Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	1-(3-Deoxy-3-fluoro-beta-D-glucopyranosyl) pyrimidine derivatives as inhibitors of glycogen phosphorylase b: Kinetic, crystallographic and modelling studies
Δημιουργός/Συγγραφέας:	Tsirkone, Vicky G. Tsoukala, Evangelia Lamprakis, Christos Manta, Stella Hayes, Joseph M. Skamnaki, Vicky T. Drakou, Christina [EL] Ζωγράφος, Σπύρος Ε.[EN] Zographos, Spyros E. Komiotis, Dimitri [EL] Λεωνίδας, Δημήτρης Δ.[EN] Leonidas, Demetres D.
Εκδότης:	Pergamon
Τόπος έκδοσης:	OXFORD
Ημερομηνία:	2010-05-15
Γλώσσα:	Αγγλικά
ISSN:	0968-0896
DOI:	10.1016/j.bmc.2010.04.004
Περίληψη:	Design of inhibitors of glycogen phosphorylase (GP) with pharmaceutical applications in improving glycaemic control in type 2 diabetes is a promising therapeutic strategy. The catalytic site of muscle glycogen phosphorylase b (GPb) has been probed with five deoxy-fluro-glucose derivatives. These inhibitors had fluorine instead of hydroxyl at the 30 position of the glucose moiety and a variety of pyrimidine derivatives at the 10 position. The best of this carbohydrate-based family of five inhibitors displays a Ki value of 46 mu M. To elucidate the mechanism of inhibition for these compounds, the crystal structures of GPb in complex with each ligand were determined and refined to high resolution. The structures demonstrated that the inhibitors bind preferentially at the catalytic site and promote the less active T state conformation of the enzyme by making several favorable contacts with residues of the 280s loop. Fluorine is engaged in hydrogen bond interactions but does not improve glucose potency. The pyrimidine groups are located between residues 284-286 of the 280s loop, Ala383 of the 380s loop, and His341 of the beta-pocket. These interactions appear important in stabilizing the inactive quaternary T state of the enzyme. As a follow up to recent computations performed on beta-D-glucose pyrimidine derivatives, tautomeric forms of ligands 1-5 were considered as potential binding states. Using Glide-XP docking and QM/MM calculations, the ligands 2 and 5 are predicted to bind in different tautomeric states in their respective GPb complexes. Also, using alpha-D-glucose as a benchmark model, a series of substitutions for glucose OH at the 30 ( equatorial) position were investigated for their potential to improve the binding affinity of glucose-based GPb catalytic site inhibitors. Glide-XP and quantum mechanics polarized ligand (QPLD-SP/XP) docking calculations revealed favorable binding at this position to be dominated by hydrogen bond contributions; none of the substitutions ( including fluorine) out-performed the native -OH substituent which can act both as hydrogen bond donor and acceptor. The structural analyses of these compounds can be exploited towards the development of better inhibitors.
Τίτλος πηγής δημοσίευσης:	Bioorganic & Medicinal Chemistry
Τόμος/Κεφάλαιο:	18
Τεύχος:	10
Σελίδες:	3413-3425
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:	Glycogen phosphorylase Diabetes X-ray crystallography Structure-assisted inhibitor design Glide docking Quantum mechanics polarized ligand (QPLD) docking Tautomers Chemistry, Medicinal
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
EU Grant identifier:	info:eu-repo/grantAgreement/EC/FP7/230146
Κάτοχος πνευματικών δικαιωμάτων:	© 2010 Elsevier Ltd. All rights reserved.
Ηλεκτρονική διεύθυνση περιοδικού (link) :	https://doi.org/10.1016/j.bmc.2010.04.004
ΙΒΦΧΒ: αρχειακή συλλογή:	Ινστιτούτο Οργανικής και Φαρμακευτικής Χημείας (ΙΟΦΧ) (έως 2012)
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο