Nanomolar Inhibitors of Glycogen Phosphorylase Based on β- D -Glucosaminyl Heterocycles: A Combined Synthetic, Enzyme Kinetic, and Protein Crystallography Study

Éva Bokor, Efthimios Kyriakis, Theodora G.A. Solovou, Csenge Koppány, Anastassia L. Kantsadi, Katalin E. Szabó, Andrea Szakács, George A. Stravodimos, T. Docsa, Vassiliki T. Skamnaki, Spyros E. Zographos, P. Gergely, Demetres D. Leonidas, L. Somsák

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Abstract

Aryl substituted 1-(β-d-glucosaminyl)-1,2,3-triazoles as well as C-β-d-glucosaminyl 1,2,4-triazoles and imidazoles were synthesized and tested as inhibitors against muscle and liver isoforms of glycogen phosphorylase (GP). While the N-β-d-glucosaminyl 1,2,3-triazoles showed weak or no inhibition, the C-β-d-glucosaminyl derivatives had potent activity, and the best inhibitor was the 2-(β-d-glucosaminyl)-4(5)-(2-naphthyl)-imidazole with a Ki value of 143 nM against human liver GPa. An X-ray crystallography study of the rabbit muscle GPb inhibitor complexes revealed structural features of the strong binding and offered an explanation for the differences in inhibitory potency between glucosyl and glucosaminyl derivatives and also for the differences between imidazole and 1,2,4-triazole analogues.

Original languageEnglish
Pages (from-to)9251-9262
Number of pages12
JournalJournal of Medicinal Chemistry
Volume60
Issue number22
DOIs
Publication statusPublished - Nov 22 2017

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Bokor, É., Kyriakis, E., Solovou, T. G. A., Koppány, C., Kantsadi, A. L., Szabó, K. E., Szakács, A., Stravodimos, G. A., Docsa, T., Skamnaki, V. T., Zographos, S. E., Gergely, P., Leonidas, D. D., & Somsák, L. (2017). Nanomolar Inhibitors of Glycogen Phosphorylase Based on β- D -Glucosaminyl Heterocycles: A Combined Synthetic, Enzyme Kinetic, and Protein Crystallography Study. Journal of Medicinal Chemistry, 60(22), 9251-9262. https://doi.org/10.1021/acs.jmedchem.7b01056