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, K. Czifrák, Béla Szőcs, László Juhász, Éva Bokor, George A. Stravodimos, Anastassia L. Kantsadi, Demetra S.M. Chatzileontiadou, Vassiliki T. Skamnaki, L. Somsák, Demetres D. Leonidas

Research output: Article

7 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 - ápr. 1 2018

Fingerprint

Glycogen Phosphorylase
Liver Glycogen
Catalytic Domain
Imidazoles
X ray crystallography
X Ray Crystallography
Medical problems
Glycogen
Metabolism
Type 2 Diabetes Mellitus
Amines
Glucose
Kinetics
Enzymes
Pharmaceutical Preparations
1,2,4-triazole

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

Cite this

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

In: Bioorganic Chemistry, Vol. 77, 01.04.2018, p. 485-493.

Research output: Article

Kyriakis, E, Solovou, TGA, Kun, S, Czifrák, K, Szőcs, B, Juhász, L, Bokor, É, Stravodimos, GA, Kantsadi, AL, Chatzileontiadou, DSM, Skamnaki, VT, Somsák, L & Leonidas, DD 2018, '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', Bioorganic Chemistry, vol. 77, pp. 485-493. https://doi.org/10.1016/j.bioorg.2018.02.008
Kyriakis, Efthimios ; Solovou, Theodora G.A. ; Kun, Sándor ; Czifrák, K. ; Szőcs, Béla ; Juhász, László ; Bokor, Éva ; Stravodimos, George A. ; Kantsadi, Anastassia L. ; Chatzileontiadou, Demetra S.M. ; Skamnaki, Vassiliki T. ; Somsák, L. ; Leonidas, Demetres D. / 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. In: Bioorganic Chemistry. 2018 ; Vol. 77. pp. 485-493.
@article{7df8c4ecd87d4b569b40c5305cdc0bc6,
title = "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",
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.",
keywords = "1, 2, 4-triazole, C-glucopyranosyl derivative, Diabetes type 2, Glycogen metabolism, Glycogen phosphorylase, Inhibitor, X-ray crystallography",
author = "Efthimios Kyriakis and Solovou, {Theodora G.A.} and S{\'a}ndor Kun and K. Czifr{\'a}k and B{\'e}la Szőcs and L{\'a}szl{\'o} Juh{\'a}sz and {\'E}va Bokor and Stravodimos, {George A.} and Kantsadi, {Anastassia L.} and Chatzileontiadou, {Demetra S.M.} and Skamnaki, {Vassiliki T.} and L. Soms{\'a}k and Leonidas, {Demetres D.}",
year = "2018",
month = "4",
day = "1",
doi = "10.1016/j.bioorg.2018.02.008",
language = "English",
volume = "77",
pages = "485--493",
journal = "Bioorganic Chemistry",
issn = "0045-2068",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - 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

AU - Kyriakis, Efthimios

AU - Solovou, Theodora G.A.

AU - Kun, Sándor

AU - Czifrák, K.

AU - Szőcs, Béla

AU - Juhász, László

AU - Bokor, Éva

AU - Stravodimos, George A.

AU - Kantsadi, Anastassia L.

AU - Chatzileontiadou, Demetra S.M.

AU - Skamnaki, Vassiliki T.

AU - Somsák, L.

AU - Leonidas, Demetres D.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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.

AB - 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.

KW - 1, 2, 4-triazole

KW - C-glucopyranosyl derivative

KW - Diabetes type 2

KW - Glycogen metabolism

KW - Glycogen phosphorylase

KW - Inhibitor

KW - X-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=85042019845&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042019845&partnerID=8YFLogxK

U2 - 10.1016/j.bioorg.2018.02.008

DO - 10.1016/j.bioorg.2018.02.008

M3 - Article

C2 - 29454281

AN - SCOPUS:85042019845

VL - 77

SP - 485

EP - 493

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

SN - 0045-2068

ER -