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

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 & PRIME; pocket of MMP-13. Three ligands were found to inhibit MMP-13 in the & mu;M 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.

Automated summary

Scientists developed a virtual screening workflow to identify selective non-zinc-binding MMP-13 inhibitors by targeting its specific structural features. Three ligands that could inhibit MMP-13 in the micromolar range were discovered, and one of them showed selectivity over other MMPs. Structure-based analysis guided the chemical optimization, resulting in a new N-acyl hydrazone-based derivative with improved inhibitory activity and selectivity for the target enzyme.