Discovery of BAZ2A bromodomain ligands

TitleDiscovery of BAZ2A bromodomain ligands
Publication TypeJournal Article
Year of Publication2017
AuthorsSpiliotopoulos D., Wamhoff E.-C., Lolli G., Rademacher C., Caflisch A.
JournalEuropean Journal of Medicinal Chemistry
Start Page564
Date Published2017 Oct 20
Type of ArticleResearch Article
KeywordsChromosomal Proteins, Non-Histone, Dose-Response Relationship, Drug, Drug Discovery, Humans, Ligands, Molecular Docking Simulation, Molecular Structure, Structure-Activity Relationship

The bromodomain adjacent to zinc finger domain protein 2A (BAZ2A) is implicated in aggressive prostate cancer. The BAZ2A bromodomain is a challenging target because of the shallow pocket of its natural ligand, the acetylated side chain of lysine. Here, we report the successful screening of a library of nearly 1500 small molecules by high-throughput docking and force field-based binding-energy evaluation. For seven of the 20 molecules selected in silico, evidence of binding to the BAZ2A bromodomain is provided by ligand-observed NMR spectroscopy. Two of these compounds show a favorable ligand efficiency of 0.42 kcal/mol per non-hydrogen atom in a competition-binding assay. The crystal structures of the BAZ2A bromodomain in complex with four fragment hits validate the predicted binding modes. The binding modes of compounds 1 and 3 are compatible with ligand growing for optimization of affinity for BAZ2A and selectivity against the close homologue BAZ2B.



Alternate JournalEur. J. Med. Chem.
PubMed ID28837921
Highlight Role: 
Drug Design