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Mechanism of molecular interaction of sitagliptin with human DPP 4 enzyme - New Insights.
Advances in Medical Sciences 2023 September
PURPOSE: 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.
MATERIALS AND METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
MATERIALS AND METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
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