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Structure based inhibitor design targeting glycogen phosphorylase b. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-ᴅ-glucopyranosylamines

Lookup NU author(s): Professor Loranne Agius

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Abstract

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.


Publication metadata

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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