H. Zhao; L. Gartenmann; J. Dong; D. Spiliotopoulos; A. Caflisch

Journal: Bioorg. Med. Chem. Lett.
Year: 2014
Volume: 24
Issue: 11
Pages: 2493-2496
DOI: 10.1016/j.bmcl.2014.04.017
Type of Publication: Journal Article

Dose-Response Relationship, Drug; Drug Discovery; High-Throughput Screening Assays; Humans; Models, Molecular; Molecular Structure; Nuclear Proteins; Small Molecule Libraries; Structure-Activity Relationship; Transcription Factors


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.