Identification of 20(R, S)-protopanaxadiol and 20(R, S)-protopanaxatriol for potential selective modulation of glucocorticoid receptor. (September 2019)

• Record Type: Journal Article
• Authors: Zhang, Tiehua; Liang, Yuan; Zuo, Peng; Yan, Mi; Jing, Siyuan; Li, Tiezhu; Wang, Yongjun; Zhang, Jie; Wei, Zhengyi
• Is Part Of: Food and chemical toxicology. Volume 131(2019)
• Publication Date: 2019-09
• Subjects: Selective glucocorticoid receptor modulators -- Ginsenosides -- Transactivation -- Transrepression; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2019.110642
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: 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). Highlights: The tested ginsenosides did not increase luciferase expression in HeLa cells. Molecular simulations suggest that ginsenosides can bind to GR. PPD( R ) is capable of separating transrepression from transactivation. PPD( R ) may serve as a potential selective GR modulator.