The design of potential antidiabetic drugs: experimental investigation of a number of β-D-glucose analogue inhibitors of glycogen phosphorylase

  • N. G. Oikonomakos
  • M. Kontou
  • S. E. Zographos
  • H. S. Tsitoura
  • L. N. Johnson
  • K. A. Watson
  • E. P. Mitchell
  • G. W. J. Fleet
  • J. C. Son
  • C. J. F. Bichard
  • D. D. Leonidas
  • K. R. Acharya
Article

DOI: 10.1007/BF03188920

Cite this article as:
Oikonomakos, N.G., Kontou, M., Zographos, S.E. et al. Eur. J. Drug Metab. Pharmacokinet. (1994) 19: 185. doi:10.1007/BF03188920

Summary

α-D-glucose is a weak inhibitor (Ki=1.7 mM) of glycogen phosphorylase (GP) and acts as physiological regulator of hepatic glycogen metabolism; it binds to GP at the catalytic site and stabilizes the inactive T state of the enzyme promoting the action of protein phosphatase 1 and stimulating glycogen synthase. The three-dimensional structures of T state rabbit muscle GPb and the GPb-α-D-glucose complex have been exploited in the design of better regulators of GP that could shift the balance between glycogen synthesis and glycogen degradation in favour of the former. Close examination of the catalytic site with α-D-glucose bound shows that there is an empty pocket adjacent to the β-1-C position. β-D-glucose is a poorer inhibitor (Ki=7.4 mM) than α-D-glucose, but mutarotaion has prevented the binding of β-D-glucose in T state GP crystals. A series of β-D-glucose analogues has been designed and tested in kinetic and crystallographic experiments. Several compounds have been discovered that have an increased affinity for GP than the parent compound.

Keywords

Glycogen phosphorylase inhibitors α-D-glucose β-D-glucose β-D-glucose analogues 

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • N. G. Oikonomakos
    • 1
  • M. Kontou
    • 1
  • S. E. Zographos
    • 1
  • H. S. Tsitoura
    • 1
  • L. N. Johnson
    • 2
  • K. A. Watson
    • 2
  • E. P. Mitchell
    • 2
  • G. W. J. Fleet
    • 3
  • J. C. Son
    • 3
  • C. J. F. Bichard
    • 3
  • D. D. Leonidas
    • 4
  • K. R. Acharya
    • 4
  1. 1.The National Hellenic Research FoundationAthensGreece
  2. 2.Laboratory of Molecular BiophysicsOxfordUK
  3. 3.Dyson Perrins LaboratoryOxfordUK
  4. 4.School of Biology and BiochemistryBathUK