Structural Analysis of Small-Molecule Binding to the BAZ2A and BAZ2B Bromodomains

ChemMedChem. 2018 Jul 18;13(14):1479-1487. doi: 10.1002/cmdc.201800234. Epub 2018 Jun 21.


The bromodomain-containing protein BAZ2A is a validated target in prostate cancer research, whereas the function of its paralogue BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand engages in essentially identical interactions in the BAZ2A and BAZ2B bromodomains. In contrast, the rest of the molecule is partially solvent-exposed and adopts different orientations with different interactions in the two bromodomains. Some of these differences could be exploited for designing inhibitors with selectivity within the BAZ2 bromodomain subfamily.

Keywords: BAZ2 bromodomains; X-ray crystallography; competition binding assays; in silico screening; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Chromosomal Proteins, Non-Histone / chemistry
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Crystallography, X-Ray
  • Drug Discovery
  • Humans
  • Ligands
  • Male
  • Molecular Docking Simulation
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / metabolism
  • Protein Binding
  • Protein Domains / drug effects
  • Proteins / chemistry
  • Proteins / metabolism*
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*
  • Transcription Factors, General


  • Antineoplastic Agents
  • BAZ2A protein, human
  • BAZ2B protein, human
  • Chromosomal Proteins, Non-Histone
  • Ligands
  • Proteins
  • Small Molecule Libraries
  • Transcription Factors, General