N-(4-Substituted-benzoyl)-N′-(β-d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods

Veronika Nagy, Nóra Felföldi, Bálint Kónya, Jean Pierre Praly, Tibor Docsa, Pál Gergely, Evangelia D. Chrysina, Costas Tiraidis, Magda N. Kosmopoulou, Kyra Melinda Alexacou, Maria Konstantakaki, Demetres D. Leonidas, Spyros E. Zographos, Nikos G. Oikonomakos, Stanislav Kozmon, Igor Tvaroška, László Somsák

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

N-(4-Substituted-benzoyl)-N′-(β-d-glucopyranosyl) ureas (substituents: Me, Ph, Cl, OH, OMe, NO2, NH2, COOH, and COOMe) were synthesised by ZnCl2 catalysed acylation of O-peracetylated β-d-glucopyranosyl urea as well as in reactions of O-peracetylated or O-unprotected glucopyranosylamines and acyl-isocyanates. O-deprotections were carried out by base or acid catalysed transesterifications where necessary. Kinetic studies revealed that most of these compounds were low micromolar inhibitors of rabbit muscle glycogen phosphorylase b (RMGPb). The best inhibitor was the 4-methylbenzoyl compound (Ki = 2.3 μM). Crystallographic analyses of complexes of several of the compounds with RMGPb showed that the analogues exploited, together with water molecules, the available space at the β-pocket subsite and induced a more extended shift of the 280s loop compared to RMGPb in complex with the unsubstituted benzoyl urea. The results suggest the key role of the water molecules in ligand binding and structure-based ligand design. Molecular docking study of selected inhibitors was done to show the ability of the binding affinity prediction. The binding affinity of the highest scored docked poses was calculated and correlated with experimentally measured Ki values. Results show that correlation is high with the R-squared (R2) coefficient over 0.9.

Original languageEnglish
Pages (from-to)1801-1816
Number of pages16
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number5
DOIs
Publication statusPublished - Mar 1 2012

Keywords

  • Glycogen phosphorylase
  • Inhibitor
  • Molecular docking
  • N-Acyl-N′-β-d-glucopyranosyl ureas
  • X-ray crystallography

ASJC Scopus subject areas

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

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    Nagy, V., Felföldi, N., Kónya, B., Praly, J. P., Docsa, T., Gergely, P., Chrysina, E. D., Tiraidis, C., Kosmopoulou, M. N., Alexacou, K. M., Konstantakaki, M., Leonidas, D. D., Zographos, S. E., Oikonomakos, N. G., Kozmon, S., Tvaroška, I., & Somsák, L. (2012). N-(4-Substituted-benzoyl)-N′-(β-d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods. Bioorganic and Medicinal Chemistry, 20(5), 1801-1816. https://doi.org/10.1016/j.bmc.2011.12.059