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

Piyush Verma; Lajpreet Kaur; Priyanka Aswal; Anju Singh; Rashmi Pandey; Himanshu Ojha; Mallika Pathak

doi:10.1016/j.saa.2023.123368

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

Spectrochim Acta A Mol Biomol Spectrosc. 2024 Jan 5:304:123368. doi: 10.1016/j.saa.2023.123368. Epub 2023 Sep 6.

Authors

Piyush Verma¹, Lajpreet Kaur², Priyanka Aswal³, Anju Singh⁴, Rashmi Pandey⁵, Himanshu Ojha², Mallika Pathak⁶

Affiliations

¹ Division of Radiological Nuclear and Imaging Sciences (RNAIS), Institute of Nuclear Medicine and Allied Sciences, Defence R&D Organisation, Brig. S K Mazumdar Road, Timarpur, Delhi 110054, India; School of Pharmaceutical Sciences, Delhi Pharmaceutical Science and Research University (DPSRU), Pushp Vihar, New Delhi 110017, India.
² Division of Radiological Nuclear and Imaging Sciences (RNAIS), Institute of Nuclear Medicine and Allied Sciences, Defence R&D Organisation, Brig. S K Mazumdar Road, Timarpur, Delhi 110054, India.
³ Department of Pharmaceutics, Uttarakhand Technical University, Sudhowala, Dehradun, Uttarakhand 248001, India.
⁴ Nucleic Acid Research Lab, Department of Chemistry, University of Delhi, Delhi 110007, India.
⁵ Guru Gobind Singh Indraprastha University, New Delhi 110078, India.
⁶ Department of Chemistry, Miranda House, University of Delhi, Delhi 110007, India. Electronic address: mallika.pathak@mirandahouse.ac.in.

PMID: 37748335
DOI: 10.1016/j.saa.2023.123368

Abstract

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 × 10³ M^-1 at 298.15 K that is non-covalent in nature. VDG-pepsin complex shows exothermic and spontaneous binding as confirmed by the calculated values of ΔH, ΔS, and ΔG, 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.

Keywords: Enzyme activity; FRET; Fluorescence spectroscopy; Molecular docking; Pepsin; Vildagliptin.

MeSH terms

Binding Sites
Circular Dichroism
Metformin*
Molecular Docking Simulation
Pepsin A* / chemistry
Protein Binding
Spectrometry, Fluorescence / methods
Thermodynamics
Vildagliptin

Substances

Pepsin A
Vildagliptin
Metformin