Abstract
Ginsenoside 20(R/S)‐Rg3, as a natural peroxisome proliferator‐activated receptor gamma (PPARγ) ligand, has been reported to exhibit differential biological effects. It is of great interest to understand the stereochemical selectivity of 20(R/S)‐Rg3 and explore whether differential PPARγ activation by Rg3 stereoisomers, if it exists, could lead to differential physiological outcome and therapeutic effects in diabetic atherosclerosis. Here, we investigated the binding modes of 20(R/S)‐Rg3 stereoisomers in the PPARγ ligand‐binding domain (PPARγ‐LBD) using molecular modelling and their effects on smooth muscle cell proliferation and migration induced by advanced glycation end products (AGEs). The results revealed that 20(S)‐Rg3 exhibited stronger antiproliferative and antimigratory effects due to stronger PPARγ activation. To validate the in vitro results, we used a mice model with diabetic atherosclerosis and obtained that 20(S)‐Rg3 markedly reduced the plaque size secondary to reducing the proliferation and migration of VSMCs, while the plaques were more stable due to improvements in other plaque compositions. The results shed light on the structural difference between Rg3 stereoisomers that can lead to significant differential physiological outcome, and the (S)‐isomer seems to be the more potent isomer to be developed as a promising drug for diabetic atherosclerosis.
Highlights
Ginseng, the root of Panax ginseng C
The objective of this study was to investigate stereo-selective binding of Rg3 enantiomers to peroxisome proliferator-activated receptor gamma (PPARc) based on the stereochemical structures and to explore whether differential PPARc activation by Rg3 stereoisomers could lead to differential effects on AGEsstimulated proliferation and migration of vascular smooth muscle cell (VSMC) and diabetic atherosclerosis formation
Previous computational modelling demonstrated that the hydroxyl group at the C20 chiral centre of 20(S)-Rg3 could interact with Tyr[473] through a hydrogen bond, similar to that of rosiglitazone,[33,34] while the sterically strained binding pocket prevented the optimal interaction of 20(R)-Rg3 with Tyr473.11 In this report, we further performed Molecular Dynamics (MD) simulation and Essential Dynamics Analysis (EDA) to investigate the binding modes of 20(R/S)-Rg3 stereoisomers in PPARc-LBD
Summary
Recent experiments have demonstrated that ginsenoside Rg3, which contains 2 neighbouring hydroxyl groups near and on the chiral centre C-20, can act as a natural ligand of PPARc.[10] Angiogenesis assay found that both Rg3 stereoisomers can induce differential angiogenesis effects via PPARc, and the PPARc agonist activity of 20(S)-Rg3 is 10 times stronger than that of 20(R)-Rg3.11 A fluorescence polarization and total internal reflection fluorescence (FP-TIRF) binding study confirmed that only 20(S)-Rg3 can quantitatively bind to the PPARc ligand-binding domain (PPARc-LBD).[12] To further understand the stereochemical selectivity of Rg3 enantiomers, it is timely and of great interest to model the binding modes of 20(R/S)Rg3 in the PPARc-LBD. PPARc is a member of the nuclear receptor superfamily of ligand-inducible transcription factors and regulates multiple pathways involved in the development of diabetes and CVDs.[13,14] Recent studies have implied the role of PPARc in regulating vascular smooth muscle cell (VSMC) proliferation and migration, an essential event in the development of diabetic atherosclerosis.[15,16] Under diabetic conditions, the accumulation of hyperglycaemia-induced AGEs and activation of the receptor for AGEs (RAGE) are key factors mediating these events.[17,18,19] The objective of this study was to investigate stereo-selective binding of Rg3 enantiomers to PPARc based on the stereochemical structures and to explore whether differential PPARc activation by Rg3 stereoisomers could lead to differential effects on AGEsstimulated proliferation and migration of VSMCs and diabetic atherosclerosis formation
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