3D-QSAR, in vitro assay and MD simulations studies on the design, bioactivities and different inhibitory modes of the novel DPP-IV inhibitory peptides

作者：Liang, Zhen; Li, Hongmei; Lu, Xiaoxing; Lin, Guimei; Li, Ying; Zhang, Rong^*

来源：Journal of Molecular Structure, 2023, 1283: 135271.

DOI：10.1016/j.molstruc.2023.135271

• DPP-IV inhibitory peptides
• 3D-QSAR
• In vitro assay
• Inhibitory mechanism
• Molecular dynamics simulations

3D-QSAR, in vitro assay and molecular dynamic simulations were adopted to investigate the DPP-IV in-hibitory peptides and its molecular mechanism. A CoMFA model (Q2= 0.837, R2= 0.991) and a CoMSIA model (Q2= 0.726, R2= 0.990) of DPP-IV inhibitory peptides were established. Six novel peptides were de-signed by the 3D-QSAR models. In vitro assay demonstrated that the activities of the six novel peptides were higher than that of most DPP-IV inhibitory peptides. Interestingly, different mechanisms of the com-petitive and non-competitive inhibitory peptides were suggested by molecular docking and molecular dy-namics simulations. Trp-of WPV bound to the S1 site destroyed the structure of DPP-IV and blocked the side opening to the active site for the non-competitive peptide. This prevented the substrates from en-tering the active pocket and reduced the activity of DPP-IV. Residues Ser630, Glu205 and Glu206 were the key residues for competitive inhibitors to inhibit DPP-IV. The binding sites and modes of competitive inhibitory peptides were the same as the substrates.

• 单位
  山东大学; 广东药学院