In search for potential antidiabetic compounds from natural sources: docking, synthesis and biological screening of small molecules from Lycium spp. (Goji)

Authors: YALAMANCHILI, CHINNI - University Of Mississippi; CHITTIBOYINA, AMAR - University Of Mississippi; HAIDER, SAQLAIN - University Of Mississippi; VASQUEZ, YELKAIRA - University Of Mississippi; KHAN, SHABANA - University Of Mississippi; DO CARMO, JUSSARA - University Of Mississippi Medical Center; DA SILVA, ALEXANDRE - University Of Mississippi Medical Center; PINKERTON, MARK - University Of Mississippi Medical Center; HALL, JOHN - University Of Mississippi Medical Center; WALKER, LARRY - University Of Mississippi; KHAN, IKHLAS - University Of Mississippi

Submitted to: Heliyon
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/29/2019
Publication Date: 1/2/2020
Citation: Yalamanchili, C., Chittiboyina, A.G., Haider, S., Vasquez, Y., Khan, S., Do Carmo, J.M., Da Silva, A.A., Pinkerton, M., Hall, J.E., Walker, L.A., Khan, I.A. 2020. In search for potential antidiabetic compounds from natural sources: docking, synthesis and biological screening of small molecules from Lycium spp. (Goji). Heliyon. 6(1):e02782. https://doi.org/10.1016/j.heliyon.2019.e02782.
DOI: https://doi.org/10.1016/j.heliyon.2019.e02782

Interpretive Summary: To identify antidiabetic compounds with reduced side effects, Goji, a traditional Chinese medicine (TCM) plant, was studied using docking studies (in silico), followed by synthesis of small molecules that are identical to phytochemicals found in Goji and tested with cell-based assays. The promising candidates including tyramines enriched extract were tested further using db/db mice. Although some tyramine derivatives possessed good activities in vitro, the results of the in vivo studies indicate no significant improvement in the biochemical parameters for both tyramine-derivative and enriched fraction from Goji.

Technical Abstract: Current clinical antidiabetic drugs, like rosiglitazone1, have been implicated in some serious side effects like edema, weight gain, and heart failure, making it necessary to find alternative agents. Partial agonists of peroxisome-proliferator activated receptor-gamma (PPAR') were determined to possess improved insulin sensitivity without undesirable side effects when compared to full agonists of PPAR', like rosiglitazone1. The traditional Chinese medicine (TCM) plants, Goji (Lycium barbarum and Lycium chinense) are widely used for treating symptoms related to various diseases including diabetes and hypertension. Twenty seven reported compounds from Goji were docked into both partial and full-agonist binding sites of PPAR'. Amongst the docked compounds, phenylethylamide-based phytochemicals (5–9) (termed as tyramine-derivatives, TDs) were found to possess good docking scores and binding poses with favorable interactions. Synthesis of 24 TDs, including three naturally occurring amides (6,8,9) were synthesized and tested for PPAR' gene induction with the cell-based assay. Three compounds showed similar or higher fold induction than the positive control, rosiglitazone. Among these three active TDs, trans-N-feruloyloctopamine (9) and tyramine derivatives-enriched extract (TEE) (21%) of the root bark of L. chinense were further studied in vivo using db/db mice. However, both TEE, as well as 9, did not show significant antidiabetic properties in db/db mice. In vivo results suggest that the proposed antidiabetic property of Lycium species may not be due to tyramine derivatives alone. Further studies of tyramine derivatives or enriched extract(s) for other bioactivities like hypocholesterolemic activities and studies of novel isolated compounds from Goji will enable a more complete understanding of their bioactivities.