Discovery of BAZ2A bromodomain ligands.
- Spiliotopoulos D Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
- Wamhoff EC 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.
- Lolli G 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: graziano.lolli@unitn.it.
- Rademacher C 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: christoph.rademacher@mpikg.mpg.de.
- Caflisch A Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. Electronic address: caflisch@bioc.uzh.ch.
- 2017-08-25
Published in:
- European journal of medicinal chemistry. - 2017
BAZ2A bromodomain
Fragment-based drug design
High-throughput docking
Ligand-observed NMR spectroscopy
Protein X-ray crystallography
Chromosomal Proteins, Non-Histone
Dose-Response Relationship, Drug
Drug Discovery
Humans
Ligands
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
English
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.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1016/j.ejmech.2017.08.028
- PMID 28837921
- Persistent URL
- https://sonar.ch/global/documents/88781
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