Crystallographic studies on two bioisosteric analogues, N-acetyl-β-D-glucopyranosylamine and N-trifluoroacetyl-β-D- glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase

Eleni Anagnostou, Magda N. Kosmopoulou, Evangelia D. Chrysina, Demetres D. Leonidas, Theodoros Hadjiloi, Costantinos Tiraidis, Spyros E. Zographos, Z. Györgydeák, L. Somsák, T. Docsa, P. Gergely, Fragiskos N. Kolisis, Nikos G. Oikonomakos

Research output: Contribution to journalArticle

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Abstract

Structure-based inhibitor design has led to the discovery of a number of potent inhibitors of glycogen phosphorylase b (GPb), N-acyl derivatives of β-d-glucopyranosylamine, that bind at the catalytic site of the enzyme. The first good inhibitor in this class of compounds, N-acetyl-β-d- glucopyranosylamine (NAG) (Ki = 32 μM), has been previously characterized by biochemical, biological and crystallographic experiments at 2.3 Å resolution. Bioisosteric replacement of the acetyl group by trifluoroacetyl group resulted in an inhibitor, N-trifluoroacetyl-β-d- glucopyranosylamine (NFAG), with a Ki = 75 μM. To elucidate the structural basis of its reduced potency, we determined the ligand structure in complex with GPb at 1.8 Å resolution. To compare the binding mode of N-trifluoroacetyl derivative with that of the lead molecule, we also determined the structure of GPb-NAG complex at a higher resolution (1.9 Å). NFAG can be accommodated in the catalytic site of T-state GPb at approximately the same position as that of NAG and stabilize the T-state conformation of the 280s loop by making several favourable contacts to Asn284 of this loop. The difference observed in the Ki values of the two analogues can be interpreted in terms of subtle conformational changes of protein residues and shifts of water molecules in the vicinity of the catalytic site, variations in van der Waals interaction, and desolvation effects.

Original languageEnglish
Pages (from-to)181-189
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number1
DOIs
Publication statusPublished - Jan 1 2006

Fingerprint

Glycogen Phosphorylase
Phosphorylase b
Muscle
Muscles
Catalytic Domain
Derivatives
Molecules
Conformations
glucopyranosylamine
Ligands
Water
Enzymes
Proteins
Experiments

Keywords

  • Bioisosteric inhibition
  • Glycogen phosphorylase
  • N-acetyl-β-D- glucopyranosylamine
  • N-trifluoroacetyl-β-D-glucopyranosylamine
  • Type 2 diabetes
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Crystallographic studies on two bioisosteric analogues, N-acetyl-β-D-glucopyranosylamine and N-trifluoroacetyl-β-D- glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase. / Anagnostou, Eleni; Kosmopoulou, Magda N.; Chrysina, Evangelia D.; Leonidas, Demetres D.; Hadjiloi, Theodoros; Tiraidis, Costantinos; Zographos, Spyros E.; Györgydeák, Z.; Somsák, L.; Docsa, T.; Gergely, P.; Kolisis, Fragiskos N.; Oikonomakos, Nikos G.

In: Bioorganic and Medicinal Chemistry, Vol. 14, No. 1, 01.01.2006, p. 181-189.

Research output: Contribution to journalArticle

Anagnostou, Eleni ; Kosmopoulou, Magda N. ; Chrysina, Evangelia D. ; Leonidas, Demetres D. ; Hadjiloi, Theodoros ; Tiraidis, Costantinos ; Zographos, Spyros E. ; Györgydeák, Z. ; Somsák, L. ; Docsa, T. ; Gergely, P. ; Kolisis, Fragiskos N. ; Oikonomakos, Nikos G. / Crystallographic studies on two bioisosteric analogues, N-acetyl-β-D-glucopyranosylamine and N-trifluoroacetyl-β-D- glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase. In: Bioorganic and Medicinal Chemistry. 2006 ; Vol. 14, No. 1. pp. 181-189.
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AU - Chrysina, Evangelia D.

AU - Leonidas, Demetres D.

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AU - Györgydeák, Z.

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