Identification of potential dual α-amylase and α-glucosidase inhibitory peptides from Humulus scandens through multi-step virtual screening, molecular docking, ligand efficiency analysis, and molecular dynamics simulation

This study systematically identified and evaluated dual inhibitory peptides from Humulus scandens (HS) with potential inhibitory effects on α-glucosidase and α-amylase through virtual enzymolysis, bioactivity prediction, molecular docking, ligand efficiency analysis, and molecular dynamics simulations. A total of 2499 peptides were initially generated, among which 42 were predicted to possess biological activity. ADMET analysis filtered these to 20 non-toxic candidates, and 10 peptides were selected based on LibDock scores for further molecular docking. Using acarbose as a control and filtering by CDOCKER interaction energy, 6 peptides with strong binding affinity were identified. Among them, YPW exhibited the highest inhibitory potential, outperforming acarbose in binding affinities and per-atom binding efficiency. Molecular docking analysis showed that YPW established stable interactions with α-glucosidase and α-amylase through hydrogen bonds, hydrophobic interactions, van der Waals forces, and electrostatic forces. In contrast to acarbose, which lacked electrostatic interactions with the enzymes, the inclusion of such interactions in YPW may contribute to their enhanced inhibitory effects. Molecular dynamics simulations further supported the stability of YPW-enzyme complexes, with root mean square deviation and root mean square fluctuation values lower than those of acarbose-bound complexes. These results suggest that YPW is promising natural dual inhibitors of α-glucosidase and α-amylase derived from HS. • The tripeptide YPW, derived from Humulus scandens , demonstrates potential dual inhibition against both α-glucosidase and α-amylase. • YPW showed better binding affinities and per-atom binding efficiency than that of acarbose. • Molecular docking confirmed that YPW engages both enzymes through hydrogen bonds, hydrophobic contacts, van der Waals forces, and critical electrostatic interactions, ensuring stable active-site binding. • Molecular dynamics simulations revealed that YPW-enzyme complexes maintain lower RMSD and RMSF values as well as comparable non-bonded interaction frequencies than that of acarbose throughout the simulation, reflecting a more tightly bound. • Given its dual-inhibition profile, exceptional binding metrics, and dynamic stability, YPW represents a compelling natural peptide candidate for the development of nutraceuticals or peptide-based therapeutics aimed at controlling postprandial blood glucose.