Molecular docking and ADMET evaluation of punicalagin from pomegranate (Punica granatum L.) peel as a dipeptidyl peptidase-4 (DPP-IV) inhibitor

Abstract

Dipeptidyl peptidase-4 (DPP-IV) is an important therapeutic target in the management of type 2 diabetes mellitus. This study aimed to evaluate the potential of punicalagin, a major polyphenol from pomegranate peel, as a natural DPP-IV inhibitor using an in silico approach. Molecular docking was performed using AutoDock Vina, and the docking protocol was validated by redocking the native ligand, yielding an RMSD value of 0.8298 Å, indicating good agreement between the experimental and predicted ligand poses. Punicalagin exhibited a more favourable predicted binding affinity toward DPP-IV, with a docking score of –10.44 kcal/mol, compared with alogliptin (–8.11 kcal/mol) and the native ligand (–8.65 kcal/mol). This favourable predicted interaction was supported by multiple hydrogen-bond and hydrophobic interactions with residues within the DPP-IV binding site, particularly Glu206, Ser209, Arg356, Arg358, and Arg669. ADMET prediction indicated a relatively favourable safety profile for punicalagin, particularly given the absence of predicted hepatotoxicity and its limited blood–brain barrier permeability. However, its lower intestinal absorption and limited volume of distribution compared with alogliptin may represent potential challenges to systemic bioavailability. Overall, punicalagin demonstrated promising in silico potential as a natural DPP-IV inhibitor based on its predicted binding affinity and interaction profile. Nevertheless, these findings represent computational predictions and do not establish actual DPP-IV inhibitory activity. Further molecular dynamics simulations, in vitro DPP-IV enzyme inhibition assays, pharmacokinetic studies, and formulation optimization are required to validate its inhibitory activity, stability, bioavailability, and potential therapeutic relevance in the management of type 2 diabetes mellitus.