In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator
The nuclear receptors (NRs) RARα, RXRα, PPARα, and PPARγ represent promising pharmacological targets for the treatment of neurodegenerative diseases. In the search for molecules able to simultaneously target all the above-mentioned NRs, we screened an in-house dev...
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| Format: | Article |
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MDPI AG
2019-02-01
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| Series: | Marine Drugs |
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| Online Access: | https://www.mdpi.com/1660-3397/17/2/110 |
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| author | Enrico D’Aniello Fabio Arturo Iannotti Lauren G. Falkenberg Andrea Martella Alessandra Gentile Fabrizia De Maio Maria Letizia Ciavatta Margherita Gavagnin Joshua S. Waxman Vincenzo Di Marzo Pietro Amodeo Rosa Maria Vitale |
| author_facet | Enrico D’Aniello Fabio Arturo Iannotti Lauren G. Falkenberg Andrea Martella Alessandra Gentile Fabrizia De Maio Maria Letizia Ciavatta Margherita Gavagnin Joshua S. Waxman Vincenzo Di Marzo Pietro Amodeo Rosa Maria Vitale |
| author_sort | Enrico D’Aniello |
| collection | DOAJ |
| description | The nuclear receptors (NRs) RARα, RXRα, PPARα, and PPARγ represent promising pharmacological targets for the treatment of neurodegenerative diseases. In the search for molecules able to simultaneously target all the above-mentioned NRs, we screened an in-house developed molecular database using a ligand-based approach, identifying (−)-Muqubilin (Muq), a cyclic peroxide norterpene from a marine sponge, as a potential hit. The ability of this compound to stably and effectively bind these NRs was assessed by molecular docking and molecular dynamics simulations. Muq recapitulated all the main interactions of a canonical full agonist for RXRα and both PPARα and PPARγ, whereas the binding mode toward RARα showed peculiar features potentially impairing its activity as full agonist. Luciferase assays confirmed that Muq acts as a full agonist for RXRα, PPARα, and PPARγ with an activity in the low- to sub-micromolar range. On the other hand, in the case of RAR, a very weak agonist activity was observed in the micromolar range. Quite surprisingly, we found that Muq is a positive allosteric modulator for RARα, as both luciferase assays and in vivo analysis using a zebrafish transgenic retinoic acid (RA) reporter line showed that co-administration of Muq with RA produced a potent synergistic enhancement of RARα activation and RA signaling. |
| first_indexed | 2024-04-11T14:08:17Z |
| format | Article |
| id | doaj.art-9283c5f004514f75897d8b4662d2299e |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-11T14:08:17Z |
| publishDate | 2019-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-9283c5f004514f75897d8b4662d2299e2022-12-22T04:19:49ZengMDPI AGMarine Drugs1660-33972019-02-0117211010.3390/md17020110md17020110In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric ModulatorEnrico D’Aniello0Fabio Arturo Iannotti1Lauren G. Falkenberg2Andrea Martella3Alessandra Gentile4Fabrizia De Maio5Maria Letizia Ciavatta6Margherita Gavagnin7Joshua S. Waxman8Vincenzo Di Marzo9Pietro Amodeo10Rosa Maria Vitale11Department of Biology and Evolution of Marine Organisms, Stazione Zoologica “Anton Dohrn”, 80121 Naples, ItalyEndocannabinoid Research Group (ERG), Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), ItalyMolecular Cardiovascular Biology Division, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USAInstitute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), ItalyInstitute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), ItalyInstitute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), ItalyInstitute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), ItalyInstitute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), ItalyMolecular Cardiovascular Biology Division, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USAEndocannabinoid Research Group (ERG), Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), ItalyInstitute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), ItalyInstitute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), ItalyThe nuclear receptors (NRs) RARα, RXRα, PPARα, and PPARγ represent promising pharmacological targets for the treatment of neurodegenerative diseases. In the search for molecules able to simultaneously target all the above-mentioned NRs, we screened an in-house developed molecular database using a ligand-based approach, identifying (−)-Muqubilin (Muq), a cyclic peroxide norterpene from a marine sponge, as a potential hit. The ability of this compound to stably and effectively bind these NRs was assessed by molecular docking and molecular dynamics simulations. Muq recapitulated all the main interactions of a canonical full agonist for RXRα and both PPARα and PPARγ, whereas the binding mode toward RARα showed peculiar features potentially impairing its activity as full agonist. Luciferase assays confirmed that Muq acts as a full agonist for RXRα, PPARα, and PPARγ with an activity in the low- to sub-micromolar range. On the other hand, in the case of RAR, a very weak agonist activity was observed in the micromolar range. Quite surprisingly, we found that Muq is a positive allosteric modulator for RARα, as both luciferase assays and in vivo analysis using a zebrafish transgenic retinoic acid (RA) reporter line showed that co-administration of Muq with RA produced a potent synergistic enhancement of RARα activation and RA signaling.https://www.mdpi.com/1660-3397/17/2/110virtual screeningnuclear receptor agonistpositive allosteric modulatorzebrafish models |
| spellingShingle | Enrico D’Aniello Fabio Arturo Iannotti Lauren G. Falkenberg Andrea Martella Alessandra Gentile Fabrizia De Maio Maria Letizia Ciavatta Margherita Gavagnin Joshua S. Waxman Vincenzo Di Marzo Pietro Amodeo Rosa Maria Vitale In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator Marine Drugs virtual screening nuclear receptor agonist positive allosteric modulator zebrafish models |
| title | In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator |
| title_full | In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator |
| title_fullStr | In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator |
| title_full_unstemmed | In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator |
| title_short | In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator |
| title_sort | in silico identification and experimental validation of muqubilin a a marine norterpene peroxide as pparα γ rxrα agonist and rarα positive allosteric modulator |
| topic | virtual screening nuclear receptor agonist positive allosteric modulator zebrafish models |
| url | https://www.mdpi.com/1660-3397/17/2/110 |
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