Author, as appears in the article.: Cuffaro, D; Gimeno, A; Bernardoni, BL; Di Leo, R; Pujadas, G; Garcia-Vallve, S; Nencetti, S; Rossello, A; Nuti, E
Department: Bioquímica i Biotecnologia
URV's Author/s: Garcia Vallve, Santiago / Pujadas Anguiano, Gerard
Keywords: Virtual screening Protein-ligand docking Osteoarthritis N-acyl hydrazones Mmp-13 inhibitors Matrix metalloproteinases protein-ligand docking osteoarthritis n-acyl hydrazones mmp-13 inhibitors isomerization highly potent discovery design
Abstract: 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.
Thematic Areas: Zootecnia / recursos pesqueiros Spectroscopy Saúde coletiva Química Psicología Physical and theoretical chemistry Organic chemistry Odontología Nutrição Molecular biology Medicine (miscellaneous) Medicina veterinaria Medicina iii Medicina ii Medicina i Materiais Interdisciplinar Inorganic chemistry Geociências Farmacia Engenharias iv Engenharias ii Engenharias i Educação física Computer science applications Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciências ambientais Ciências agrárias i Ciência de alimentos Ciência da computação Chemistry, multidisciplinary Catalysis Biotecnología Biodiversidade Biochemistry & molecular biology Astronomia / física
licence for use: https://creativecommons.org/licenses/by/3.0/es/
Author's mail: gerard.pujadas@urv.cat santi.garcia-vallve@urv.cat
Author identifier: 0000-0003-2598-8089 0000-0002-0348-7497
Record's date: 2024-01-14
Papper version: info:eu-repo/semantics/publishedVersion
Link to the original source: https://www.mdpi.com/1422-0067/24/13/11098
Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: International Journal Of Molecular Sciences. 24 (13):
APA: Cuffaro, D; Gimeno, A; Bernardoni, BL; Di Leo, R; Pujadas, G; Garcia-Vallve, S; Nencetti, S; Rossello, A; Nuti, E (2023). Identification of N-Acyl Hydrazones as New Non-Zinc-Binding MMP-13 Inhibitors by Structure-Based Virtual Screening Studies and Chemical Optimization. International Journal Of Molecular Sciences, 24(13), -. DOI: 10.3390/ijms241311098
Article's DOI: 10.3390/ijms241311098
Entity: Universitat Rovira i Virgili
Journal publication year: 2023
Publication Type: Journal Publications
Repositori URV