Articles producció científica> Química Analítica i Química Orgànica

Targeting dihydroceramide desaturase 1 (Des1): Syntheses of ceramide analogues with a rigid scaffold, inhibitory assays, and AlphaFold2-assisted structural insights reveal cyclopropenone PR280 as a potent inhibitor

  • Dades identificatives

    Identificador: imarina:9364727
    Autors:
    Rivero PIvanova VBarril XCasampere MCasas JFabriàs GDíaz YMatheu MI
    Resum:
    Dihydroceramide desaturase 1 (Des1) catalyzes the formation of a CC double bond in dihydroceramide to furnish ceramide. Inhibition of Des1 is related to cell cycle arrest and programmed cell death. The lack of the Des1 crystalline structure, as well as that of a close homologue, hampers the detailed understanding of its inhibition mechanism and difficults the design of new inhibitors, thus making Des1 a strategic target. Based on previous structure-activity studies, different ceramides containing rigid scaffolds were designed. The synthesis and evaluation of these compounds as Des1 inhibitors allowed the identification of PR280 as a better Des 1 inhibitor in vitro (IC50 = 700 nM) than GT11 and XM462, the current reference inhibitors. This cyclopropenone ceramide was obtained in a 6-step synthesis with a 24 % overall yield. The highly confident 3D structure of Des1, recently predicted by AlphaFold2, served as the basis for conducting docking studies of known Des1 inhibitors and the ceramide derivatives synthesized by us in this study. For this purpose, a complete holoprotein structure was previously constructed. This study has allowed a better knowledge of key ligand-enzyme interactions for Des1 inhibitory activity. Furthermore, it sheds some light on the inhibition mechanism of GT11.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
  • Altres:

    Autor segons l'article: Rivero P; Ivanova V; Barril X; Casampere M; Casas J; Fabriàs G; Díaz Y; Matheu MI
    Departament: Química Analítica i Química Orgànica
    Autor/s de la URV: Díaz Giménez, María Yolanda / Matheu Malpartida, María Isabel / Rivero Prieto, Pablo
    Paraules clau: Pr280 Organic synthesis Dihydroceramide desaturase 1 Des1 inhibition Ceramide derivatives Alphafold2
    Resum: Dihydroceramide desaturase 1 (Des1) catalyzes the formation of a CC double bond in dihydroceramide to furnish ceramide. Inhibition of Des1 is related to cell cycle arrest and programmed cell death. The lack of the Des1 crystalline structure, as well as that of a close homologue, hampers the detailed understanding of its inhibition mechanism and difficults the design of new inhibitors, thus making Des1 a strategic target. Based on previous structure-activity studies, different ceramides containing rigid scaffolds were designed. The synthesis and evaluation of these compounds as Des1 inhibitors allowed the identification of PR280 as a better Des 1 inhibitor in vitro (IC50 = 700 nM) than GT11 and XM462, the current reference inhibitors. This cyclopropenone ceramide was obtained in a 6-step synthesis with a 24 % overall yield. The highly confident 3D structure of Des1, recently predicted by AlphaFold2, served as the basis for conducting docking studies of known Des1 inhibitors and the ceramide derivatives synthesized by us in this study. For this purpose, a complete holoprotein structure was previously constructed. This study has allowed a better knowledge of key ligand-enzyme interactions for Des1 inhibitory activity. Furthermore, it sheds some light on the inhibition mechanism of GT11.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
    Àrees temàtiques: Saúde coletiva Química Organic chemistry Molecular biology Medicina veterinaria Medicina i Farmacia Drug discovery Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Chemistry, organic Biotecnología Biochemistry & molecular biology Biochemistry
    Accès a la llicència d'ús: https://creativecommons.org/licenses/by/3.0/es/
    Adreça de correu electrònic de l'autor: pablo.rivero@urv.cat yolanda.diaz@urv.cat maribel.matheu@urv.cat
    Identificador de l'autor: 0000-0001-5567-8108 0000-0001-5216-9260
    Data d'alta del registre: 2024-09-21
    Versió de l'article dipositat: info:eu-repo/semantics/publishedVersion
    Enllaç font original: https://www.sciencedirect.com/science/article/pii/S004520682400138X?via%3Dihub
    URL Document de llicència: https://repositori.urv.cat/ca/proteccio-de-dades/
    Referència a l'article segons font original: Bioorganic Chemistry. 145 107233-107233
    Referència de l'ítem segons les normes APA: Rivero P; Ivanova V; Barril X; Casampere M; Casas J; Fabriàs G; Díaz Y; Matheu MI (2024). Targeting dihydroceramide desaturase 1 (Des1): Syntheses of ceramide analogues with a rigid scaffold, inhibitory assays, and AlphaFold2-assisted structural insights reveal cyclopropenone PR280 as a potent inhibitor. Bioorganic Chemistry, 145(), 107233-107233. DOI: 10.1016/j.bioorg.2024.107233
    DOI de l'article: 10.1016/j.bioorg.2024.107233
    Entitat: Universitat Rovira i Virgili
    Any de publicació de la revista: 2024
    Tipus de publicació: Journal Publications
  • Paraules clau:

    Biochemistry,Biochemistry & Molecular Biology,Chemistry, Organic,Drug Discovery,Molecular Biology,Organic Chemistry
    Pr280
    Organic synthesis
    Dihydroceramide desaturase 1
    Des1 inhibition
    Ceramide derivatives
    Alphafold2
    Saúde coletiva
    Química
    Organic chemistry
    Molecular biology
    Medicina veterinaria
    Medicina i
    Farmacia
    Drug discovery
    Ciências biológicas iii
    Ciências biológicas ii
    Ciências biológicas i
    Chemistry, organic
    Biotecnología
    Biochemistry & molecular biology
    Biochemistry
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