Agius L

Archontis G

Chatzileontiadou DSM

Hayes JM

Kantsadi AL

Komiotis D

Leonidas DD

Manta S

Molfeta C

Parmenopoulou V

Tsirkone VG

Zographos SE

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 \u27consensus scoring\u27 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\u27 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

Newcastle University E-Prints

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

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

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