-Ramos JFGarcia-Herrera ACRivas-Santiago BSantos-Mena AOReyes-Ruiz JMMontano SLira-Hernandez FICalderon-Sandate DNAngel RMDNoriega SHernandez-Rodriguez XLeon-Juarez MCanedo-Figueroa DMFarfan-Morales CNfalseFisetin as an Antiviral Agent Targeting the RNA-Dependent RNA Polymerase of SARS-CoV-2: Computational Prediction and In Vitro Experimental Validation.SARS-CoV-2 continues to evolve into immune-evasive variants, and although vaccination remains the cornerstone of prevention, the search for antiviral molecules targeting conserved viral enzymes remains essential. The RNA-dependent RNA polymerase (NSP12) is a central component of coronavirus replication, and natural polyphenols have been recurrently proposed as modulators of viral polymerases. Among these compounds, Fisetin has been reported to interact with multiple viral and cellular pathways, yet its direct antiviral activity against SARS-CoV-2 remained largely unexplored. Here, we first analyzed the interaction of Fisetin with the catalytic and NiRAN domains of NSP12 using molecular docking and molecular dynamics simulations, revealing stable and energetically favorable binding througho2025-01-01T00:00:00Z2025 Dec2026-05-28T03:20:45.994Z2026-05-28T03:11:42.312ZS-EPMC127363554147201310.3390/microorganisms13122809