Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Discovery of New non-steroidal selective glucocorticoid receptor agonists
Δημιουργός/Συγγραφέας:	Potamitis C. Siakouli D. Papavasileiou K.D. Boulaka A. [EL] Γάνου, Βασιλική[EN] Ganou, Vassiliki Roussaki M. [EL] Καλογεροπούλου, Θεοδώρα[EN] Calogeropoulou, Theodora [EL] Ζουμπουλάκης, Παναγιώτης[EN] Zoumpoulakis, Panagiotis [EL] Αλέξης, Μιχαήλ Ν.[EN] Alexis, Michael N. [EL] Ζερβού, Μαρία[EN] Zervou, Maria [EL] Μήτσιου, Δήμητρα[EN] Mitsiou, Dimitra J.
Εκδότης:	Elsevier Ltd
Ημερομηνία:	2019
Γλώσσα:	Αγγλικά
ISSN:	0960-0760
DOI:	10.1016/j.jsbmb.2018.10.007
Άλλο:	PubMed ID: 30321666
Περίληψη:	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 and 13) 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 of 1 and 13 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.
Τίτλος πηγής δημοσίευσης:	Journal of Steroid Biochemistry and Molecular Biology
Τόμος/Κεφάλαιο:	186
Σελίδες:	142-153
Θεματική Κατηγορία:	[EL] Φαρμακευτική χημεία[EN] Pharmaceutical chemistry [EL] Βιοχημεία[EN] Biochemistry
Λέξεις-Κλειδιά:	Anti-Inflammatory action Glucocorticoid receptor MD simulations Pharmacophore model Selective agonists Virtual screening
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© 2018 Elsevier Ltd
Σημειώσεις:	pr001017; RI-261600; MIS 447,985, MIS 5002398; Seventh Framework Programme, FP7; European Commission, EC; European Regional Development Fund, FEDER. This work was supported by STHENOS and STHENOS-β projects (GRANTS: MIS 447,985 and MIS 5002398 , respectively) funded by the Operational Programme "Competitiveness, Entrepreneurship and Innovation" (NSRF 2007–2013 and NSRF 2014–2020) and co-financed by Greece and the European Union (European Regional Development Fund) . We thank Dr. MG Papadopoulos for providing advice and support for the molecular dynamics calculations. The GPU accelerated MD simulations were performed at the LinkSCEEM Cy-Tera GPU cluster, supported by the LinkSCEEM-2 project, funded by the European Commission under the 7th Framework Programme through Capacities Research Infrastructure, INFRA-2010-1.2.3 Virtual Research Communities, Combination of Collaborative Project and Coordination and Support Actions (CP-CSA) under grant agreement no RI-261600. The MM-PBSA calculations were supported by computational time granted from the Greek Research & Technology Network (GRNET) in the National HPC facility - ARIS - under project ID pr001017.
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο