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

TitleDiscovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking
Publication TypeJournal Article
Year of Publication2014
AuthorsZhao H., Gartenmann L., Dong J., Spiliotopoulos D., Caflisch A.
JournalBioorganic & Medicinal Chemistry Letters
Date Published2014 Jun 1
Type of ArticleResearch Article
KeywordsDose-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.



Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID24767840