Discovery of potential antiviral compounds and accelerating the therapeutic discovery against monkeypox virus.

Monkeypox virus is a zoonotic virus of the genus Orthopox viruses. It can be transmitted through direct or indirect contact with animals or infected ones. Owing similarity of pathogenesis with smallpox, the same drugs can be used for both viruses, but they are not specific and only help to relieve the symptoms only. Therefore, the absence of antiviral treatment or licensed vaccine highlights an urgent need, especially due to its rapid prevalence. The study screened the library of compounds to retrieve drug-like molecules that can act against monkeypox virus. The highly virulent target gene B8R having uniport ID Q3I8J0 was chosen. Targeting B8R is substantial for global health and can align with SDG 3 and awareness of disease management. The B8R was modelled via Artificial intelligence (AI) AlphaFold method and then exposed to a library of compounds. Complementary interactions in the active site were shown by molecular docking. The Complex-1 had the greatest binding affinity (–8.4 kcal/mol), followed by Complex-2 (–8.1 kcal/mol) and Complex-3 (–7.7 kcal/mol). After 125 ns, Complex-1 reached equilibrium at 7.5 Å RMSD, according to MD simulations, exhibiting stable ligand retention and reliable interactions with crucial residues Gly135 and Lys136. Complex-3 shown intermediate protein stability (6 Å RMSD) but notable ligand fluctuation (48 Å RMSF), while Complex-2 displayed increased protein RMSD (8 Å RMSD) and delayed ligand stabilisation (16 Å RMSF). These results were corroborated by PCA analysis, which showed that Complex-1 exhibits coherent structural development whereas Complex-2 and Complex-3 show scattered and compact trajectories, respectively. Complex-1 promise for Mpox viral inhibition was highlighted by the fact that it was the most stable and dynamically favourable contender overall. The N-terminal follows the folding trend. The insilico analysis not only proposed a potent compound but also provides deep insight into the behavior of protein. The proposed potent compound against this zoonotic virus can be helpful to combat the monkeypox virus by subjecting it further towards experimental investigation.