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• W2885684849 endingPage "3057" @default.
• W2885684849 startingPage "3048" @default.
• W2885684849 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" @default.
• W2885684849 created "2018-08-22" @default.
• W2885684849 creator A5050031621 @default.
• W2885684849 creator A5063629314 @default.
• W2885684849 creator A5085568163 @default.
• W2885684849 date "2018-11-17" @default.
• W2885684849 modified "2023-10-17" @default.
• W2885684849 title "Structure investigation, enrichment analysis and structure-based repurposing of FDA-approved drugs as inhibitors of BET-BRD4" @default.
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• W2885684849 doi "https://doi.org/10.1080/07391102.2018.1507838" @default.
• W2885684849 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30079805" @default.
• W2885684849 hasPublicationYear "2018" @default.
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