Identification of PPARgamma Partial Agonists of Natural Origin (II): In Silico Prediction in Natural Extracts with Known Antidiabetic Activity

Abstract

BackgroundNatural extracts have played an important role in the prevention and treatment of diseases and are important sources for drug discovery. However, to be effectively used in these processes, natural extracts must be characterized through the identification of their active compounds and their modes of action.Methodology/Principal FindingsFrom an initial set of 29,779 natural products that are annotated with their natural source and using a previously developed virtual screening procedure (carefully validated experimentally), we have predicted as potential peroxisome proliferators-activated receptor gamma (PPARγ) partial agonists 12 molecules from 11 extracts known to have antidiabetic activity. Six of these molecules are similar to molecules with described antidiabetic activity but whose mechanism of action is unknown. Therefore, it is plausible that these 12 molecules could be the bioactive molecules responsible, at least in part, for the antidiabetic activity of the extracts containing them. In addition, we have also identified as potential PPARγ partial agonists 10 molecules from 16 plants with undescribed antidiabetic activity but that are related (i.e., they are from the same genus) to plants with known antidiabetic properties. None of the 22 molecules that we predict as PPARγ partial agonists show chemical similarity with a group of 211 known PPARγ partial agonists obtained from the literature.Conclusions/SignificanceOur results provide a new hypothesis about the active molecules of natural extracts with antidiabetic properties and their mode of action. We also suggest plants with undescribed antidiabetic activity that may contain PPARγ partial agonists. These plants represent a new source of potential antidiabetic extracts. Consequently, our work opens the door to the discovery of new antidiabetic extracts and molecules that can be of use, for instance, in the design of new antidiabetic drugs or functional foods focused towards the prevention/treatment of type 2 Diabetes Mellitus.

O-prenylated flavonoid, an antidiabetes constituent in Melicope lunu-ankenda

“…M. lunu-ankenda is also used for the treatment of high blood pressure and diabetes in Malaysia (Othman et al, 2014). Guasch and co-workers recently studied Euodia lunuankenda, Evodia elleryana, Evodia officinalis and Melicope ptelefolia extracts and their active molecules for antidiabetic activity by in silico analyses (Guasch et al, 2013). Over 1200 medicinal plants are now reported to be used for their antihyperglycemic activity (Rajasekaran et al, 2006;Qi et al, 2010).…”

Identification of PPARγ Agonists from Natural Sources Using Different In Silico Approaches

“…4), which also shows a binding mode different from full agonists. Lately, Guasch et al [62,63] performed a VS study to identify potential PPARγ partial agonists in extracts with known antidiabetic activity. They developed a structure-based pharmacophore and anti-pharmacophore (i.e., a 3D interaction pattern that matches those molecules, which describes the binding to undesired PPARγ isoforms or binding modes) to identify potential PPARγ partial agonists.…”

Discovery of Natural Products that Modulate the Activity of PPARgamma: A Source for New Antidiabetics

“…S. miltiorrhiza has been used traditionally to treat diabetes [31]. The molecules deoxyneocryptotanshinone and miltionone I from S. miltiorrhiza are extremely similar to tanshinone IIA, and have been predicted to be PPARγ partial agonists [70]. A possible mechanism for the antidiabetic activity of PPARγ antagonists is that they might block the CDK5-mediated phosphorylation of PPARγ at Ser273.…”

“…Five out of the eight tested compounds were confirmed to be PPARγ partial agonists as they bind to PPARγ, do not or only moderately stimulate the transactivation activity of PPARγ, do not induce adipogenesis of preadipocyte cells and stimulate insulin-induced glucose uptake by adipocytes [30]. Using a slightly modified version of their VS workflow, Guasch and coworkers [70] predicted, as potential PPARγ partial agonists, 12 molecules from 11 natural extracts known to have antidiabetic activity. In addition, they also identified 10 molecules from 16 plants with undescribed antidiabetic activity but that are related to plants with known antidiabetic properties [70].…”

“…Using a slightly modified version of their VS workflow, Guasch and coworkers [70] predicted, as potential PPARγ partial agonists, 12 molecules from 11 natural extracts known to have antidiabetic activity. In addition, they also identified 10 molecules from 16 plants with undescribed antidiabetic activity but that are related to plants with known antidiabetic properties [70].…”