Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation

Background: Although there are successful examples of the discovery of new PPARc agonists, it has recently been of great interest to identify new PPARc partial agonists that do not present the adverse side effects caused by PPARc full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARc partial agonists among natural products. Methodology/Principal Findings: We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPARc partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPARc partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPARc partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPARc partial agonists: they bind to PPARc, do not or only moderately stimulate the transactivation activity of PPARc, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. Conclusions/Significance: We have demonstrated that our virtual screening protocol was successful in identifying nove