Fragment-based in silico screening of bromodomain ligands

TitleFragment-based in silico screening of bromodomain ligands
Publication TypeJournal Article
Year of Publication2016
AuthorsSpiliotopoulos D., Caflisch A.
JournalDrug Discovery Today. Technologies
Start Page81
Date Published2016 Mar
Type of ArticleResearch Article
KeywordsComputer 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.



Alternate JournalDrug Discov. Today Technol.
PubMed ID27769362
Highlight Role: 
Drug Design