Discovery of New non-steroidal selective glucocorticoid receptor agonists. Issue 186 (February 2019)

• Record Type: Journal Article
• Authors: Potamitis, Constantinos; Siakouli, Dimitra; Papavasileiou, Konstantinos D.; Boulaka, Athina; Ganou, Vassiliki; Roussaki, Marina; Calogeropoulou, Theodora; Zoumpoulakis, Panagiotis; Alexis, Michael N.; Zervou, Maria; Mitsiou, Dimitra J.
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 186(2019)
• Page Start: 142
• Page End: 153
• Publication Date: 2019-02
• Subjects: GC glucocorticoids -- GR glucocorticoid receptor -- GRE glucocorticoid responsive element -- SEGRA selective glucocorticoid receptor agonist -- NF-kB nuclear factor kB -- HC hydrocortizone -- Dex dexamethasone -- RU486 mifepristone -- TNF tumor necrosis factor -- CCL2 chemokine (C-C motif) ligand 2 -- IL6 interleukin 6 -- FKBP5 FK506 binding protein 5 -- IL8 interleukin 8; Glucocorticoid receptor -- Selective agonists -- Anti-Inflammatory action -- Pharmacophore model -- Virtual screening -- MD simulations; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2018.10.007
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: Virtual Screening utilizing a structure-based pharmacophore model of GR-LBD. Discovery of two 1, 3-benzothiazole analogs (1 and13 ) acting as genuine SEGRA. 1 and13 transrepress a subset of NFKB targets genes in a GR-dependent manner. New proposed binding contacts of1 and13 at the extended cavity of GR-LBD. Abstract: Glucocorticoids (GCs) are widely used as potent anti-inflammatory drugs; however, GC therapy is often accompanied by adverse side effects. The anti-inflammatory action of GCs is exerted through the glucocorticoid receptor (GR) in part by antagonizing the pro-inflammatory nuclear factor k B (NF-kB) whereas the majority of side effects are assumed to be mediated by transactivation of GR target genes. We set out to identify novel non-steroidal selective GR agonists (SEGRA) favoring transrepression of NF-kB target genes over transactivation of genes associated with undesirable effects. Our virtual screening protocol was driven by a pharmacophore model based on a pyrrolidinone amide analogue (named as 'compound 12′ in Biggadike et al 2009, PNAS USA 106, 18, 114) bound to the extended binding pocket of the GR ligand binding domain (GR-LBD). Ambinter library (7.8 million compounds) was queried by our validated pharmacophore hypothesis and the prioritized compounds were biologically evaluated using a series of well-established screening assays. Two structurally similar hits (1 and13 ) were identified that bind to GR, induce its translocation to the nucleus, do not mediate transactivation of GR target genes whereas partially repress a number of pro-inflammatory NF-kB target genes, in a GR-dependent manner. Explanatory molecular dynamics (MD) calculations could detail the per-residue interactions accounting for the binding of1 and13 to the extended binding pocket of GR. The discovered 1, 3-benzothiazole analogs introduce a new class of genuine SEGRA paving the way for hit-to-lead optimization.