Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	N-(4-Substituted-benzoyl)-N '-(beta-D-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods
Δημιουργός/Συγγραφέας:	Veronika Nagy Nora Felfoeldi Balint Konya Praly, Jean-Pierre Tibor Docsa Pal Gergely [EL] Χρυσίνα, Ευαγγελία Δ.[EN] Chrysina, Evangelia D. Tiraidis, Costas Kosmopoulou, Magda N. Alexacou, Kyra-Melinda Konstantakaki, Maria [EL] Λεωνίδας, Δημήτρης Δ.[EN] Leonidas, Demetres D. [EL] Ζωγράφος, Σπύρος Ε.[EN] Zographos, Spyros E. [EL] Οικονομάκος, Νίκος Γ.[EN] Oikonomakos, Nikos G. Kozmon, Stanislav Tvaroska, Igor Laszlo Somsak
Εκδότης:	Pergamon
Τόπος έκδοσης:	OXFORD
Ημερομηνία:	2012-03-01
Γλώσσα:	Αγγλικά
ISSN:	0968-0896
DOI:	10.1016/j.bmc.2011.12.059
Περίληψη:	N-(4-Substituted-benzoyl)-N'-(beta-D-glucopyranosyl)ureas (substituents: Me, Ph, Cl, OH, OMe, NO2, NH2, COOH, and COOMe) were synthesised by ZnCl2 catalysed acylation of O-peracetylated beta-D-glucopyranosyl urea as well as in reactions of O-peracetylated or O-unprotected glucopyranosylamines and acyl-isocyanates. O-deprotections were carried out by base or acid catalysed transesterifications where necessary. Kinetic studies revealed that most of these compounds were low micromolar inhibitors of rabbit muscle glycogen phosphorylase b (RMGPb). The best inhibitor was the 4-methylbenzoyl compound (K-i = 2.3 mu M). Crystallographic analyses of complexes of several of the compounds with RMGPb showed that the analogues exploited, together with water molecules, the available space at the beta-pocket subsite and induced a more extended shift of the 280s loop compared to RMGPb in complex with the unsubstituted benzoyl urea. The results suggest the key role of the water molecules in ligand binding and structure-based ligand design. Molecular docking study of selected inhibitors was done to show the ability of the binding affinity prediction. The binding affinity of the highest scored docked poses was calculated and correlated with experimentally measured K-i values. Results show that correlation is high with the R-squared (R-2) coefficient over 0.9.
Τίτλος πηγής δημοσίευσης:	Bioorganic & Medicinal Chemistry
Τόμος/Κεφάλαιο:	20
Τεύχος:	5
Σελίδες:	1801-1816
Θεματική Κατηγορία:	[EL] Βιολογία (Γενικά)[EN] Biology (General) [EL] Χημεία (Γενικά)[EN] Chemistry (General) [EL] Οργανική χημεία[EN] Organic chemistry [EL] Φαρμακευτική[EN] Pharmacy and materia medica
Λέξεις-Κλειδιά:	N-Acyl-N '-beta-D-glucopyranosyl ureas Glycogen phosphorylase Inhibitor X-ray crystallography Molecular docking Chemistry, Medicinal
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
EU Grant identifier:	info:eu-repo/grantAgreement/EC/FP7/245866 info:eu-repo/grantAgreement/EC/FP7/230146
Κάτοχος πνευματικών δικαιωμάτων:	© 2012 Elsevier Ltd. All rights reserved.
Ηλεκτρονική διεύθυνση περιοδικού (link) :	http://www.elsevier.com/locate/bmc
ΙΒΦΧΒ: αρχειακή συλλογή:	Ινστιτούτο Οργανικής και Φαρμακευτικής Χημείας (ΙΟΦΧ) (έως 2012)
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο