Title :

Computer-aided discovery of small molecule inhibitors of transcriptional activity of tlx (nr2e1) nuclear receptor

Author(s) :

Dueva, Evgenia [Auteur]
Singh, Priyanka [Auteur]
Kalyta, Anastasia [Auteur]
Leblanc, Eric [Auteur]
Rennie, Paul S. [Auteur]
Cherkasov, Artem [Auteur]

Journal title :

Molecules (Basel, Switzerland)

Abbreviated title :

Molecules

Volume number :

23

Publication date :

2018-11-14

ISSN :

1420-3049

Keyword(s) :

structure-based drug design
nuclear receptor
transcriptional factor
NR2E1
TLX
prostate cancer

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

Orphan nuclear receptor TLX (NR2E1) plays a critical role in the regulation of neural stem cells (NSC) as well as in the development of NSC-derived brain tumors. In the last years, new data have emerged implicating TLX in ...
Show more >Orphan nuclear receptor TLX (NR2E1) plays a critical role in the regulation of neural stem cells (NSC) as well as in the development of NSC-derived brain tumors. In the last years, new data have emerged implicating TLX in prostate and breast cancer. Therefore, inhibitors of TLX transcriptional activity may have a significant impact on the treatment of several critical malignancies. However, the TLX protein possesses a non-canonical ligand-binding domain (LBD), which lacks a ligand-binding pocket (conventionally targeted in case of nuclear receptors) that complicates the development of small molecule inhibitors of TLX. Herein, we utilized a rational structure-based design approach to identify small molecules targeting the Atro-box binding site of human TLX LBD. As a result of virtual screening of ~7 million molecular structures, 97 compounds were identified and evaluated in the TLX-responsive luciferase reporter assay. Among those, three chemicals demonstrated 40(-)50% inhibition of luciferase-detected transcriptional activity of the TLX orphan nuclear receptor at a dose of 35 microM. The identified compounds represent the first class of small molecule inhibitors of TLX transcriptional activity identified via methods of computer-aided drug discovery.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

INSERM
Université de Lille

Collections :

• Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192

Submission date :

2022-06-15T13:58:41Z