Parmenopoulou, Vanessa, Kantsadi, Anastassia L., Tsirkone, Vicky G., Chatzileontiadou, Demetra S.M., Manta, Stella, Zographos, Spyros E., Molfeta, Christina, Archontis, Georgios, Agius, Loranne, Hayes, Joseph M., Leonidas, Demetres D. and Komiotis, Dimitri (2014) Structure based inhibitor design targeting glycogen phosphorylase b. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-d-glucopyranosylamines. Bioorganic & Medicinal Chemistry, 22 (17). pp. 4810-4825. ISSN 09680896
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Official URL: http://dx.doi.org/10.1016/j.bmc.2014.06.058
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 β- D-glucopyranose-NH-CO-R 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.
|Uncontrolled Keywords (separate with ;):||glycogen metabolism; diabetes type 2; inhibitor; glycogen phosphorylase; X-ray crystallography; glucopyranosyl amides; virtual screening, consensus scoring|
|Subjects:||Physical sciences > Chemistry|
B - Subjects allied to medicine > B230 - Pharmacy
|Schools:||Faculty of Science and Technology > School of Physical Sciences and Computing|
|Deposited By:||T Richard Hull|
|Deposited On:||25 Feb 2016 12:13|
|Last Modified:||24 Oct 2016 06:49|
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