Fenugreek-derived bioactive compounds as high-affinity inhibitors of Monkeypox virus identified by integrated molecular docking, dynamics simulations, and ADMET profiling of promising candidates

The re-emergence of monkeypox virus (MPXV) demands rapid discovery of novel antivirals. Using molecular docking, molecular dynamics (MD) simulations, and ADMET profiling, we identified fenugreek-derived tannic acid and the tripeptide RRY as inhibitors of three essential MPXV targets: D8L ectodomain (4E9O), VP39 methyltransferase (8CEQ), and A42R profilin-like protein (4QWO). Tannic acid exhibited exceptional binding affinities (− 12.2 to − 14.4 kcal/mol; inhibition constants Ki = 1.1 nM to 12 nM), outperforming ribavirin at VP39 (− 14.4 vs. − 7.3 kcal/mol). The RRY peptide showed consistent moderate affinities (− 6.4 to − 6.9 kcal/mol; Ki = 22–38 µM) across all targets. MD simulations (100 ns for 4E9O/8CEQ, 50 ns for 4QWO) confirmed stable binding: the 4E9O–tannic acid complex converged earliest (∼20 ns) with lowest RMSD (3.0 ± 0.3 Å) and strongest MM-PBSA free energy (− 98.5 ± 11.2 kJ/mol). Both compounds displayed favourable pharmacokinetic and safety profiles: high predicted oral LD₅₀ (~ 2.48 mol/kg), low CNS permeability (log PS ≤ − 6.33), and no mutagenic or cardiotoxic risks. These structurally and dynamically validated candidates prioritise immediate in vitro and in vivo evaluation as next-generation MPXV therapeutics.