Mechanism of molecular interaction of sitagliptin with human DPP₄ enzyme - New Insights

Dipeptidyl peptidase 4 (DPP₄) inactivates a range of bioactive peptides. The cleavage of insulinotropic peptides and glucagon-like peptide 1 (GLP₁) by DPP₄ directly influences glucose homeostasis. This study aimed to describe the mode of interaction between sitagliptin (an antidiabetic drug) and human DPP₄ using in silico approaches.

Docking studies were conducted using AutoDock Vina, 2D and 3D schematic drawings were obtained using PoseView and PLIP servers, and the DPP₄-sitagliptin complex was visualized with Pymol software.

The best affinity energy to form the DPP₄-sitagliptin complex was E-value ​= ​- 8.1 ​kcal ​mol^-1, as indicated by docking simulations. This result suggests a strong interaction. According to our observations, hydrophobic interactions involving the amino acids residues Tyr⁶⁶³ and Val⁷¹², hydrogen bonds (Glu²⁰³, Glu²⁰⁴, Tyr⁶⁶³, and Tyr⁶⁶⁷), π-Stacking interactions (Phe³⁵⁵ and Tyr⁶⁶⁷), and halogenic bonds (Arg¹²³, Glu²⁰⁴, and Arg³⁵⁶) were prevalent in the DPP₄-sitagliptin complex. Root Mean Square Deviation prediction also demonstrated that the global structure of the human DPP₄ did not have a significant change in its topology, even after the formation of the DPP₄-sitagliptin complex.

The stable interaction between the sitagliptin ligand and the DPP₄ 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 iDPP₄ inhibitors.