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

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 â€‹= â€‹- 8.1 â€‹kcal â€‹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.

New insights about the EptA protein and its correlation with the pmrC gene in polymyxin resistance in Pseudomonas aeruginosa.

Nowadays, clinical and scientific interest in antibiotics, as polymyxin, has increased due to the large number of reports of multiresistant Gram-negative bacteria, as Pseudomonas aeruginosa. The aim of this study was to investigate a related group of proteins for resistance to polymyxins, encoded by P. aeruginosa genome, through in silico analysis. The mobilized colistin resistance 1 (MCR1) protein from Escherichia coli was used for comparison. Similar sequences to the protein MCR1 in P. aeruginosa were analysed for physicochemical properties. 31 protein isoforms in P. aeruginosa (EptA) were found able to confer resistance to polymyxin showing protein lengths between 551 and 572 amino acids, with molecular mass values between 61.36 - 62. 80 kDa, isoelectric point between 6.10 to 7.17, instability index between 33.76 to 41.87, aliphatic index between 98.67 to 102.63 and the hydropathyindex between - 0.008 to 0.094. These proteins belong to the DUF1705 superfamily with bit-score values between 559.81 and 629.78. A high degree of similarity between EpTAs in P. aeruginosa was observed in relation to other proteins that confer resistance to polymyxins, present in Gram-negative bacteria species of clinical interest. Although, further studies are needed to identify the actual contribution of EptAs in P. aeruginosa species.