Pharmacophore-driven identification of PPARγ agonists from natural sources.
In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPARγ agonist through bioassay-guided chromatographic fractionations of Chios mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPARγ. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPARγ agonists; while at the same time it manifests that natural products are highly relevant for use in virtual screening-based drug discovery.
Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
Rasmus K
RK
Petersen
Kathrine B
KB
Christensen
Andreana N
AN
Assimopoulou
Xavier
X
Fretté
Vassilios P
VP
Papageorgiou
Karsten
K
Kristiansen
Irene
I
Kouskoumvekaki
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods; D005347:Fibroblasts; D007004:Hypoglycemic Agents / Q000032:analysis* / Q000737:chemistry; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000032:analysis* / Q000737:chemistry; D027927:Pistacia / Q000737:chemistry*; D010936:Plant Extracts / Q000032:analysis / Q000737:chemistry*; D014315:Triterpenes / Q000032:analysis / Q000737:chemistry*
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D010936:Plant Extracts; D014315:Triterpenes; C450739:oleanonic acid; C018620:oleoresins