High-throughput fragment docking into the BAZ2B bromodomain: Efficient in silico screening for X-Ray crystallography

TitleHigh-throughput fragment docking into the BAZ2B bromodomain: Efficient in silico screening for X-Ray crystallography
Publication TypeJournal Article
Year of Publication2016
AuthorsLolli G., Caflisch A.
JournalACS Chemical Biology
Volume11
Start Page800
Issue3
Pagination800-807
Date Published2016 Mar 18
Type of ArticleResearch Article
ISSN1554-8937
KeywordsBinding Sites, Chemical Hazard Release, Computer Simulation, Crystallography, X-Ray, High-Throughput Screening Assays, Models, Molecular, Protein Conformation, Protein Domains, Proteins
Abstract

Bromodomains are protein modules that bind to acetylated lysine side chains in histones and other proteins. The bromodomain adjacent to zinc finger domain protein 2B (BAZ2B) has been reported to be poorly druggable. Here, we screened an in-house library of 350 fragments by automatic docking to the BAZ2B bromodomain. The top 12 fragments according to the predicted binding energy were selected for experiments of soaking into apo crystals of BAZ2B which yielded the structure of the complex for four of them, which is a hit rate of 33%. Additional crystal structures were solved for BAZ2B and two scaffolds identified by analogy. For three topologically similar fragments, the crystal structures reveal binding modes with different penetration, i.e., with zero, one, and two water molecules, respectively, located between the fragment and the side chain of a conserved tyrosine (Tyr1901) in the bottom of the acetyl lysine pocket of BAZ2B. Furthermore, a remarkable stereoselectivity of the acetyl lysine pocket emerges from the crystal structures of the bromodomains of BAZ2B and SMARCA4 in complex with the chiral diol MPD (2-methyl-2,4-pentanediol).

DOI10.1021/acschembio.5b00914
pubindex

0211

Alternate JournalACS Chem. Biol.
PubMed ID26942307
Highlight Role: 
Drug Design