RT Journal Article
SR Electronic
T1 Discovery of BAZ2A Bromodomain Ligands
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 122317
DO 10.1101/122317
A1 Dimitrios Spiliotopoulos
A1 Eike-Christian Wamhoff
A1 Graziano Lolli
A1 Christoph Rademacher
A1 Amedeo Caflisch
YR 2017
UL http://biorxiv.org/content/early/2017/06/07/122317.abstract
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.BAZ2Abromodomain adjacent to zinc finger domain protein 2ABAZ2Bbromodomain adjacent to zinc finger domain 2BBETbromodomain and extra terminalCPMGCarr-Purcell-Meiboom-Gill sequenceCREBcAMP response element-binding proteinCSPchemical shift perturbationDMSOdimethyl sulfoxideDPFGSEDouble Pulsaed Field Gradient Spin Echo sequenceIMACimmobilized metal affinity chromatographyIPTGisopropyl β-D-1-thiogalactopyranosideKacacetyllysineLEligand efficiencySTDsaturation transfer differenceTSPtrimethylsilylpropanoic acid.