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

Bioorg Med Chem Lett. 2014 Jun 1;24(11):2493-6. doi: 10.1016/j.bmcl.2014.04.017. Epub 2014 Apr 13.

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.

Keywords: Diazepam; Epigenetics; Fragment-based drug discovery; Molecular dynamics; Virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • High-Throughput Screening Assays*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nuclear Proteins / antagonists & inhibitors*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*

Substances

  • BRD4 protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Small Molecule Libraries
  • Transcription Factors