Mechanism of molecular interaction of sitagliptin with human DPP enzyme - New Insights.

PURPOSE

Dipeptidyl peptidase 4 (DPP) inactivates a range of bioactive peptides. The cleavage of insulinotropic peptides and glucagon-like peptide 1 (GLP) by DPP directly influences glucose homeostasis. This study aimed to describe the mode of interaction between sitagliptin (an antidiabetic drug) and human DPP using in silico approaches.

MATERIALS AND METHODS

Docking studies were conducted using AutoDock Vina, 2D and 3D schematic drawings were obtained using PoseView and PLIP servers, and the DPP-sitagliptin complex was visualized with Pymol software.

RESULTS

The best affinity energy to form the DPP-sitagliptin complex was E-value ​= ​- 8.1 ​kcal ​mol, as indicated by docking simulations. This result suggests a strong interaction. According to our observations, hydrophobic interactions involving the amino acids residues Tyr and Val, hydrogen bonds (Glu, Glu, Tyr, and Tyr), π-Stacking interactions (Phe and Tyr), and halogenic bonds (Arg, Glu, and Arg) were prevalent in the DPP-sitagliptin complex. Root Mean Square Deviation prediction also demonstrated that the global structure of the human DPP did not have a significant change in its topology, even after the formation of the DPP-sitagliptin complex.

CONCLUSION

The stable interaction between the sitagliptin ligand and the DPP enzyme was demonstrated through molecular docking simulations. The findings presented in this work enhance the understanding of the physicochemical properties of the sitagliptin interaction site, supporting the design of more efficient gliptin-like iDPP inhibitors.