Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Structure based inhibitor design targeting glycogen phosphorylase b. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-d-glucopyranosylamines
Δημιουργός/Συγγραφέας:	Parmenopoulou V. Kantsadi A.L. Tsirkone V.G. Chatzileontiadou D.S.M. Manta S. [EL] Ζωγράφος, Σπύρος Ε.[EN] Zographos, Spyros E. Molfeta C. Archontis G. Agius L. Hayes J.M. [EL] Λεωνίδας, Δημήτρης Δ.[EN] Leonidas, Demetres D. Komiotis D.
Εκδότης:	Elsevier Ltd
Ημερομηνία:	2014
Γλώσσα:	Αγγλικά
ISSN:	0968-0896
DOI:	10.1016/j.bmc.2014.06.058
Άλλο:	PubMed ID: 25092521
Περίληψη:	Glycogen phosphorylase (GP) is a validated target for the development of new type 2 diabetes treatments. Exploiting the Zinc docking database, we report the in silico screening of 1888 N-acyl-β-d-glucopyranosylamines putative GP inhibitors differing only in their R groups. CombiGlide and GOLD docking programs with different scoring functions were employed with the best performing methods combined in a 'consensus scoring' approach to ranking of ligand binding affinities for the active site. Six selected candidates from the screening were then synthesized and their inhibitory potency was assessed both in vitro and ex vivo. Their inhibition constants' values, in vitro, ranged from 5 to 377 μM while two of them were effective at causing inactivation of GP in rat hepatocytes at low μM concentrations. The crystal structures of GP in complex with the inhibitors were defined and provided the structural basis for their inhibitory potency and data for further structure based design of more potent inhibitors.
Τίτλος πηγής δημοσίευσης:	Bioorganic and Medicinal Chemistry
Τόμος/Κεφάλαιο:	22
Τεύχος:	17
Σελίδες:	4810-4825
Θεματική Κατηγορία:	[EL] Βιολογία (Γενικά)[EN] Biology (General) [EL] Χημεία (Γενικά)[EN] Chemistry (General)
Λέξεις-Κλειδιά:	Consensus scoring Diabetes type 2 Glycogen metabolism Glycogen phosphorylase Inhibitor N-Acyl-β-d-glucopyranosylamines Virtual screening X-ray crystallography
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© 2014 Elsevier Ltd. All rights reserved.
Όροι και προϋποθέσεις δικαιωμάτων:	All Open Access, Green
Σημειώσεις:	Seventh Framework Programme, FP7: 283570; European Social Fund, ESF; Seventh Framework Programme, FP7. This Project was implemented under the “ARISTEIA” Action of the ‘Operational Programme Education and Lifelong Learning’ and is co-funded by the European Social Fund (ESF) and National Resources. This work was supported in part by the Postgraduate Programmes ‘Biotechnology-Quality assessment in Nutrition and the Environment’, ‘Application of Molecular Biology-Molecular Genetics-Molecular Markers’, Department of Biochemistry and Biotechnology, University of Thessaly. Work at the Synchrotron Radiation Sources, MAX-lab, Lund, Sweden and EMBL Hamburg Outstation, Germany, was supported from the European Community’s Seventh Framework Programme (FP7/2007-2013) under BioStruct-X (Grant agreement N°283570).
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο