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Lookup NU author(s): Professor Loranne Agius
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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-beta-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 mu M while two of them were effective at causing inactivation of GP in rat hepatocytes at low mu M 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. (C) 2014 Elsevier Ltd. All rights reserved.
Author(s): Parmenopoulou V, Kantsadi AL, Tsirkone VG, Chatzileontiadou DSM, Manta S, Zographos SE, Molfeta C, Archontis G, Agius L, Hayes JM, Leonidas DD, Komiotis D
Publication type: Article
Publication status: Published
Journal: Bioorganic & Medicinal Chemistry
Year: 2014
Volume: 22
Issue: 17
Pages: 4810-4825
Print publication date: 01/09/2014
Online publication date: 16/07/2014
Acceptance date: 30/06/2014
ISSN (print): 0968-0896
ISSN (electronic): 1464-3391
Publisher: Pergamon Press
URL: http://dx.doi.org/10.1016/j.bmc.2014.06.058
DOI: 10.1016/j.bmc.2014.06.058
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