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

Autor: Magda Kosmopoulou, Pál Gergely, Tibor Docsa, Veronika Nagy, László Somsák, Evangelia D. Chrysina, Igor Tvaroška, Bálint Kónya, Spyros E. Zographos, K.-M. Alexacou, Jean Pierre Praly, C. Tiraidis, Nóra Felföldi, Demetres D. Leonidas, Maria Konstantakaki, Nikos G. Oikonomakos, Stanislav Kozmon
Přispěvatelé: Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of medical chemistry, University of Debrecen, Institute of Chemistry, Slovak Academy of Science [Bratislava] (SAS), Institute of Chemistry, Centre for Glycomics
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Zdroj: Bioorganic and Medicinal Chemistry
Bioorganic and Medicinal Chemistry, Elsevier, 2012, 20 (5), pp.1801-16. ⟨10.1016/j.bmc.2011.12.059⟩
ISSN: 0968-0896
1464-3391
DOI: 10.1016/j.bmc.2011.12.059⟩
Popis: International audience; N-(4-Substituted-benzoyl)-N'-(β-d-glucopyranosyl) ureas (substituents: Me, Ph, Cl, OH, OMe, NO(2), NH(2), COOH, and COOMe) were synthesised by ZnCl(2) 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 (K(i)=2.3μM). 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 K(i) values. Results show that correlation is high with the R-squared (R(2)) coefficient over 0.9.
Databáze: OpenAIRE
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