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

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.

Nobiletin Reduces Lipid Accumulation in Sebocytes and Inhibits PPAR Delta Activation in Epidermal Tissue Models

“…RA at 1µM produced a significant stimulation (214%) of the reporter expression compared to the vehicle control (Figure 2). Our data on RA stimulation of the PPAR pathway are in agreement with other studies showing activation of PPAR by RA [21,22].…”

Molecular Image-Based Prediction Models of Nuclear Receptor Agonists and Antagonists Using the DeepSnap-Deep Learning Approach with the Tox21 10K Library

“…In the absence of a ligand, the type I NR forms inactive complexes with chaperone proteins in the cytoplasm, whereas type II NR, regardless of the ligand-binding status, is located in the nucleus and binds to the DNA response elements of its target genes along with corepressors [6,14,16]. For these types of NRs, a number of allosteric modulators have been identified that can act as either agonist or antagonist by occupying the active pocket of the NR and blocking the recruitment of coactivators or corepressors to the transcriptional complex [11,[17][18][19][20].…”

Identification and Characterization of Cannabimovone, a Cannabinoid from Cannabis sativa, as a Novel PPARγ Agonist via a Combined Computational and Functional Study

“…Due to its role in adipocyte differentiation, lipid metabolism, glucose homeostasis, insulin sensitivity, and, more recently, in inflammatory and immune responses, PPARγ represents an attractive pharmacological target to address metabolic disorders. As part of our discovery program on nuclear receptor ligands from marine [24,25] and terrestrial sources [15], we focused on cannabimovone (CBM), a polar pCB characterized by a unique abeo-menthane terpenyl moiety isolated in 2010 from a non-psychotropic variety of C. sativa (Italian cultivar Carmagnola) [17]. The chemical structure of cannabimovone, including stereochemical details, was recently confirmed by total synthesis, which can also be considered as an alternative to the exploitation of the natural source [26].…”