Structural analysis of small molecule binding to the BAZ2A and BAZ2B bromodomains

TitleStructural analysis of small molecule binding to the BAZ2A and BAZ2B bromodomains
Publication TypeJournal Article
Year of Publication2018
AuthorsDalle Vedove A., Spiliotopoulos D., D'Agostino V.G, Marchand J.-R., Unzue A., Nevado C., Lolli G., Caflisch A.
JournalChemMedChem
Volume13
Start Page1479
Issue14
Pagination1479-1487
Date Published2018 May 17
Type of ArticleResearch Article
ISSN1860-7187
KeywordsBAZ2A, BAZ2B, bromodomains, Crystallography, Drug Discovery, X-Ray
Abstract

The bromodomain-containing protein BAZ2A is a validated target in prostate cancer, while the function of its paralog BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a very similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand makes essentially identical interactions in the BAZ2A and BAZ2B bromodomains. In contrast, the rest of the molecule is partially solvent exposed and shows different orientations and interactions in the two bromodomains. Some of these differences could be exploited for designing selective inhibitors within the BAZ2 bromodomain subfamily.

DOI10.1002/cmdc.201800234
pubindex

0235

Alternate JournalChemMedChem
PubMed ID29770599
Highlight Role: 
Drug Design