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

作者：Zhao Hongtao^*; Gartenmann Lisa; Dong Jing; Spiliotopoulos Dimitrios; Caflisch Amedeo

来源：Bioorganic & Medicinal Chemistry Letters, 2014, 24(11): 2493-2496.

DOI：10.1016/j.bmcl.2014.04.017

• Fragment-based drug discovery
• Virtual screening
• Molecular dynamics
• Epigenetics
• Diazepam

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.

• 出版日期2014-6-1