Computational repurposing of drugs against dengue virus targeting NS5 and methyltransferase proteins

Dengue virus (DENV) remains a significant global health challenge, infecting approximately 400 million individuals annually. This study utilizes molecular docking and molecular dynamics (MD) simulations to investigate the binding dynamics and stability of Avermectin and Doramectin with DENV Methyltransferase (MTase) and NS5 proteins. Root Mean Squared Deviation (RMSD) analysis revealed stable complexes, with values ranging from 2.5 to 3.2 Å. The radius of gyration (Rg) values stabilized around 20-23 Å, indicating compact structural integrity. Binding free energy calculations demonstrated that Doramectin exhibited stronger predicted binding and may offer improved inhibitory potential, with ΔG values of -13.9 ± 2.8 kcal/mol for MTase and - 23.8 ± 0.82 kcal/mol for NS5, compared to Avermectin (-5.8 ± 1.2 kcal/mol and - 4.8 ± 0.52 kcal/mol, respectively). Dynamic Cross-Correlation Matrix (DCCM) analysis identified critical correlated motions in key binding residues, such as Gly79 and Arg78 in MTase and Gly104 and Arg155 in NS5, emphasizing Doramectin's role in stabilizing protein conformations. Key interactions through hydrogen bonding and residue mapping, involving Ser50, Gly52, and Asp141, played pivotal roles in inhibitor binding. This study highlights Doramectin as a promising candidate for further investigation in the treatment of Dengue.