International Journal of Molecular Sciences (Jul 2023)

Identification of <i>N</i>-Acyl Hydrazones as New Non-Zinc-Binding MMP-13 Inhibitors by Structure-Based Virtual Screening Studies and Chemical Optimization

  • Doretta Cuffaro,
  • Aleix Gimeno,
  • Bianca Laura Bernardoni,
  • Riccardo Di Leo,
  • Gerard Pujadas,
  • Santiago Garcia-Vallvé,
  • Susanna Nencetti,
  • Armando Rossello,
  • Elisa Nuti

DOI
https://doi.org/10.3390/ijms241311098
Journal volume & issue
Vol. 24, no. 13
p. 11098

Abstract

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Matrix metalloproteinase 13 plays a central role in osteoarthritis (OA), as its overexpression induces an excessive breakdown of collagen that results in an imbalance between collagen synthesis and degradation in the joint, leading to progressive articular cartilage degradation. Therefore, MMP-13 has been proposed as a key therapeutic target for OA. Here we have developed a virtual screening workflow aimed at identifying selective non-zinc-binding MMP-13 inhibitors by targeting the deep S1′ pocket of MMP-13. Three ligands were found to inhibit MMP-13 in the µM range, and one of these showed selectivity over other MMPs. A structure-based analysis guided the chemical optimization of the hit compound, leading to the obtaining of a new N-acyl hydrazone-based derivative with improved inhibitory activity and selectivity for the target enzyme.

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