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

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

  • Zhao H Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address: h.zhao@bioc.uzh.ch.
  • Gartenmann L Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
  • Dong J Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
  • Spiliotopoulos D Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
  • Caflisch A Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address: caflisch@bioc.uzh.ch.
  • 2014-04-29
Published in:
  • Bioorganic & medicinal chemistry letters. - 2014
Diazepam
Epigenetics
Fragment-based drug discovery
Molecular dynamics
Virtual screening
Cell Cycle Proteins
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
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/255337
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