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

Abstract

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
• epigenetic reader
• docking
• enrichment
• drug repurposing

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Notes on contributors

Padmaja Wakchaure

Conceptualization, P.W., R.V., and K.K.R.; Methodology, P.W. and K.K.R.; Formal analysis, P.W. and K.K.R.; Writing, Original draft preparation, P.W.; Writing, review & editing, P.W., R.V., and K.K.R. All authors reviewed and approved the final version.

Ravichandiran Velayutham

Conceptualization, P.W., R.V., and K.K.R.; Methodology, P.W. and K.K.R.; Formal analysis, P.W. and K.K.R.; Writing, Original draft preparation, P.W.; Writing, review & editing, P.W., R.V., and K.K.R. All authors reviewed and approved the final version.

Kuldeep K. Roy

Conceptualization, P.W., R.V., and K.K.R.; Methodology, P.W. and K.K.R.; Formal analysis, P.W. and K.K.R.; Writing, Original draft preparation, P.W.; Writing, review & editing, P.W., R.V., and K.K.R. All authors reviewed and approved the final version.