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

Discovery of BAZ2A bromodomain ligands / Spiliotopoulos, Dimitrios; Wamhoff, Eike-christian; Lolli, Graziano; Rademacher, Christoph; Caflisch, Amedeo. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 139:(2017), pp. 564-572. [10.1016/j.ejmech.2017.08.028]

Discovery of BAZ2A bromodomain ligands

Lolli, Graziano;
2017

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
Spiliotopoulos, Dimitrios; Wamhoff, Eike-christian; Lolli, Graziano; Rademacher, Christoph; Caflisch, Amedeo
Discovery of BAZ2A bromodomain ligands / Spiliotopoulos, Dimitrios; Wamhoff, Eike-christian; Lolli, Graziano; Rademacher, Christoph; Caflisch, Amedeo. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 139:(2017), pp. 564-572. [10.1016/j.ejmech.2017.08.028]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11572/188283
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