Author, as appears in the article.: Rivero P; Ivanova V; Barril X; Casampere M; Casas J; Fabriàs G; Díaz Y; Matheu MI
Department: Química Analítica i Química Orgànica
URV's Author/s: Díaz Giménez, María Yolanda / Matheu Malpartida, María Isabel / Rivero Prieto, Pablo
Keywords: Pr280 Organic synthesis Dihydroceramide desaturase 1 Des1 inhibition Ceramide derivatives Alphafold2
Abstract: 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.
Thematic Areas: 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
licence for use: https://creativecommons.org/licenses/by/3.0/es/
Author's mail: pablo.rivero@urv.cat yolanda.diaz@urv.cat maribel.matheu@urv.cat
Author identifier: 0000-0001-5567-8108 0000-0001-5216-9260
Record's date: 2024-09-21
Papper version: info:eu-repo/semantics/publishedVersion
Link to the original source: https://www.sciencedirect.com/science/article/pii/S004520682400138X?via%3Dihub
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: Bioorganic Chemistry. 145 107233-107233
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
Article's DOI: 10.1016/j.bioorg.2024.107233
Entity: Universitat Rovira i Virgili
Journal publication year: 2024
Publication Type: Journal Publications
Repositori URV