Discovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking
| Title | Discovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking |
| Publication Type | Journal Article |
| Year of Publication | 2014 |
| Authors | Zhao H., Gartenmann L., Dong J., Spiliotopoulos D., Caflisch A. |
| Journal | Bioorganic & Medicinal Chemistry Letters |
| Volume | 24 |
| Issue | 11 |
| Pagination | 2493-2496 |
| Date Published | 2014 Jun 1 |
| Type of Article | Research Article |
| Keywords | 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 |
| 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. |
| DOI | 10.1016/j.bmcl.2014.04.017 |
| pubindex | 0186 |
| Alternate Journal | Bioorg. Med. Chem. Lett. |
| PubMed ID | 24767840 |
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