Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects
Phosphodiesterase (PDE) enzymes regulate the levels of cyclic nucleotides, cAMP, and/or cGMP, being attractive therapeutic targets. In order to modulate PDE activity in a selective way, we focused our efforts on the search of allosteric modulators. Based on the crystal structure of the PDE10A GAF-B...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2017-09-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/22/9/1472 |
| _version_ | 1819017962014638080 |
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| author | Ana M. García José Brea Alejandro González-García Concepción Pérez María Isabel Cadavid María Isabel Loza Ana Martinez Carmen Gil |
| author_facet | Ana M. García José Brea Alejandro González-García Concepción Pérez María Isabel Cadavid María Isabel Loza Ana Martinez Carmen Gil |
| author_sort | Ana M. García |
| collection | DOAJ |
| description | Phosphodiesterase (PDE) enzymes regulate the levels of cyclic nucleotides, cAMP, and/or cGMP, being attractive therapeutic targets. In order to modulate PDE activity in a selective way, we focused our efforts on the search of allosteric modulators. Based on the crystal structure of the PDE10A GAF-B domain, a virtual screening study allowed the discovery of new hits that were also tested experimentally, showing inhibitory activities in the micromolar range. Moreover, these new PDE10A inhibitors were able to decrease the nitrite production in LPS-stimulated cells, thus demonstrating their potential as anti-inflammatory agents. |
| first_indexed | 2024-12-21T03:11:51Z |
| format | Article |
| id | doaj.art-639d5c4f602e435fad3f53935fb52770 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-21T03:11:51Z |
| publishDate | 2017-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-639d5c4f602e435fad3f53935fb527702022-12-21T19:17:58ZengMDPI AGMolecules1420-30492017-09-01229147210.3390/molecules22091472molecules22091472Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory EffectsAna M. García0José Brea1Alejandro González-García2Concepción Pérez3María Isabel Cadavid4María Isabel Loza5Ana Martinez6Carmen Gil7Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, SpainInstituto de Farmacia Industrial, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Universitario Sur s/n, 15782 Santiago de Compostela, SpainInstituto de Farmacia Industrial, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Universitario Sur s/n, 15782 Santiago de Compostela, SpainInstituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, SpainInstituto de Farmacia Industrial, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Universitario Sur s/n, 15782 Santiago de Compostela, SpainInstituto de Farmacia Industrial, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Universitario Sur s/n, 15782 Santiago de Compostela, SpainCentro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, SpainCentro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, SpainPhosphodiesterase (PDE) enzymes regulate the levels of cyclic nucleotides, cAMP, and/or cGMP, being attractive therapeutic targets. In order to modulate PDE activity in a selective way, we focused our efforts on the search of allosteric modulators. Based on the crystal structure of the PDE10A GAF-B domain, a virtual screening study allowed the discovery of new hits that were also tested experimentally, showing inhibitory activities in the micromolar range. Moreover, these new PDE10A inhibitors were able to decrease the nitrite production in LPS-stimulated cells, thus demonstrating their potential as anti-inflammatory agents.https://www.mdpi.com/1420-3049/22/9/1472PDE10 inhibitorsallosteric modulatorscAMPGAF domainanti-inflammatory |
| spellingShingle | Ana M. García José Brea Alejandro González-García Concepción Pérez María Isabel Cadavid María Isabel Loza Ana Martinez Carmen Gil Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects Molecules PDE10 inhibitors allosteric modulators cAMP GAF domain anti-inflammatory |
| title | Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects |
| title_full | Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects |
| title_fullStr | Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects |
| title_full_unstemmed | Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects |
| title_short | Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects |
| title_sort | targeting pde10a gaf domain with small molecules a way for allosteric modulation with anti inflammatory effects |
| topic | PDE10 inhibitors allosteric modulators cAMP GAF domain anti-inflammatory |
| url | https://www.mdpi.com/1420-3049/22/9/1472 |
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