Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	The binding of beta-D-glucopyranosyl-thiosemicarbazone derivatives to glycogen phosphorylase: A new class of inhibitors
Δημιουργός/Συγγραφέας:	Alexacou, Kyra-Melinda Tenchiu (Deleanu), Alia-Cristina [EL] Χρυσίνα, Ευαγγελία Δ.[EN] Chrysina, Evangelia D. Charavgi, Maria-Despoina [EL] Κώστας, Ιωάννης Δ.[EN] Kostas, Ioannis D. [EL] Ζωγράφος, Σπύρος Ε.[EN] Zographos, Spyros E. [EL] Οικονομάκος, Νίκος Γ.[EN] Oikonomakos, Nikos G. [EL] Λεωνίδας, Δημήτρης Δ.[EN] Leonidas, Demetres D.
Εκδότης:	Pergamon
Τόπος έκδοσης:	OXFORD
Ημερομηνία:	2010-11-15
Γλώσσα:	Αγγλικά
ISSN:	0968-0896
DOI:	10.1016/j.bmc.2010.09.039
Περίληψη:	Glycogen phosphorylase (GP) is a promising target for the treatment of type 2 diabetes. In the process of structure based drug design for GP, a group of 15 aromatic aldehyde 4-(beta-D-glucopyranosyl) thiosemicarbazones have been synthesized and evaluated as inhibitors of rabbit muscle glycogen phosphorylase b (GPb) by kinetic studies. These compounds are competitive inhibitors of GPb with respect to alpha-D-glucose- 1-phosphate with IC(50) values ranging from 5.7 to 524.3 mu M. In order to elucidate the structural basis of their inhibition, the crystal structures of these compounds in complex with GPb at 1.95-2.23 angstrom resolution were determined. The complex structures reveal that the inhibitors are accommodated at the catalytic site with the glucopyranosyl moiety at approximately the same position as alpha-D-glucose and stabilize the T conformation of the 280s loop. The thiosemicarbazone part of the studied glucosyl thiosemicarbazones possess a moiety derived from substituted benzaldehydes with NO(2), F, Cl, Br, OH, OMe, CF(3), or Me at the ortho-, meta- or para-position of the aromatic ring as well as a moiety derived from 4-pyridinecarboxaldehyde. These fit tightly into the beta-pocket, a side channel from the catalytic site with no access to the bulk solvent. The differences in their inhibitory potency can be interpreted in terms of variations in the interactions of the aldehyde-derived moiety with protein residues in the beta-pocket. In addition, 14 out of the 15 studied inhibitors were found bound at the new allosteric site of the enzyme.
Τίτλος πηγής δημοσίευσης:	Bioorganic & Medicinal Chemistry
Τόμος/Κεφάλαιο:	18
Τεύχος:	22
Σελίδες:	7911-7922
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:	Type 2 diabetes Glycogen phosphorylase Glucopyranosyl-thiosemicarbazones Inhibition X-ray crystallography 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) :	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