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

Authors :
Ester Colarusso
Erica Gazzillo
Eleonora Boccia
Stefania Terracciano
Ines Bruno
Giuseppe Bifulco
Maria Giovanna Chini
Gianluigi Lauro
Source :
Molecules, Vol 29, Iss 17, p 4025 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

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 2, 5, and 6 showed high affinity for BRD4, with IC50 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.

Details

Language :
English
ISSN :
14203049
Volume :
29
Issue :
17
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.4c4d5af09cf840049e468ff4e7d95879
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules29174025