Development of a Protocol for Virtual Screening of PPARγ Weak Partial Agonists and Their Metabolites: Case Study on Naturally-derived Oleanane Triterpenoids

Triterpenoids are well known metabolic syndrome (MetS) modulators. One of the suggested molecular mechanisms of action involves peroxisome proliferator-activated receptor gamma (PPARγ) activation. In this study we aimed to: (i) develop a virtual screening (VS) protocol for PPARγ weak partial agonists, (ii) predict potential metabolic transformations of naturally-derived triterpenoids, and (iii) perform VS of the triterpenoids and their metabolites. The NIH PubMed system was searched for publications about naturally-derived oleanane triterpenoids which are agonists or up-regulators of PPARγ. Structure- and ligand-based methods were combined in the development of the VS protocol. Metabolites were predicted using Meteor Nexus expert system (Lhasa Limited). Two in-house virtual libraries of PPARγ weak partial agonists and naturally-derived triterpenoids with their predicted metabolites were compiled. The pharmacophore-based docking protocol was applied for VS of the collected triterpenoids. Most of the docking poses reproduced the binding mode of caulophyllogenin (a weak partial agonist) in a complex with PPARγ (PDB ID 5F9B). Our results contribute to the mechanistic explanation of the effects of triterpenoids suggesting possible weak partial agonistic activity toward PPARγ. This research can direct further studies on triterpenoids’ role in MetS modulation. The developed protocol can be applied for VS of any PPARγ weak partial agonists.