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Discovery of Nine Dipeptidyl Peptidase-4 Inhibitors from Coptis chinensis Using Virtual Screening, Bioactivity Evaluation, and Binding Studies

Authors :
Zixi Zhao
Ruonan Ma
Yuqing Ma
Liqiang Zhao
Lele Wang
Yuzhen Fang
Yuxin Zhang
Xia Wu
Xing Wang
Source :
Molecules, Vol 29, Iss 10, p 2304 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

Abstract

The objective of this study was to identify multiple alkaloids in Coptis chinensis that demonstrate inhibitory activity against DPP-4 and systematically evaluate their activity and binding characteristics. A combined strategy that included molecular docking, a DPP-4 inhibition assay, surface plasmon resonance (SPR), and a molecular dynamics simulation technique was employed. The results showed that nine alkaloids in Coptis chinensis directly inhibited DPP-4, with IC50 values of 3.44–53.73 μM. SPR-based binding studies revealed that these alkaloids display rapid binding and dissociation characteristics when interacting with DPP-4, with KD values ranging from 8.11 to 29.97 μM. A molecular dynamics analysis revealed that equilibrium was rapidly reached by nine DPP-4–ligand systems with minimal fluctuations, while binding free energy calculations showed that the ∆Gbind values for the nine test compounds ranged from −31.84 to −16.06 kcal/mol. The most important forces for the binding of these alkaloids with DPP-4 are electrostatic interactions and van der Waals forces. Various important amino acid residues, such as Arg125, His126, Phe357, Arg358, and Tyr547, were involved in the inhibition of DPP-4 by the compounds, revealing a mechanistic basis for the further optimization of these alkaloids as DPP-4 inhibitors. This study confirmed nine alkaloids as direct inhibitors of DPP-4 and characterized their binding features, thereby providing a basis for further research and development on novel DPP-4 inhibitors.

Details

Language :
English
ISSN :
14203049
Volume :
29
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.4b834febe2ad44ab8b9d3c1cbc9e89fb
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules29102304