TY - JOUR KW - Humans KW - Molecular Docking Simulation KW - Structure-Activity Relationship KW - Ligands KW - Molecular Structure KW - Drug Discovery KW - Chromosomal Proteins, Non-Histone KW - Dose-Response Relationship, Drug AU - D. Spiliotopoulos AU - E.-C. Wamhoff AU - G. Lolli AU - C. Rademacher AU - A. Caflisch AB -

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.

BT - European Journal of Medicinal Chemistry C1 - 0225 DA - 2017 Oct 20 DO - 10.1016/j.ejmech.2017.08.028 J2 - Eur. J. Med. Chem. LA - eng M3 - Research Article N2 -

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.

PY - 2017 SE - 564 SP - 564 EP - 572 T2 - European Journal of Medicinal Chemistry TI - Discovery of BAZ2A bromodomain ligands VL - 139 SN - 1768-3254 ER -