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

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.

journal_name

Bioorg Med Chem Lett

authors

Zhao H,Gartenmann L,Dong J,Spiliotopoulos D,Caflisch A

doi

10.1016/j.bmcl.2014.04.017

subject

Has Abstract

pub_date

2014-06-01 00:00:00

pages

2493-6

issue

11

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(14)00353-9

journal_volume

24

pub_type

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