Structure investigation, enrichment analysis and structure-based repurposing of FDA-approved drugs as inhibitors of BET-BRD4

J Biomol Struct Dyn. 2019 Aug;37(12):3048-3057. doi: 10.1080/07391102.2018.1507838. Epub 2018 Nov 17.


We report herein detailed structural insights into the ligand recognition modes guiding bromodomain selectivity, enrichment analysis and docking-based database screening for the identification of the FDA-approved drugs that have potential to be the human BRD4 inhibitors. Analysis of multiple X-ray structures prevailed that the lysine-recognition sites are highly conserved, and apparently, the dynamic ZA loop guides the specific ligand-recognition. The protein-ligand interaction profiling revealed that both BRD2 and BRD4 shared hydrophobic interaction of bound ligands with PRO-98/PRO-82, PHE-99/PHE-83, LEU-108/LEU-92 and direct H-bonding with ASN-156/ASN-140 (BRD2/BRD4), while on the other hand the water-mediated H-bonding of bound ligands with PRO-82, GLN-85, PRO-86, VAL-87, ASP-88, LEU-92, TYR-97 and MET-132, and aromatic π-π stacking with TRP-81 prevailed as unique interaction in BRD4, and were not observed in BRD2. Subsequently, through ROC curve analysis, the best enrichment was found with PDB-ID 4QZS of BRD4 structures. Finally, through docking-based database screening study, we found that several drugs have better binding affinity than the control candidate lead (+)-JQ1 (Binding affinity = -7.9 kcal/mol), a well-known BRD4 inhibitor. Among the top-ranked drugs, azelastine, a selective histamine H1 receptor antagonist, showed the best binding affinity of -9.3 kcal/mol and showed interactions with several key residues of the acetyl lysine binding pocket. Azelastine may serve as a promising template for further medicinal chemistry. These insights may serve as basis for structure-based drug design, drug repurposing and the discovery of novel BRD4 inhibitors. Communicated by Ramaswamy H. Sarma.

Keywords: BET–Bromodomain; docking; drug repurposing; enrichment; epigenetic reader.

MeSH terms

  • Binding Sites
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Drug Design
  • Drug Repositioning / methods
  • Humans
  • Ligands
  • Molecular Docking Simulation / methods
  • Molecular Dynamics Simulation
  • Pharmaceutical Preparations / metabolism*
  • Protein Binding
  • Protein Domains
  • Proteins / metabolism*
  • Transcription Factors / antagonists & inhibitors*


  • BRD4 protein, human
  • Cell Cycle Proteins
  • Ligands
  • Pharmaceutical Preparations
  • Proteins
  • Transcription Factors
  • bromodomain and extra-terminal domain protein, human