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, 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.
- Marine drugs 17(2): (Journal)
- Registered Authors
- Waxman, Joshua
- nuclear receptor agonist, positive allosteric modulator, virtual screening, zebrafish models
- MeSH Terms
- Allosteric Regulation
- Animals, Genetically Modified
- Drug Synergism
- High-Throughput Screening Assays
- Models, Molecular
- Molecular Docking Simulation
- PPAR alpha/agonists*
- PPAR gamma/agonists*
- Retinoic Acid Receptor alpha/agonists*
- 30759808 Full text @ Mar. Drugs
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. (2019) 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. 17(2).
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes