Probing the β-pocket of the active site of human liver glycogen phosphorylase with 3-(C-β-D-glucopyranosyl)-5-(4-substituted-phenyl)-1, 2, 4-triazole inhibitors

Efthimios Kyriakis, Theodora G.A. Solovou, Sándor Kun, Katalin Czifrák, Béla Szőcs, László Juhász, Éva Bokor, George A. Stravodimos, Anastassia L. Kantsadi, Demetra S.M. Chatzileontiadou, Vassiliki T. Skamnaki, László Somsák, Demetres D. Leonidas

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11 Citations (Scopus)

Abstract

Human liver glycogen phosphorylase (hlGP), a key enzyme in glycogen metabolism, is a valid pharmaceutical target for the development of new anti-hyperglycaemic agents for type 2 diabetes. Inhibitor discovery studies have focused on the active site and in particular on glucopyranose based compounds with a β-1 substituent long enough to exploit interactions with a cavity adjacent to the active site, termed the β-pocket. Recently, C-β-D-glucopyranosyl imidazoles and 1, 2, 4-triazoles proved to be the best known glucose derived inhibitors of hlGP. Here we probe the β-pocket by studying the inhibitory effect of six different groups at the para position of 3-(β-D-glucopyranosyl phenyl)-5-phenyl-, 1, 2, 4-triazoles in hlGP by kinetics and X-ray crystallography. The most bioactive compound was the one with an amine substituent to show a Ki value of 0.43 μM. Structural studies have revealed the physicochemical diversity of the β-pocket providing information for future rational inhibitor design studies.

Original languageEnglish
Pages (from-to)485-493
Number of pages9
JournalBioorganic Chemistry
Volume77
DOIs
Publication statusPublished - 1 Apr 2018

Keywords

  • 1, 2, 4-triazole
  • C-glucopyranosyl derivative
  • Diabetes type 2
  • Glycogen metabolism
  • Glycogen phosphorylase
  • Inhibitor
  • X-ray crystallography

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