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

被引：2

作者：

Cuffaro, Doretta ^{[1
]}

Gimeno, Aleix ^{[2
]}

Bernardoni, Bianca Laura ^{[1
]}

Di Leo, Riccardo ^{[1
]}

Pujadas, Gerard ^{[2
]}

Garcia-Vallve, Santiago ^{[2
]}

Nencetti, Susanna ^{[1
]}

Rossello, Armando ^{[1
]}

Nuti, Elisa ^{[1
]}

机构：

[1] Univ Pisa, Dept Pharm, Via Bonanno 6, I-56126 Pisa, Italy

[2] Univ Rovira i Virgili, Dept Bioquim & Biotecnol, Res Grp Cheminformat & Nutr, Campus Sescelades, Tarragona 43007, Spain

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2023年 / 24卷 / 13期

关键词：

virtual screening; MMP-13; inhibitors; osteoarthritis; N-acyl hydrazones; protein-ligand docking; MATRIX METALLOPROTEINASES; HIGHLY POTENT; DISCOVERY; ISOMERIZATION; DESIGN;

D O I：

10.3390/ijms241311098

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：26

共 49 条

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