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bioRxiv · 10.1101/122317

Discovery of BAZ2A Bromodomain Ligands

Spiliotopoulos, D.·Wamhoff, E.-C.·Lolli, G.·Rademacher, C.·Caflisch, A.
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Abstract

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.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC=\"FIGDIR/small/122317_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (36K):\norg.highwire.dtl.DTLVardef@aba498org.highwire.dtl.DTLVardef@c32ddeorg.highwire.dtl.DTLVardef@1f85fc0org.highwire.dtl.DTLVardef@15671bb_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Spiliotopoulos, D., Wamhoff, E.-C., Lolli, G., Rademacher, C., Caflisch, A.. 2017-06-07. Discovery of BAZ2A Bromodomain Ligands. https://doi.org/10.1101/122317

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