Binding interactions of Vildagliptin with pepsin: A multi-spectroscopic and in-silico approach and a comparative account with metformin

Vildagliptin (VDG) and Metformin (Met) belong to a class of dipeptidylpeptidase-4 (DPP-4) inhibitor and biguanide, respectively and used for the management of diabetes mellitus type II (DMTII). Both the drugs are orally available which leads to various side effects due to its oral ingestion. Occurrence of these side effects might be due to some interactions with pepsin at a molecular level. Therefore, in order to investigate these interactions, multi-spectroscopic and in-silico techniques have been extensively studied to identify the binding characteristics of VDG with pepsin. Fluorescence data suggested that the quenching is due to dynamic and static mechanism and static was dominant one. However, fluorescence and UV-Vis spectroscopic measurement analysis suggested that VDG tends to associate with pepsin, via ground-state complex formation. Fluorescence study revealed the binding-constant value which was found to be 0.559 x 103 M-1 at 298.15 K that is non-covalent in nature. VDGpepsin complex shows exothermic and spontaneous binding as confirmed by the calculated values of Delta H, Delta S, and Delta G, are majorly caused by van der Waals forces and H-bonding interactions. CD spectra of pepsin in presence of VDG confirmed post binding conformational change. Enzyme-activity assay showed that activity of pepsin was decreased by upto 28 %. FRET analysis suggested that energy transfer efficiency is negligible for VDG-pepsin interaction. In-silico analysis reveals that H-bonding and electrostatic negative forces are the significant driving forces involved in the interaction of VDG and pepsin.