Synthesis and elaboration of N-methylpyrrolidone as an acetamide fragment substitute in bromodomain inhibition.
Binding Sites
Cell Cycle Proteins
/ chemistry
Crystallography, X-Ray
Drug Design
Fluorescence Resonance Energy Transfer
Gene Expression Regulation
/ drug effects
Humans
Models, Molecular
Molecular Structure
Protein Binding
Protein Conformation
Pyrrolidinones
/ chemical synthesis
Structure-Activity Relationship
Transcription Factors
/ chemistry
Acetyl-lysine
BRD4
Bromodomain
Fragment-based drug design
N-Methylpyrrolidone
NMP
Olinone
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
15 12 2019
15 12 2019
Historique:
received:
14
08
2019
revised:
07
10
2019
accepted:
08
10
2019
pubmed:
16
11
2019
medline:
24
9
2020
entrez:
16
11
2019
Statut:
ppublish
Résumé
N-Methylpyrrolidone is a solvent molecule which has been shown to compete with acetyl-lysine-containing peptides for binding to bromodomains. From crystallographic studies, it has also been shown to closely mimic the acetamide binding motif in several bromodomains, but has not yet been directly pursued as a fragment in bromodomain inhibition. In this paper, we report the elaboration of N-methylpyrrolidone as a potential lead in fragment-based drug design. Firstly, N-methylpyrrolidone was functionalised to provide points for chemical elaboration. Then, the moiety was incorporated into analogues of the reported bromodomain inhibitor, Olinone. X-ray crystallography revealed that the modified analogues showed comparable binding affinity and structural mimicry to Olinone in the bromodomain binding site.
Identifiants
pubmed: 31727451
pii: S0968-0896(19)31357-4
doi: 10.1016/j.bmc.2019.115157
pii:
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
Pyrrolidinones
0
Transcription Factors
0
N-methylpyrrolidone
JR9CE63FPM
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
115157Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.