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Molecules (Basel, Switzerland)
Aug 26, 2024;29 (17):

Identification of Novel Bromodomain-Containing Protein 4 (BRD4) Binders through 3D Pharmacophore-Based Repositioning Screening Campaign.

Ester Colarusso, Erica Gazzillo, Eleonora Boccia, Stefania Terracciano, Ines Bruno, Giuseppe Bifulco, Maria Giovanna Chini, Gianluigi Lauro
Author Information
  1. Ester Colarusso: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy. ORCID
  2. Erica Gazzillo: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
  3. Eleonora Boccia: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
  4. Stefania Terracciano: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
  5. Ines Bruno: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
  6. Giuseppe Bifulco: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
  7. Maria Giovanna Chini: Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy.
  8. Gianluigi Lauro: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy. ORCID
PMID: 39274873 DOI: 10.3390/molecules29174025

Abstract

A 3D structure-based pharmacophore model built for bromodomain-containing protein 4 (BRD4) is reported here, specifically developed for investigating and identifying the key structural features of the (+)-JQ1 known inhibitor within the BRD4 binding site. Using this pharmacophore model, 273 synthesized and purchased compounds previously considered for other targets but yielding poor results were screened in a drug repositioning campaign. Subsequently, only six compounds showed potential as BRD4 binders and were subjected to further biophysical and biochemical assays. Compounds , , and showed high affinity for BRD4, with IC values of 0.60 ± 0.25 µM, 3.46 ± 1.22 µM, and 4.66 ± 0.52 µM, respectively. Additionally, these compounds were tested against two other bromodomains, BRD3 and BRD9, and two of them showed high selectivity for BRD4. The reported 3D structure-based pharmacophore model proves to be a straightforward and useful tool for selecting novel BRD4 ligands.

Keywords

anticancer agents bromodomain chemical synthesis computational techniques drug discovery drug repositioning

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Grants

  1. MFAG 2017 - ID. 20160 project/Italian Association for Cancer Research

MeSH Term

Transcription Factors
Cell Cycle Proteins
Humans
Protein Binding
Ligands
Drug Repositioning
Binding Sites
Nuclear Proteins
Triazoles
Azepines
Molecular Docking Simulation
Models, Molecular
Structure-Activity Relationship
Drug Evaluation, Preclinical
Pharmacophore
Bromodomain Containing Proteins

Chemicals

Transcription Factors
Cell Cycle Proteins
BRD4 protein, human
Ligands
Nuclear Proteins
Triazoles
Azepines
(+)-JQ1 compound
BRD3 protein, human
BRD9 protein, human
Bromodomain Containing Proteins
Journal Article

Word Cloud

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