Prediction of Interactions Between Chemical Compounds of Polygala fallax Hemsl. and Key Proteins Involved in PI3K/AKT/mTOR Signaling Pathway via Molecular Docking Technology and Mechanism of This Plant Contributing to Anti-aging

Aging is one of the biggest risk factors for most human diseases. Anti-aging have become common challenges to the world. Over-activation of the PI3K/AKT/mTOR signaling pathway has been proved to promote the aging process. Polygala fallax Hemsl. (PFH) is a traditional Chinese medicinal (TCM) herb and used in folk for many diseases including anti-aging. Molecular docking is a computer-aided technique which is used to predict the interaction between a small molecule (ligand) and a target macromolecule (usually a protein) for drug design and discovery. In order to explore the effect, possible mechanism and potential application of PFH for anti-aging, in this study, the interactions between 13 chemical compounds from PFH and 4 target proteins (PI3K, AKT, mTOR and S6K1) involved in PI3K/AKT/mTOR sigaling pathway were predicted through molecular docking technology; animal experiment also was carried out to investigate the effect of PFH on anti-aging. D-galactose was administered to induce aging in rats at a dose of 500mg/kg body weight for 42 days, then extract of PFH was administered to aging rats at a dose of 3.75, 7.5 and 15 g/kg body weight for 28 days, respectively. After that, the rat thymus was taken and used in thymus index evaluation to confirm the establishment of aging-rat model; rat brain was subjected to western blot to determine the expression of PI3K, AKT, mTOR and S6K1. Results of molecular docking showed that xanthones were the major compounds showing high affinities with target proteins. The compound which bond to PI3K, AKT, mTOR, and S6K1 with the lowest binding energy (BE) reflecting highest affinity was 1,7-dimethoxy-2,3-methylenedioxyxanthone (BE= - 7.568 kcal/mol), 1,7-dihydroxy-2,3-dimethoxyxanthone (BE= - 8.651 kcal/mol), 1,3-Dihydroxyxanthone (BE= -6.472 kcal/mol) and sinapinic acid (BE= -8.304 kcal/mol), respectively. Animal experiments showed that thymus indices of all D-galactose-treated rats decreased significantly and the proportions of phosphorylation of PI3K, AKT, mTOR and S6K1 in brain were decreased significantly in groups treated with extract of PFH. Findings of this study suggested that a variety of chemical components could bind with key proteins involved in PI3K/AKT/mTOR signaling pathway, with xanthones being the predominant one; PFH might delay aging through down-regulating the phosphorylation of key proteins involved in this pathway and has a promising application in anti-aging.