In Silico Screening for Antidiabetic Compounds from Goji Berries: Identification and Lead Optimization of Novel PPARγ Activators

Type 2 diabetes mellitus (T2DM) is a highly prevalent chronic disease. Recently, many biological targets were discovered for treatment of this disease. The identification of the nuclear hormone receptor peroxisome proliferator activated receptors (PPAR) and their subtypes α, γ and δ or β as targets for controlling lipid, glucose and energy homeostasis has proved to be exciting. PPARγ has been the most extensively studied isoform and is known to be involved in adipogenesis and lipid metabolism, insulin sensitivity, cell proliferation and inflammation, whereas PPAR α is primarily involved in the regulation of lipid oxidation[2]. However, the currently used PPARγ-agonists display serious side effects including heart failure and edema, which has led to a great interest in the discovery of novel ligands with favorable properties. Goji berries and juice are being sold as health food products in western countries and praised in advertisements and in the media for well-being and as an anti-aging remedy. Goji is a relatively new name given to Lycium barbarum and L. chinense, two close species with a long tradition of use as medicinal and food plants in East Asia, in particular in China. Investigations of the fruit have focused on proteoglycans, known as „Lycium barbarum polysaccharides“, which showed antioxidative properties and some interesting pharmacological activities in the context of age related diseases such as atherosclerosis and diabetes. The aim of our study is to identify new PPARγ agonists by a pharmacophore-based virtual screening of 3D natural products from Goji berries. This in silico approach led to the identification of several small molecule amides predicted to bind the receptor ligand binding domain (LBD). Docking studies, synthesis, structure activity relationships of small molecule amides along with biological activity in both PPARα and PPARγ will be presented.

Figure 1a: Small molecule amide identified from Goji berries by virtual screening

Figure 1b: The proposed binding mode of 1 (pink) superimposed on the cocrystal structure of rosiglitazone (green) in the PPARγ LBD.

Acknowledgements: This research is supported in part by Science Based Authentication of Dietary Supplements and Botanical Dietary Supplement Research funded by the Food and Drug Administration grant numbers 5U01FD002071–10 and 1U01FD003871–02.

References: [1] Rotella DP, (2004)J Med Chem, 47: 4111. [2] Willson TM, Brown PJ, et al. (2000)J Med Chem, 43: 527–550. [3] Zhao R, Li Q, et al. (2005) Yakugaku Zasshi 125: 981–988