title: Fragment-based in silico screening of bromodomain ligands.
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.
authors: Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland. Electronic address: d.spiliotopoulos@bioc.uzh.ch.
authors: Dimitrios
authors: D
authors: Spiliotopoulos
authors: Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland. Electronic address: caflisch@bioc.uzh.ch.
authors: Amedeo
authors: A
authors: Caflisch
mesh_terms: D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000737:chemistry*; D018797:Cell Cycle Proteins; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008024:Ligands; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000072417:Protein Domains; D054852:Small Molecule Libraries; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000092468:Bromodomain Containing Proteins
chemical_list: D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D008024:Ligands; D009687:Nuclear Proteins; D054852:Small Molecule Libraries; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C494363:CREBBP protein, human