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Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor
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| Zeitschriftentitel: | Molecules |
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| Personen und Körperschaften: | , , , , , |
| In: | Molecules, 23, 2018, 11, S. 2967 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
MDPI AG
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| Schlagwörter: |
| Zusammenfassung: | <jats:p>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 µM. The identified compounds represent the first class of small molecule inhibitors of TLX transcriptional activity identified via methods of computer-aided drug discovery.</jats:p> |
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| Umfang: | 2967 |
| ISSN: |
1420-3049
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| DOI: | 10.3390/molecules23112967 |