Pharmacoinformatics studies on discovery of novel andrographolide derivatives as monkeypox methyltransferase VP39 inhbitors

Abstract Andrographis paniculata (Burm.f.) Nees has long been used as a traditional medicinal plant in several Asian countries, including China, India, Vietnam, Malaysia, and Indonesia. Its major diterpenoid constituent, andrographolide, and its derivatives have attracted considerable attention due to their broad antiviral potential, including activity against the monkeypox virus (MPXV). In this study, a comprehensive pharmacoinformatics framework was employed to evaluate the binding affinity, stability, and pharmacokinetic properties of 25 andrographolide derivatives as potential inhibitors of MPXV methyltransferase VP39. Molecular docking analysis identified derivatives C10 and C11 as the top-performing compounds, exhibiting stronger binding affinities than the native ligand, sinefungin. Subsequent 100 ns molecular dynamics simulations confirmed the structural stability of the VP39–C10 and VP39–C11 complexes, as demonstrated by consistent root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA) profiles. MM-PBSA binding free energy calculations further supported these findings, with C10 and C11 showing more favorable binding free energies, with values of −85.009 and −97.523 kJ/mol, respectively, compared to −73.566 kJ/mol for native ligand. These findings suggest that the proposed andrographolide derivatives from this computational study could be further examined in vitro for their potential as MPXV methyltransferase VP39 inhibitors.