ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Theoretical investigation of vitexin/isovitexin interactions with the [Zn-(His)₃]²⁺ containing MMP-9 active site using DFT methods

Beyza Simal Bozdag and Emine Esra Kasapbasi

Department of Computer Technologies, Istanbul Commerce University, Istanbul, Turkey

E-mail: emineesrakasapbasi@beykoz.edu.tr

Received: 1 April 2026  Accepted: 23 April 2026

Abstract:

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases essential for extracellular matrix remodeling and implicated in numerous pathological conditions. The catalytic activity of MMPs depends on a conserved zinc-binding motif in which three histidine residues coordinate the catalytic Zn²⁺ ion. Although the inhibitory interactions of vitexin and isovitexin—two C-glycosyl flavonoids abundant in Ficus deltoidei extracts—with MMP-9 have been demonstrated experimentally, the underlying molecular mechanism has not been theoretically characterized. In the present study, the MMP-9 active site was modeled as the [Zn-(His)₃]²⁺ ligand, and the interaction mechanisms of vitexin and isovitexin were investigated by density functional theory (DFT) at the B3LYP/6-31G(d,p) level. The results demonstrate that Zn²⁺ forms stable, penta-coordinated complexes through coordination with three histidine nitrogen atoms and the phenolic oxygen atoms of the flavonoid ligands. Natural Bond Orbital (NBO) charge analysis reveals that vitexin induces a more substantial decrease in the positive charge of the Zn(II) center than isovitexin, indicating stronger coordination. Time-dependent DFT (TD-DFT) calculations show that complex formation significantly modulates electronic transition energies, with the isovitexin complex exhibiting enhanced charge-transfer character in polar environments. These findings are consistent with experimental data and provide molecular-level insight into Zn(II)-dependent MMP-9 inhibition by flavonoid compounds.

Keywords: MMP-9; DFT; Vitexin; Isovitexin; Zinc coordination; Flavonoid inhibition

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-026-04956-6

Chemical Papers 80 (8) 9351–9359 (2026)