Abstract
BackgroundP2Y12 receptor (P2Y12R) is a newly discovered Gi-coupled ADP receptor that plays critical role in platelet function. Ginsenosides are the main constituents responsible for most of pharmacological actions of ginseng, especially cardio-cerebrovascular protective efficacy that is closely related to the influence on platelet function. Hypothesis/PurposeTo explore stereoselective effect of naturally abundant ginsenoside isomers, including the C-20 epimers of protopanaxadiol (PPD), protopanaxatriol (PPT), and their glycosides Rg2, Rg3, Rh1, Rh2 on P2Y12R in platelets. Study Design/MethodsBoth in vitro assay and in silico molecular docking study were performed to investigate the stereoselective effects. ResultsIn vitro assay using washed rat platelets revealed differential effects of ginsenoside isomers on ADP-induced platelet aggregation with the direction and degree of action varying with chemical structures. More to the point, the ginsenoside 20S-Rh2 but not its 20R-epimer was found to be the only one that could significantly promote in vitro platelets aggregation induced by ADP. The correlation analysis demonstrated that ginsenosides may have impact on P2Y12R related platelet functions through a cAMP-dependent pathway. Molecular docking stimulation further indicated that ginsenoside isomers could be potent substrate of P2Y12R with differential protein–ligand interaction that would be responsible for the stereoselective efficacy of C-20 ginsenoside epimers. Hydrogen bonding with Asp266 via the C-20 hydroxyl may provide ginsenosides with promoting effect on ADP-induced platelets aggregation, whereas interactions with Tyr105 could contribute to the promotion of inhibitory efficacy. ConclusionGinsenosides are potent P2Y12R substrate with stereoselective effects on P2Y12R-related platelet function, which result from their chemical diversity and are closely related to the different interaction ways as P2Y12R ligand.
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