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Discovery of BAZ2A bromodomain ligands


Spiliotopoulos, Dimitrios; Wamhoff, Eike-Christian; Lolli, Graziano; Rademacher, Christoph; Caflisch, Amedeo (2017). Discovery of BAZ2A bromodomain ligands. European journal of medicinal chemistry, 139:564-572.

Abstract

The bromodomain adjacent to zinc finger domain protein 2A (BAZ2A) is implicated in aggressive prostate cancer. The BAZ2A bromodomain is a challenging target because of the shallow pocket of its natural ligand, the acetylated side chain of lysine. Here, we report the successful screening of a library of nearly 1500 small molecules by high-throughput docking and force field-based binding-energy evaluation. For seven of the 20 molecules selected in silico, evidence of binding to the BAZ2A bromodomain is provided by ligand-observed NMR spectroscopy. Two of these compounds show a favorable ligand efficiency of 0.42 kcal/mol per non-hydrogen atom in a competition-binding assay. The crystal structures of the BAZ2A bromodomain in complex with four fragment hits validate the predicted binding modes. The binding modes of compounds 1 and 3 are compatible with ligand growing for optimization of affinity for BAZ2A and selectivity against the close homologue BAZ2B.

Abstract

The bromodomain adjacent to zinc finger domain protein 2A (BAZ2A) is implicated in aggressive prostate cancer. The BAZ2A bromodomain is a challenging target because of the shallow pocket of its natural ligand, the acetylated side chain of lysine. Here, we report the successful screening of a library of nearly 1500 small molecules by high-throughput docking and force field-based binding-energy evaluation. For seven of the 20 molecules selected in silico, evidence of binding to the BAZ2A bromodomain is provided by ligand-observed NMR spectroscopy. Two of these compounds show a favorable ligand efficiency of 0.42 kcal/mol per non-hydrogen atom in a competition-binding assay. The crystal structures of the BAZ2A bromodomain in complex with four fragment hits validate the predicted binding modes. The binding modes of compounds 1 and 3 are compatible with ligand growing for optimization of affinity for BAZ2A and selectivity against the close homologue BAZ2B.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Organic Chemistry, Pharmacology, Drug Discovery, General Medicine
Language:English
Date:20 October 2017
Deposited On:26 Sep 2017 14:41
Last Modified:19 Aug 2018 10:23
Publisher:Elsevier
ISSN:0223-5234
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.ejmech.2017.08.028
PubMed ID:28837921
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_169007
  • : Project TitleAnalysis of protein simulations and neural activity data

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