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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 developed molecular database using a li...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410278/ https://www.ncbi.nlm.nih.gov/pubmed/30759808 http://dx.doi.org/10.3390/md17020110 |
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author | D’Aniello, Enrico Iannotti, Fabio Arturo Falkenberg, Lauren G. Martella, Andrea Gentile, Alessandra De Maio, Fabrizia Ciavatta, Maria Letizia Gavagnin, Margherita Waxman, Joshua S. Di Marzo, Vincenzo Amodeo, Pietro Vitale, Rosa Maria |
author_facet | D’Aniello, Enrico Iannotti, Fabio Arturo Falkenberg, Lauren G. Martella, Andrea Gentile, Alessandra De Maio, Fabrizia Ciavatta, Maria Letizia Gavagnin, Margherita Waxman, Joshua S. Di Marzo, Vincenzo Amodeo, Pietro Vitale, Rosa Maria |
author_sort | D’Aniello, Enrico |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-6410278 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-64102782019-03-29 In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator D’Aniello, Enrico Iannotti, Fabio Arturo Falkenberg, Lauren G. Martella, Andrea Gentile, Alessandra De Maio, Fabrizia Ciavatta, Maria Letizia Gavagnin, Margherita Waxman, Joshua S. Di Marzo, Vincenzo Amodeo, Pietro Vitale, Rosa Maria Mar Drugs Article 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. MDPI 2019-02-12 /pmc/articles/PMC6410278/ /pubmed/30759808 http://dx.doi.org/10.3390/md17020110 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article D’Aniello, Enrico Iannotti, Fabio Arturo Falkenberg, Lauren G. Martella, Andrea Gentile, Alessandra De Maio, Fabrizia Ciavatta, Maria Letizia Gavagnin, Margherita Waxman, Joshua S. Di Marzo, Vincenzo Amodeo, Pietro Vitale, Rosa Maria In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator |
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 | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410278/ https://www.ncbi.nlm.nih.gov/pubmed/30759808 http://dx.doi.org/10.3390/md17020110 |
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