Structure-based virtual screening of cyanobacterial metabolites against key influenza A virus targets

Influenza A virus (IAV) remains a major threat to global health and livestock industries, necessitating the discovery of new antiviral agents. In this study, a structure-based virtual screening of 1288 cyanobacterial secondary metabolites was performed against key IAV proteins, including hemagglutinin (H3 and H5), neuraminidase (N1 and N2), and RNA polymerase subunits (PB2 and PA). Molecular docking was conducted using AutoDock Vina with a rigid receptor–flexible ligand approach, and binding conformations were evaluated based on docking scores, molecular size, binding orientation, and interactions with functionally critical residues. A multi-target docking strategy combined with multiple docking-related criteria identified several promising candidates with more favorable predicted docking scores than the corresponding native ligands for H3, H5, N1, and N2, but slightly less favorable scores for PB2 and PA. Key compounds included 11,12-didehydrospironostoic acid, 7-formyl-3-methoxy-5-methylindanone, mycosporine-glycine-alanine, palythine-serine, Asterina-330, toyocamycin, usujirene, tjipanazole derivatives, tubercidin, and didmolamide A. Notably, among the prioritized compounds, metabolites from Calothrix exhibited the broadest predicted multi-target binding profile, followed by Tolypothrix , while compounds derived from Lyngbya/Moorea , Scytonema , Leptolyngbya , Nostoc , and Fischerella demonstrated target-specific or limited multi-target binding profiles. Scaffold-based analysis revealed key structural classes, including nucleoside-like compounds, mycosporine-like amino acids, and peptide/alkaloid derivatives, contributing to favorable predicted binding interactions with functionally critical residues. ADMET evaluation revealed variable predicted pharmacokinetic and toxicity profiles among the prioritized compounds, with several candidates exhibiting low predicted intestinal absorption or elevated mutagenicity risk, highlighting the need for further safety and pharmacokinetic evaluation. Overall, this study highlights cyanobacterial metabolites as a structurally diverse and underexplored source of potential multi-target antiviral candidates against IAV and provides a framework for future computational refinement and experimental validation toward applications in both human and animal health.