2. Academic Validation
  3. Discovery of BAZ2A bromodomain ligands

Discovery of BAZ2A bromodomain ligands

  • Eur J Med Chem. 2017 Oct 20:139:564-572. doi: 10.1016/j.ejmech.2017.08.028.
Dimitrios Spiliotopoulos 1,  Eike-Christian Wamhoff 2,  Graziano Lolli 3,  Christoph Rademacher 4,  Amedeo Caflisch 5
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
  • 2 Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany; Institute of Chemistry and Biochemistry, Department of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany.
  • 3 Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland; Protein Crystallography and Structure-Based Drug Design, CIBIO, University of Trento, via Sommarive 9, 38123 Povo (TN), Italy. Electronic address: [email protected].
  • 4 Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany; Institute of Chemistry and Biochemistry, Department of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany. Electronic address: [email protected].
  • 5 Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. Electronic address: [email protected].
PMID: 28837921 DOI: 10.1016/j.ejmech.2017.08.028
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.

Keywords

BAZ2A bromodomain; Fragment-based drug design; High-throughput docking; Ligand-observed NMR spectroscopy; Protein X-ray crystallography.

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