The triterpene echinocystic acid and its 3-O-glucoside derivative are revealed as potent and selective glucocorticoid receptor agonists

Abstract

. (2016) The triterpene echinocystic acid and its 3Oglucoside derivative are revealed as potent and selective glucocorticoid receptor agonists. The International Journal of Biochemistry & Cell Biology, 79 . pp. 277287. ISSN 13572725 It is advisable to refer to the publisher's version if you intend to cite from the work.http://dx.doi.org/10. 1016/j.biocel.2016.08.028 For more information about UCLan's research in this area go to http://www.uclan.ac.uk/researchgroups/ and search for <name of research Group>.

Potential Dissociative Glucocorticoid Receptor Activity for Protopanaxadiol and Protopanaxatriol

“…Activation of the AMPK is demonstrated to take place upon conditions of glucocorticoids-stress [55], but also upon treatment with the Rb1 ginsenoside [54]. In addition, in line with our observation, and in support of the notion of a potent GCs-like activity of the compounds, reduction in GR protein level, in the presence of DEX at concentrations higher than 10 −7 M, has also been reported in various types of cells, including HeLa cells [26,56,57,58]. The ligand–induced repression of the GR gene is proposed to be mediated by an NCoR1 (nuclear repressor co-repressor 1) repression complex formation [59], however, GCs non-genomic mechanisms of action could also be involved in this action.…”

“…Our data from induced fit docking analysis showed that the aglycone form of the PPD- and PPT- type compound is capable of binding to GR ligand binding domain. In fact, comparable binding strengths to DEX are predicted as well as similar interactions with GR LBD helices/residues, previously cited as important for nuclear translocation [26,36]. As we have previously stated [26], the crucial factor is the ligand-dependent structural reorganizations of the LBD that allow a receptor to function as a more potent activator.…”

“…In fact, comparable binding strengths to DEX are predicted as well as similar interactions with GR LBD helices/residues, previously cited as important for nuclear translocation [26,36]. As we have previously stated [26], the crucial factor is the ligand-dependent structural reorganizations of the LBD that allow a receptor to function as a more potent activator. PPT is predicted to bind slightly stronger than PPD in the predicted docking models (Table 1).…”

“…For comparative purposes, therefore, DEX was also considered in these calculations. There are numerous examples of IFD used to successfully predict ligand-induced protein conformational changes and the effects on biochemical pathways in agreement with experiment [26,32,33,34,35], including for GR [26]. The results of the IFD are shown in Table 1, with both PPD and PPT predicted to bind well.…”

“…Triterpenoids, that share structural similarities with GCs proved to be potent and selective glucocorticoid receptor modulators. Experimental observations showed that triterpenoids, such as avidin D [25], echynocystic acid and its 3-O-glucoside derivative [26], induced GR nuclear translocation and GR transrepressional activities with no or limited GR transactivation. Some reports also demonstrate the ability of protopanaxadiol (PPD) and protopanaxatriol (PPT) to bind to nuclear receptors, such as estrogen and glucocorticoid receptor, and to control their actions [27,28].…”