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Mar. Drugs 2019, 17(2), 110; https://doi.org/10.3390/md17020110

In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator

1
Department of Biology and Evolution of Marine Organisms, Stazione Zoologica “Anton Dohrn”, 80121 Naples, Italy
2
Endocannabinoid Research Group (ERG), Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy
3
Institute of Biomolecular Chemistry, National Research Council (ICB-CNR), Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy
4
Molecular Cardiovascular Biology Division, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
5
Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND)-Université Laval, Quebec, QC G1V 0A6, Canada
*
Authors to whom correspondence should be addressed.
Received: 16 January 2019 / Revised: 6 February 2019 / Accepted: 7 February 2019 / Published: 12 February 2019
(This article belongs to the Special Issue Molecular Docking in Marine Drug Discovery & Design)
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Abstract

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. View Full-Text
Keywords: virtual screening; nuclear receptor agonist; positive allosteric modulator; zebrafish models virtual screening; nuclear receptor agonist; positive allosteric modulator; zebrafish models
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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D’Aniello, E.; Iannotti, F.A.; Falkenberg, L.G.; Martella, A.; Gentile, A.; De Maio, F.; Ciavatta, M.L.; Gavagnin, M.; Waxman, J.S.; Di Marzo, V.; Amodeo, P.; Vitale, R.M. In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator. Mar. Drugs 2019, 17, 110.

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