Articles producció científica> Bioquímica i Biotecnologia

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

  • Identification data

    Identifier: imarina:9325786
    Authors:
    Cuffaro, DGimeno, ABernardoni, BLDi Leo, RPujadas, GGarcia-Vallve, SNencetti, SRossello, ANuti, E
    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.
  • Others:

    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: santi.garcia-vallve@urv.cat gerard.pujadas@urv.cat
    Author identifier: 0000-0002-0348-7497 0000-0003-2598-8089
    Record's date: 2024-08-03
    Papper version: info:eu-repo/semantics/publishedVersion
    Link to the original source: https://www.mdpi.com/1422-0067/24/13/11098
    Licence document URL: https://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
  • Keywords:

    Biochemistry & Molecular Biology,Catalysis,Chemistry, Multidisciplinary,Computer Science Applications,Inorganic Chemistry,Medicine (Miscellaneous),Molecular Biology,Organic Chemistry,Physical and Theoretical Chemistry,Spectroscopy
    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
    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
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