Discovery and functional mechanism of novel dipeptidyl peptidase Ⅳ inhibitory peptides from Chinese traditional fermented fish (Chouguiyu)

Dipeptidyl peptidase-IV (DPP-IV) inhibitory peptides from fermented foods exhibit great potential to alleviate type 2 diabetes mellitus (T2DM). In this study, the DPP-IV inhibition activity of peptide extract from Chouguiyu was obviously enhanced after 4–8 d fermentation. A total of 125 DPP-IV inhibitory peptides in Chouguiyu were identified by peptidomics and were obtained from 46 precursor proteins, mainly including nebulin, titin, muscle-type creatine kinase, hemoglobin, and actin. After molecular docking with DPP-IV, four novel DPP-IV inhibitory peptides possessing the lowest docking energy were selected, including EPAEAVGDWR (D37), IPHESVDVIK (D22), PDLSKHNNHM (D35), and PFGNTHNNFK (D1). The DPP-IV inhibition activity of D37, D22, D35, and D1 were further verified after synthesis with the IC(50) of 0.10 mM, 2.69 mM, 3.88 mM, and 8.51 mM, respectively, in accordance with their docking energies. Energy interaction showed that the structures of EP-, IPH-, -NHM, and PF- in these peptides were easy to connect with DPP-IV enzyme through hydrogen bond, salt bridge, and alkyl. The surface force including the H-bond interaction, hydrophobicity, aromatic interaction, and SAS, played a major role in the interaction between DPP-IV enzyme and peptides. The peptides that possess high hydrophobicity and can form strong hydrogen bond and salt bridge are potential DPP-IV inhibitory peptides using for T2DM remission.