Dipeptidyl peptidase-4 (DPP-4) is the vital enzyme responsible for inactivating intestinal peptides Glucagon like peptide-1 (GLP-1) and Gastric inhibitory polypeptide (GIP), which stimulates a decrease in blood glucose levels. The aim of this study was to explore the inhibition activity of small-molecule inhibitors to DPP-4. AutoDock, CDOCKER and Standard dynamics cascade were used for molecular docking and molecular dynamics studies. Molecular docking was performed for structurally diverse compounds (Aminopiperdine-fused imidazoles, Thiazolopyrimidine derivatives, and quinolin-fused imidazoles) and the differences in their binding modes were investigated. Furthermore, good correlation (R2=0.72) was acquired for the DPP-4 inhibitors based on the predicted binding affinities (pKi) determined by using AutoDock, CDOCKER and experimental activity values (pIC50). Based on molecular docking receptor-ligand interactions, pharmacophore generation was carried out to determine the binding modes of structurally diverse compounds in the receptor active site. Study of the stability and flexibility of the DPP-4 inhibitor complexes by means of MD simulation specified that the inhibitors retained the binding mode observed in the docking study. The present studies provides some guiding information for further structural optimization and are helpful for future DPP-4 inhibitors discoveries in treatment of type-2 diabetes.
