In Silico Identification and Experimental Validation of (−)-Muqubilin A, a Marine Norterpene Peroxide, as PPARα/γ-RXRα Agonist and RARα Positive Allosteric Modulator
| Autor: | Andrea Martella, Fabio Arturo Iannotti, Joshua S. Waxman, Rosa Maria Vitale, Maria Letizia Ciavatta, Enrico D'Aniello, Alessandra Gentile, Lauren G Falkenberg, Pietro Amodeo, Vincenzo Di Marzo, Fabrizia De Maio, Margherita Gavagnin |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Retinoic acid Pharmaceutical Science 01 natural sciences Animals Genetically Modified chemistry.chemical_compound nuclear receptor agonist Drug Discovery Pharmacology Toxicology and Pharmaceutics (miscellaneous) lcsh:QH301-705.5 Zebrafish 0303 health sciences Retinoic Acid Receptor alpha Drug Synergism Ligand (biochemistry) humanities 3. Good health Cell biology Peroxides Porifera Molecular Docking Simulation zebrafish models Larva embryonic structures Agonist Allosteric modulator medicine.drug_class Transgene In silico Tretinoin Article 03 medical and health sciences Allosteric Regulation medicine Animals Humans Luciferase PPAR alpha 030304 developmental biology PPAR receptors 010405 organic chemistry Terpenes organic chemicals virtual screening muqubilin A 0104 chemical sciences High-Throughput Screening Assays body regions PPAR gamma Nuclear receptor chemistry lcsh:Biology (General) positive allosteric modulator human activities |
| Zdroj: | Marine Drugs, Vol 17, Iss 2, p 110 (2019) Marine drugs 17 (2019). doi:10.3390/md17020110 info:cnr-pdr/source/autori: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./titolo:In silico identification and experimental validation of (-)-muqubilin A, a marine norterpene peroxide, as PPARalpha%2Fgamma-RXRalpha agonist and RARalpha positive allosteric modulator/doi:10.3390%2Fmd17020110/rivista:Marine drugs/anno:2019/pagina_da:/pagina_a:/intervallo_pagine:/volume:17 Marine Drugs Volume 17 Issue 2 |
| ISSN: | 1660-3397 |
| DOI: | 10.3390/md17020110 |
| Popis: | The nuclear receptors (NRs) RAR&alpha RXR&alpha PPAR&alpha and PPAR&gamma 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 (&minus )-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 RXR&alpha and both PPAR&alpha whereas the binding mode toward RAR&alpha showed peculiar features potentially impairing its activity as full agonist. Luciferase assays confirmed that Muq acts as a full agonist for RXR&alpha 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 RAR&alpha 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 RAR&alpha activation and RA signaling. |
| Databáze: | OpenAIRE |
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