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

V. Nagy, Nóra Felföldi, Bálint Kónya, Jean Pierre Praly, T. Docsa, P. 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, L. Somsák

Research output: Article

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 - márc. 1 2012

Fingerprint

Phosphorylase b
Glycogen Phosphorylase
Molecular modeling
Muscle
Urea
Rabbits
Muscles
Kinetics
Ligands
Isocyanates
Acylation
Molecules
Water
Transesterification
Acids

ASJC Scopus subject areas

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

Cite this

N-(4-Substituted-benzoyl)-N′-(β-d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase : Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods. / Nagy, V.; Felföldi, Nóra; Kónya, Bálint; Praly, Jean Pierre; Docsa, T.; Gergely, P.; Chrysina, Evangelia D.; Tiraidis, Costas; Kosmopoulou, Magda N.; Alexacou, Kyra Melinda; Konstantakaki, Maria; Leonidas, Demetres D.; Zographos, Spyros E.; Oikonomakos, Nikos G.; Kozmon, Stanislav; Tvaroška, Igor; Somsák, L.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 5, 01.03.2012, p. 1801-1816.

Research output: Article

Nagy, V, Felföldi, N, Kónya, B, Praly, JP, Docsa, T, Gergely, P, Chrysina, ED, Tiraidis, C, Kosmopoulou, MN, Alexacou, KM, Konstantakaki, M, Leonidas, DD, Zographos, SE, Oikonomakos, NG, 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, vol. 20, no. 5, pp. 1801-1816. https://doi.org/10.1016/j.bmc.2011.12.059
Nagy, V. ; Felföldi, Nóra ; Kónya, Bálint ; Praly, Jean Pierre ; Docsa, T. ; Gergely, P. ; Chrysina, Evangelia D. ; Tiraidis, Costas ; Kosmopoulou, Magda N. ; Alexacou, Kyra Melinda ; Konstantakaki, Maria ; Leonidas, Demetres D. ; Zographos, Spyros E. ; Oikonomakos, Nikos G. ; Kozmon, Stanislav ; Tvaroška, Igor ; Somsák, L. / N-(4-Substituted-benzoyl)-N′-(β-d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase : Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 5. pp. 1801-1816.
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AU - Nagy, V.

AU - Felföldi, Nóra

AU - Kónya, Bálint

AU - Praly, Jean Pierre

AU - Docsa, T.

AU - Gergely, P.

AU - Chrysina, Evangelia D.

AU - Tiraidis, Costas

AU - Kosmopoulou, Magda N.

AU - Alexacou, Kyra Melinda

AU - Konstantakaki, Maria

AU - Leonidas, Demetres D.

AU - Zographos, Spyros E.

AU - Oikonomakos, Nikos G.

AU - Kozmon, Stanislav

AU - Tvaroška, Igor

AU - Somsák, L.

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