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Fragment-based in silico screening of bromodomain ligands

D. Spiliotopoulos; A. Caflisch

Journal: Drug Discov. Today Technol.
Year: 2016
Volume: 19
Pages: 81-90
DOI: 10.1016/j.ddtec.2016.06.003
Type of Publication: Journal Article

Computer Simulation; CREB-Binding Protein; Drug Design; Humans; Ligands; Nuclear Proteins; Protein Domains; Small Molecule Libraries; Transcription Factors


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.