RT Journal Article
SR Electronic
T1 Computer-aided discovery, validation and mechanistic characterisation of novel neolignan activators of PPARγ
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.109.062141
DO 10.1124/mol.109.062141
A1 Nanang Fakhrudin
A1 Angela Ladurner
A1 Atanas Georgiev Atanasov
A1 Elke H. Heiss
A1 Lisa Baumgartner
A1 Patrick Markt
A1 Daniela Schuster
A1 Ernst P. Ellmerer
A1 Gerhard Wolber
A1 Judith M. Rollinger
A1 Hermann Stuppner
A1 Verena M. Dirsch
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/01/11/mol.109.062141.abstract
AB Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are used for the treatment of type 2 diabetes and metabolic syndrome. However, the currently used PPARγ agonists display serious side effects leading to a great interest in the discovery of novel ligands with favourable properties. Aim of our study was to identify new PPARγ agonists by a PPARγ pharmacophore-based virtual screening of 3D natural product libraries. This in silico approach led to the identification of several neolignans predicted to bind the receptor ligand binding domain (LBD). To confirm this prediction, the neolignans dieugenol, tetrahydrodieugenol, and magnolol were isolated from the respective natural source or synthesized and subsequently tested for PPARγ receptor binding. The neolignans bound to the PPARγ LBD with EC50s in the nanomolar range, exhibiting a binding pattern highly similar to the clinically used agonist pioglitazone. In intact cells, dieugenol and tetrahydrodieugenol selectively activated hPPARγ-, but not hPPARα- or hPPARβ/δ-mediated luciferase reporter expression, with a pattern suggesting partial PPARγ agonism. The coactivator recruitment study also demonstrated partial agonism of the tested neolignans. Dieugenol, tetrahydrodieugenol, and magnolol but not the structurally related eugenol induced 3T3-L1 preadipocyte differentiation confirming effectiveness in a cell model with endogenous PPARγ expression. In conclusion, we identified neolignans as novel ligands for PPARγ, which exhibited interesting activation profiles, recommending them as potential pharmaceutical leads or dietary supplements.The American Society for Pharmacology and Experimental Therapeutics