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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 |
|---|---|
| Personen und Körperschaften: | , , , , , |
| In: | Molecules, 23, 2018, 11, S. 2967 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
MDPI AG
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| Schlagwörter: |
| author_facet |
Dueva, Evgenia Singh, Kriti Kalyta, Anastasia LeBlanc, Eric Rennie, Paul Cherkasov, Artem Dueva, Evgenia Singh, Kriti Kalyta, Anastasia LeBlanc, Eric Rennie, Paul Cherkasov, Artem |
|---|---|
| author |
Dueva, Evgenia Singh, Kriti Kalyta, Anastasia LeBlanc, Eric Rennie, Paul Cherkasov, Artem |
| spellingShingle |
Dueva, Evgenia Singh, Kriti Kalyta, Anastasia LeBlanc, Eric Rennie, Paul Cherkasov, Artem Molecules Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor Chemistry (miscellaneous) Analytical Chemistry Organic Chemistry Physical and Theoretical Chemistry Molecular Medicine Drug Discovery Pharmaceutical Science |
| author_sort |
dueva, evgenia |
| spelling |
Dueva, Evgenia Singh, Kriti Kalyta, Anastasia LeBlanc, Eric Rennie, Paul Cherkasov, Artem 1420-3049 MDPI AG Chemistry (miscellaneous) Analytical Chemistry Organic Chemistry Physical and Theoretical Chemistry Molecular Medicine Drug Discovery Pharmaceutical Science http://dx.doi.org/10.3390/molecules23112967 <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> Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor Molecules |
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MDPI AG, 2018 |
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| title |
Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor |
| title_unstemmed |
Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor |
| title_full |
Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor |
| title_fullStr |
Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor |
| title_full_unstemmed |
Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor |
| title_short |
Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor |
| title_sort |
computer-aided discovery of small molecule inhibitors of transcriptional activity of tlx (nr2e1) nuclear receptor |
| topic |
Chemistry (miscellaneous) Analytical Chemistry Organic Chemistry Physical and Theoretical Chemistry Molecular Medicine Drug Discovery Pharmaceutical Science |
| url |
http://dx.doi.org/10.3390/molecules23112967 |
| publishDate |
2018 |
| physical |
2967 |
| description |
<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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| author | Dueva, Evgenia, Singh, Kriti, Kalyta, Anastasia, LeBlanc, Eric, Rennie, Paul, Cherkasov, Artem |
| author_facet | Dueva, Evgenia, Singh, Kriti, Kalyta, Anastasia, LeBlanc, Eric, Rennie, Paul, Cherkasov, Artem, Dueva, Evgenia, Singh, Kriti, Kalyta, Anastasia, LeBlanc, Eric, Rennie, Paul, Cherkasov, Artem |
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| description | <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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| spelling | Dueva, Evgenia Singh, Kriti Kalyta, Anastasia LeBlanc, Eric Rennie, Paul Cherkasov, Artem 1420-3049 MDPI AG Chemistry (miscellaneous) Analytical Chemistry Organic Chemistry Physical and Theoretical Chemistry Molecular Medicine Drug Discovery Pharmaceutical Science http://dx.doi.org/10.3390/molecules23112967 <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> Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor Molecules |
| spellingShingle | Dueva, Evgenia, Singh, Kriti, Kalyta, Anastasia, LeBlanc, Eric, Rennie, Paul, Cherkasov, Artem, Molecules, Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor, Chemistry (miscellaneous), Analytical Chemistry, Organic Chemistry, Physical and Theoretical Chemistry, Molecular Medicine, Drug Discovery, Pharmaceutical Science |
| title | Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor |
| title_full | Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor |
| title_fullStr | Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor |
| title_full_unstemmed | Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor |
| title_short | Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor |
| title_sort | computer-aided discovery of small molecule inhibitors of transcriptional activity of tlx (nr2e1) nuclear receptor |
| title_unstemmed | Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor |
| topic | Chemistry (miscellaneous), Analytical Chemistry, Organic Chemistry, Physical and Theoretical Chemistry, Molecular Medicine, Drug Discovery, Pharmaceutical Science |
| url | http://dx.doi.org/10.3390/molecules23112967 |