Investigation of Royal Jelly Jellein Peptides as Novel DPP-۴ Entrance-Blocker Inhibitors: A Molecular Docking Study

Background: Dipeptidyl peptidase-۴ (DPP-۴) degrades incretin hormones and represents a key therapeutic target in Type ۲ Diabetes Mellitus. Jellein peptides (I–IV), short antimicrobial peptides from Apis mellifera Royal Jelly, possess emerging bioactive potential, yet their interaction with DPP-۴ remains uninvestigated. Objective: To evaluate the binding affinity and inhibitory mechanism of four Jellein peptides (Jellein-I: PFKLSLHL; Jellein-II: TPFKLSLHL; Jellein-III: EPFKLSLHL; Jellein-IV: TPFKLSLH) against DPP-۴ (PDB: ۱PFQ). Methods: Protein–peptide docking was performed using HADDOCK ۲.۴, targeting nine critical residues including the catalytic triad (Ser۶۳۰, His۷۴۰, Asp۷۰۸), S۱ pocket (Val۶۵۶, Trp۶۵۹, Tyr۶۶۲), and electrostatic clamp (Glu۲۰۵, Glu۲۰۶). Interaction profiles were analyzed using LigPlot+. Results: Jellein-IV demonstrated the strongest binding (−۹۱.۹±۵.۵ kcal/mol) with superior van der Waals energy (−۵۱.۰ kcal/mol), followed by Jellein-II (−۸۹.۲±۳.۶), which achieved the most hydrogen bonds (۴) and largest buried surface area (۱۲۶۲.۷ A ۲). Jellein-I ranked third (−۸۱.۱±۲.۸) with the best electrostatic contribution (−۱۷۷.۷ kcal/mol), while Jellein-III performed worst (−۷۵.۲±۹.۰) due to N-terminal glutamate repulsion with the anionic Glu۲۰۵/Glu۲۰۶clamp. Crucially, no peptide contacted the catalytic triad or S۱ pocket; all binding occurred exclusively at entrance-rim residues (Arg۳۵۸, Phe۳۵۷, Ser۱۲۷, Glu۲۰۵). N-terminal residue identity governed efficacy: threonine provided optimal anchoring, proline moderate engagement, and glutamate caused destabilizing repulsion.

کلیدواژه ها:

DPP-۴ inhibitor ، Jellein peptides ، Royal Jelly ، HADDOCK ، molecular docking ، Type ۲ Diabetes