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

Vanessa Parmenopoulou, Anastassia L. Kantsadi, Vicky G. Tsirkone, Demetra S.M. Chatzileontiadou, Stella Manta, Spyros E. Zographos, Christina Molfeta, Georgios Archontis, Loranne Agius, Joseph M. Hayes, Demetres D. Leonidas, Dimitri Komiotis

Research output: Contribution to journalArticleResearchpeer-review

16 Citations (Scopus)

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-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 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.

Original languageEnglish
Pages (from-to)4810-4825
Number of pages16
JournalBioorganic & Medicinal Chemistry
Volume22
Issue number17
DOIs
Publication statusPublished - 1 Sep 2014
Externally publishedYes

Keywords

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

Cite this