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Discovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking


Zhao, Hongtao; Gartenmann, Lisa; Dong, Jing; Spiliotopoulos, Dimitrios; Caflisch, Amedeo (2014). Discovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking. Bioorganic & Medicinal Chemistry Letters, 24(11):2493-2496.

Abstract

Bromodomains (BRDs) recognize acetyl-lysine modified histone tails mediating epigenetic processes. BRD4, a protein containing two bromodomains, has emerged as an attractive therapeutic target for several types of cancer as well as inflammatory diseases. Using a fragment-based in silico screening approach, we identified two small molecules that bind to the first bromodomain of BRD4 with low-micromolar affinity and favorable ligand efficiency (0.37 kcal/mol per non-hydrogen atom), selectively over other families of bromodomains. Notably, the hit rate of the fragment-based in silico approach is about 10% as only 24 putative inhibitors, from an initial library of about 9 million molecules, were tested in vitro.

Abstract

Bromodomains (BRDs) recognize acetyl-lysine modified histone tails mediating epigenetic processes. BRD4, a protein containing two bromodomains, has emerged as an attractive therapeutic target for several types of cancer as well as inflammatory diseases. Using a fragment-based in silico screening approach, we identified two small molecules that bind to the first bromodomain of BRD4 with low-micromolar affinity and favorable ligand efficiency (0.37 kcal/mol per non-hydrogen atom), selectively over other families of bromodomains. Notably, the hit rate of the fragment-based in silico approach is about 10% as only 24 putative inhibitors, from an initial library of about 9 million molecules, were tested in vitro.

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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
Language:English
Date:2014
Deposited On:01 Jul 2014 15:25
Last Modified:05 Apr 2016 17:56
Publisher:Elsevier
ISSN:0960-894X
Publisher DOI:https://doi.org/10.1016/j.bmcl.2014.04.017
PubMed ID:24767840

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