Fragment-based in silico screening of bromodomain ligands
| Title | Fragment-based in silico screening of bromodomain ligands |
| Publication Type | Journal Article |
| Year of Publication | 2016 |
| Authors | Spiliotopoulos D., Caflisch A. |
| Journal | Drug Discovery Today. Technologies |
| Volume | 19 |
| Start Page | 81 |
| Pagination | 81-90 |
| Date Published | 2016 Mar |
| Type of Article | Research Article |
| Keywords | Computer Simulation, CREB-Binding Protein, Drug Design, Humans, Ligands, Nuclear Proteins, Protein Domains, Small Molecule Libraries, Transcription Factors |
| Abstract | We review the results of fragment-based high-throughput docking to the N-terminal bromodomain of BRD4 and the CREBBP bromodomain. In both docking campaigns the ALTA (anchor-based library tailoring) procedure was used to reduce the size of the initial library by selecting for flexible docking only the molecules that contain a fragment with favorable predicted binding energy. Ranking by a force field-based energy with solvation has resulted in small-molecule hits with low-micromolar affinity and favorable ligand efficiency. Importantly, the binding modes predicted by docking have been validated by X-ray crystallography. One of the hits for the CREBBP bromodomain has been optimized by medicinal chemistry into a series of potent and selective ligands. |
| DOI | 10.1016/j.ddtec.2016.06.003 |
| pubindex | 0212 |
| Alternate Journal | Drug Discov. Today Technol. |
| PubMed ID | 27769362 |
