Spiliotopoulos D Wamhoff EC Lolli G Rademacher C Caflisch A 2017 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. application/pdf https://sonar.ch/global/documents/88781 eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejmech.2017.08.028 info:eu-repo/semantics/altIdentifier/pmid/28837921 info:eu-repo/semantics/openAccess European journal of medicinal chemistry. - 2017 BAZ2A bromodomain Fragment-based drug design High-throughput docking Ligand-observed NMR spectroscopy Protein X-ray crystallography Chromosomal Proteins, Non-Histone Dose-Response Relationship, Drug Drug Discovery Humans Ligands Molecular Docking Simulation Molecular Structure Structure-Activity Relationship Discovery of BAZ2A bromodomain ligands. http://purl.org/coar/resource_type/c_6501