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
Volume19
Start Page81
Pagination81-90
Date Published2016 Mar
Type of ArticleResearch Article
ISSN1740-6749
KeywordsComputer 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.

DOI10.1016/j.ddtec.2016.06.003
pubindex

0212

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