Identification of 20(R, S)-protopanaxadiol and 20(R, S)-protopanaxatriol for potential selective modulation of glucocorticoid receptor

文献类型： 外文期刊

第一作者： Zhang, Tiehua

作者： Zhang, Tiehua;Liang, Yuan;Yan, Mi;Jing, Siyuan;Zhang, Jie;Zuo, Peng;Li, Tiezhu;Wang, Yongjun;Wei, Zhengyi

作者机构：

关键词： Selective glucocorticoid receptor modulators; Ginsenosides; Transactivation; Transrepression

期刊名称：FOOD AND CHEMICAL TOXICOLOGY （ 影响因子：6.023； 五年影响因子：5.844 ）

ISSN： 0278-6915

年卷期： 2019 年 131 卷

页码：

收录情况： SCI

摘要： Although glucocorticoids (GCs) are widely used as anti-inflammatory drugs, they are often accompanied by adverse effects, which are mainly due to the transactivation of glucocorticoid receptor (GR) target genes. In order to screen novel plant-derived GR ligands (phytocorticoids) capable of separating transrepression from transactivation, this work focuses on the estimation of 20(R, S)-protopanaxadiol [PPD(R, S)] and 20(R, S)-protopanaxatriol [PPT(R, S)] for their dissociated characteristics. The reporter gene assay shows that ginsenosides cannot enhance glucocorticoid-responsive element-driven genes. The cytotoxicity assay shows that PPT(S), PPT(R), and PPD(S) can inhibit cell proliferation while PPD(R) does not suppress cell growth at available concentration. Further analysis of transactivation and transrepression activities indicates that PPD(R) can repress the transcription of GR target transrepressed gene without activating the expression of the GR target transactivated gene. Results of molecular docking suggest that PPD(R) yields more hydrogen bond interactions and a lower binding energy than its counterparts, resulting in tighter binding between PPD(R) and GR. In addition, PPD(R) achieves stability in the pocket after 2 ns, thereby facilitating exerting its regulatory role of GR target genes. By contrast, other ginsenosides fluctuate drastically during the simulations. In conclusion, PPD(R) may serve as a potential selective GR modulator (SEGRM).

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