| Summary: | Inhibition of dipeptidyl peptidase-4 (DPP-4) is an effective way to control blood glucose in diabetic patients. <i>Tenebrio (T.) molitor</i> is an edible insect containing abundant protein. <i>T. molitor</i> protein-derived peptides can suppress the DPP-4 activity. However, the amino acid sequence and binding mechanism of these DPP-4 inhibitory peptides remain unclear. This study used the flavourzyme for <i>T. molitor</i> protein hydrolysis, identified the released peptides with DPP-4 inhibitory effect, and investigated the binding interactions of these peptides with DPP-4. The results showed that flavourzyme efficiently hydrolyzed the <i>T. molitor</i> protein, as demonstrated by the high degree of hydrolysis, disappearance of protein bands in SDS-PAGE, and changes to protein structure. The 4-h flavourzyme hydrolysates showed a good inhibitory effect on DPP-4 (IC<sub>50</sub> value of 1.64 mg/mL). The fragment of 1000–3000 Da accounted for 10.39% of the total peptides, but showed the strongest inhibitory effect on DPP-4. The peptides LPDQWDWR and APPDGGFWEWGD were identified from this fraction, and their IC<sub>50</sub> values against DPP-4 were 0.15 and 1.03 mg/mL, respectively. Molecular docking showed that these two peptides interacted with the DPP-4 active site via hydrogen bonding, hydrophobic interactions, salt bridge formation, π-cation interactions, and π-π stacking. Our findings indicated that <i>T. molitor</i> protein-derived peptides could be used as natural DPP-4 inhibitors.
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