Linked magnolol dimer as a selective PPARγ agonist – Structure-based rational design, synthesis, and bioactivity evaluation

• Published in: Scientific reports 2017-10, Vol.7 (1), p.13002-10, Article 13002
• Main Authors: Dreier, Dominik, Latkolik, Simone, Rycek, Lukas, Schnürch, Michael, Dymáková, Andrea, Atanasov, Atanas G., Ladurner, Angela, Heiss, Elke H., Stuppner, Hermann, Schuster, Daniela, Mihovilovic, Marko D., Dirsch, Verena M.
• Format: Article
• Language: English
• Subjects: 13; 38; 42/109; 631/154/436; 639/638; Biological activity; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Crystal structure; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Dimerization; Drug Design; HEK293 Cells; Humanities and Social Sciences; Humans; Ligands; Lignans - chemical synthesis; Lignans - chemistry; Lignans - pharmacology; Medical treatment; Metabolic disorders; Metabolic syndrome; multidisciplinary; Nuclear receptors; Pioglitazone - pharmacology; PPAR gamma - agonists; PPAR gamma - chemistry; PPAR gamma - metabolism; Protein Domains; Retinoid X Receptor alpha - metabolism; Science; Science (multidisciplinary); Structure-Activity Relationship
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-12628-5

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 ( K i 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.