Xu_2024_Food.Chem_441_138370

Our previous study has demonstrated that both the amino acid at N3 position and peptide length affected the DPP-IV inhibitory activity of Gly-Pro-type peptides. To further elucidate their molecular mechanism, a combined approach of QSAR modeling, enzymatic kinetics and molecular docking was used. Results showed that the QSAR models of Gly-Pro-type tripeptides and Gly-Pro-type peptides containing 3-12 residues were successfully constructed by 5z-scale descriptor with R(2) of 0.830 and 0.797, respectively. The lower values of electrophilicity, polarity, and side-chain bulk of amino acid at N3 position caused higher DPP-IV inhibitory activity of Gly-Pro-type peptides. Moreover, an appropriate increase in the length of Gly-Pro-type peptides did not change their competitive inhibition mode, but decreased their inhibition constants (K(i) values) and increased interactions with DPP-IV. More importantly, the interactions between the residues at C-terminal of Gly-Pro-type peptides containing 5 - 6 residues with S2 extensive subsites (Ser209, Phe357, Arg358) of DPP-IV increased the interactions of Gly residue at N1 position with the S2 subsites (Glu205, Glu206, Asn710, Arg125, Tyr662) and decreased the acylation level of DPP-IV-peptide complex, and thereby increasing peptides' DPP-IV inhibitory activity.