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

Bioorg Med Chem. 2014 Sep 1;22(17):4810-25. doi: 10.1016/j.bmc.2014.06.058. Epub 2014 Jul 16.


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 377μM 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.

Keywords: Consensus scoring; Diabetes type 2; Glycogen metabolism; Glycogen phosphorylase; Inhibitor; N-Acyl-β-d-glucopyranosylamines; Virtual screening; X-ray crystallography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glucosamine / analogs & derivatives*
  • Glucosamine / chemical synthesis
  • Glucosamine / chemistry
  • Glucosamine / pharmacology
  • Glycogen Phosphorylase, Liver Form / antagonists & inhibitors*
  • Glycogen Phosphorylase, Liver Form / metabolism
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Glycogen Phosphorylase, Liver Form
  • Glucosamine