Linked magnolol dimer as a selective PPAR? agonist - Structure-based rational design, synthesis, and bioactivity evaluation.

ABSTRACT: The nuclear receptors peroxisome proliferator-activated receptor ? (PPAR?) and its hetero-dimerization partner retinoid X receptor ? (RXR?) 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 PPAR? to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPAR? and RXR?. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPAR? and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPAR? agonist in vitro with the purified PPAR? 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 PPAR? ligand binding domain than magnolol (K i values of 5.03 and 64.42?nM, respectively). Regarding their potency to transactivate a PPAR?-dependent luciferase gene both compounds were equally effective. This is likely due to the PPAR? specificity of the newly designed magnolol dimer and lack of RXR?-driven transactivation activity by this dimeric compound.

SUBMITTER: Dreier D 

PROVIDER: S-EPMC5651862 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature