In silico assessment of cyanobacterial alkaloids as probable medications against SARS-CoV-2

• 131 cyanobacterial alkaloids were screened in silico against CLpro, PLpro, and NSP16 of SARS-CoV-2. • Four alkaloids showed strong inhibition of CLpro, targeting key catalytic residues. • Fourteen alkaloids exhibited high binding affinity to NSP16, including nucleoside analogues. • Tubercidin demonstrated the most stable NSP16 binding in 100 ns MD simulations. • MM-GBSA and ADME/Tox profiling supported tubercidin as the most promising lead. The COVID-19 a devastating global pandemic of this century, has taken massive tolls in terms of morbidity and mortality due to high transmissibility and most severe post-recovery consequences. This pandemic continues to pose major global health challenges, driven by rapid viral evolution and limited availability of broad-spectrum antivirals. Efficacies of the well-known antiviral drugs (hydroxychloroquine, lopinavir/ritonavir, and ribavirin) against COVID-19 were later disproved. Strategies such as repurposing existing therapeutics and vaccine development were notable steps in combating this disease. Cyanobacteria are a rich source of bioactive alkaloids with diverse pharmacological properties, yet their antiviral potential against SARS-CoV-2 remains underexplored. In this study, 131 cyanobacterial alkaloids were screened in silico against three key viral targets 3CLpro, PLpro, and the nsp10-nsp16 methyltransferase complex. The molecular docking study found that Calothrixin A, Cylindrospermopsin, Gonyautoxin I, and Mycosporine Glutaminol Glucoside exhibited notable affinities towards 3CLpro, interacting with essential catalytic residues. Fourteen alkaloids such as 9-deazaadenosine, Bauerine B, Gonyautoxin I, Mycosporine Glutaminol Glucoside, Nostocine A etc. have demonstrated strong binding to NSP16, with nucleoside analogues Toyocamycin and Tubercidin showing the highest docking scores of -9.40 and -8.99 kcal/mol respectively. The 100 ns MD simulation study further confirmed the stability of the Tubercidin–NSP16 complex, supported by persistent interactions with conserved residues (GLY71, ASP99, CYS115). MM-GBSA energy values and comprehensive ADME/Tox profiling further highlighted Tubercidin as a favourable lead molecule, exhibiting non-mutagenicity, absence of hERG inhibition, and acceptable toxicity parameters. Overall, this study identifies cyanobacterial alkaloids especially Tubercidin as promising inhibitors of SARS-CoV-2 replication and immune evasion pathways, warranting further experimental validation as potential antiviral therapeutics.