Beta-terpineol from citrus essential oil modulated dipeptidyl peptidase-IV towards type 2 diabetes care: An experimental- and molecular dynamics simulation-based study

Despite the reported antidiabetic potential of citrus essential oils (CEOs), their inhibitory effect on dipeptidyl peptidase 4 (DPP-IV) remains elusive. This study investigated the anti-DPP-IV potential of six citrus species ( Citrus aurantifolia, Citrus bergamia, Citrus limon, Citrus paradisi, Citrus reticulata, and Citrus sinensis ) essential oils using experimental and computational approaches. In vitro analysis revealed that the six CEOs exhibited significant inhibitory effect on DPP-IV with C. reticulata being the most potent (IC 50 =8.00 μg/mL) relative to the effect observed with the reference standard, sitagliptin (IC 50 =196.40 μg/mL). Bioactive constituent identification produced a library of 64 metabolites while the top ranked metabolites produced good pharmacokinetic properties and remarkably safety. Molecular dynamics simulation study of the top five metabolites revealed beta-terpineol as having the best affinity (binding free energy: -35.78 kcal/mol) for DPP-IV compared to sitagliptin (-34.80 kcal/mol). While the resulting complexes from the other top-ranked metabolites were relatively stable, further structural analysis positioned beta-terpineol as having superior binding interaction, stability, hydrogen bond formation, and interaction with catalytic residues critical for the modulation of DPP-IV. Findings from this study demonstrate the inhibitory potential and binding mechanism of CEO metabolites against DPP-IV for enhanced glucose homeostasis via glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide actions. Overall, CEOs afforded the identification of beta-terpineol as hit metabolite that can be studied as drug candidates towards type 2 diabetes care. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany