by Laura Guasch, Esther Sala, Anna Castell-Auví, Lidia Cedó, Klaus R. Liedl, Gerhard Wolber, Markus Muehlbacher, Miquel Mulero, Montserrat Pinent, Anna Ardévol, Cristina Valls, Gerard Pujadas, Santiago Garcia-Vallvé
Although there are successful examples of the discovery of new PPAR? agonists, it has recently been of great interest to identify new PPAR? partial agonists that do not present the adverse side effects caused by PPAR? full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPAR? 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 PPAR? partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPAR? partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPAR? 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 PPAR? partial agonists: they bind to PPAR?, do not or only moderately stimulate the transactivation activity of PPAR?, 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 novel scaffolds for PPAR? partial agonists.