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Computer-aided discovery of small molecule ...
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Document type :
Article dans une revue scientifique: Article original
DOI :
10.3390/molecules23112967
PMID :
30441799
Permalink :
http://hdl.handle.net/20.500.12210/75089
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] refId
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 ...
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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
Université de Lille

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