Abstract
The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and its hetero-dimerization partner retinoid X receptor α (RXRα) are considered as drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. Effort has been made to develop new agonists for PPARγ to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPARγ and RXRα. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPARγ and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPARγ agonist in vitro with the purified PPARγ ligand binding domain (LBD) and in a cell-based nuclear receptor transactivation model in HEK293 cells. We determined the synthesized magnolol dimer to bind with much higher affinity to the purified PPARγ ligand binding domain than magnolol (Ki values of 5.03 and 64.42 nM, respectively). Regarding their potency to transactivate a PPARγ-dependent luciferase gene both compounds were equally effective. This is likely due to the PPARγ specificity of the newly designed magnolol dimer and lack of RXRα-driven transactivation activity by this dimeric compound.
Highlights
The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a central signal integrator in maintaining lipid and glucose homeostasis and is used as clinical target to treat diseases such as type 2 diabetes mellitus and the metabolic syndrome[1,2]
Whereas two molecules of magnolol are positioned in rather close spatial proximity within the human PPARγ receptor ligand binding domain (LBD), only one magnolol molecule binds to the LBD of RXRα
We found that magnolol dimer (1) binds with a more than 12-fold higher affinity to human PPARγ LBD compared to magnolol (Ki values of 5.03 nM, 95% CI 2.31-10.93 nM, and 64.42 nM, 95% CI 29.02-143.00 nM, respectively) and with more than 16-fold higher affinity compared to pioglitazone (Ki values of 5.03 nM, 95% CI 2.31-10.93 nM and 85.43, 95% CI 47.28-154.30 nM, respectively) (Fig. 7A)
Summary
The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a central signal integrator in maintaining lipid and glucose homeostasis and is used as clinical target to treat diseases such as type 2 diabetes mellitus and the metabolic syndrome[1,2]. It has been shown that partial PPARγ agonists eliciting submaximal activation produce fewer side effects keeping beneficial effects for clinical treatments[5]. Whereas two molecules of magnolol are positioned in rather close spatial proximity within the human PPARγ receptor ligand binding domain (LBD), only one magnolol molecule binds to the LBD of RXRα. This prompted us to hypothesize that a molecule combining the structural features of two magnolol entities tethered within a single compound could potentially fit only into the ligand binding domain of PPARγ in a very selective way. The aim of this study was to design, synthesize, and evaluate the impact of a magnolol-derived dimer on PPARγ and RXRα activity
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