Show simple item record

dc.contributor.authorAlexacou, Kyra Melindaen
dc.contributor.authorHayes, Joseph M.en
dc.contributor.authorTiraidis, Costasen
dc.contributor.authorZographos, Spyros E.en
dc.contributor.authorLeonidas, Demetres D.en
dc.contributor.authorChrysina, Evangelia D.en
dc.contributor.authorArchontis, Georgios Z.en
dc.contributor.authorOikonomakos, Nikos G.en
dc.contributor.authorPaul, J. V.en
dc.contributor.authorVarghese, B.en
dc.contributor.authorLoganathan, D.en
dc.creatorAlexacou, Kyra Melindaen
dc.creatorHayes, Joseph M.en
dc.creatorTiraidis, Costasen
dc.creatorZographos, Spyros E.en
dc.creatorLeonidas, Demetres D.en
dc.creatorChrysina, Evangelia D.en
dc.creatorArchontis, Georgios Z.en
dc.creatorOikonomakos, Nikos G.en
dc.creatorPaul, J. V.en
dc.creatorVarghese, B.en
dc.creatorLoganathan, D.en
dc.description.abstract4-Phenyl-N-(β-D-glucopyranosyl)-1H-1,2,3-triazole-1-acetamide (glucosyltriazolylacetamide) has been studied in kinetic and crystallographic experiments with glycogen phosphorylase b (GPb), in an effort to utilize its potential as a lead for the design of potent antihyperglycaemic agents. Docking and molecular dynamics (MD) calculations have been used to monitor more closely the binding modes in operation and compare the results with experiment. Kinetic experiments in the direction of glycogen synthesis showed that glucosyltriazolylacetamide is a better inhibitor (Ki = 0.18 mM) than the parent compound α-D-glucose (Ki = 1.7 mM) or β-D-glucose (Ki = 7.4 mM) but less potent inhibitor than the lead compound N-acetyl-β-D-glucopyranosylamine (Ki = 32 μM). To elucidate the molecular basis underlying the inhibition of the newly identified compound, we determined the structure of GPb in complex with glucosyltriazolylacetamide at 100 K to 1.88 Å resolution, and the structure of the compound in the free form. Glucosyltriazolylacetamide is accommodated in the catalytic site of the enzyme and the glucopyranose interacts in a manner similar to that observed in the GPb-α-D-glucose complex, while the substituent group in the β-posi tion of the C1 atom makes additional hydrogen bonding and van der Waals interactions to the protein. A bifurcated donor type hydrogen bonding involving O3H, N3, and N4 is seen as an important structural motif strengthening the binding of glucosyltriazolylacetamide with GP which necessitated change in the torsion about C8-N2 bond by about 62° going from its free to the complex form with GPb. On binding to GP, glucosyltriazolylacetamide induces significant conformational changes in the vicinity of this site. Specifically, the 280s loop (residues 282-288) shifts 0.7 to 3.1 Å (CA atoms) to accommodate glucosyltriazolylacetamide. These conformational changes do not lead to increased contacts between the inhibitor and the protein that would improve ligand binding compared with the lead compound. In the molecular modeling calculations, the GOLD docking runs with and without the crystallographic ordered cavity waters using the GoldScore scoring function, and without cavity waters using the ChemScore scoring function successfully reproduced the crystallographic binding conformation. However, the GLIDE docking calculations both with (GLIDE XP) and without (GLIDE SP and XP) the cavity water molecules were, impressively, further able to accurately reproduce the finer details of the GPb-glucosyltriazolylacetamide complex structure. The importance of cavity waters in flexible receptor MD calculations compared to "rigid" (docking) is analyzed and highlighted, while in the MD itself very little conformational flexibility of the glucosyltriazolylacetamide ligand was observed over the time scale of the simulations. © 2007 Wiley-Liss, Inc.en
dc.sourceProteins: Structure, Function and Geneticsen
dc.subjectpriority journalen
dc.subjectComputational Biologyen
dc.subjectprotein analysisen
dc.subjectunclassified drugen
dc.subjectEnzyme Inhibitorsen
dc.subjectprotein bindingen
dc.subjectType 2 diabetesen
dc.subjectprotein motifen
dc.subjectMolecular dynamicsen
dc.subjectcrystal structureen
dc.subjectstructure analysisen
dc.subjectX ray crystallographyen
dc.subjectchemical bonden
dc.subjecthydrogen bonden
dc.subjectprotein conformationen
dc.subjectprotein protein interactionen
dc.subjectmolecular dockingen
dc.subjectmolecular modelen
dc.subjectprotein structureen
dc.subjectBinding Sitesen
dc.subjectenzyme active siteen
dc.subjectCrystallography, X-Rayen
dc.subjectconformational transitionen
dc.subjectenzyme bindingen
dc.subjectligand bindingen
dc.subject4 phenyl n beta dextro glucopyanosyl 1h 1,2,3 triazole 1 acetamideen
dc.subjectalpha glucoseen
dc.subjectenzyme inhibitoren
dc.subjectenzyme kineticsen
dc.subjectglucose derivativeen
dc.subjectGlycogen phosphorylaseen
dc.subjectglycogen synthesisen
dc.subjectn acetyl beta dextro glucopyranosylamineen
dc.subjectn benzoyl n beta dextro glucopyranosyl ureaen
dc.subjectX-ray crystallographyen
dc.titleCrystallographic and computational studies on 4-phenyl-N-(β-D- glucopyranosyl)-1H-1,2, 3-triazole-1-acetamide, an inhibitor of glycogen phosphorylase: Comparison with α-D-glucose, N-acetyl-β-D- glucopyranosylamine and N-benzoyl-N′-β-D-glucopyranosyl urea bindingen
dc.description.endingpage1323Σχολή Θετικών και Εφαρμοσμένων Επιστημών / Faculty of Pure and Applied SciencesΤμήμα Φυσικής / Department of Physics
dc.description.notes<p>Cited By :27</p>en
dc.source.abbreviationProteins Struct.Funct.Genet.en
dc.contributor.orcidZographos, Spyros E. [0000-0001-8455-2352]
dc.contributor.orcidChrysina, Evangelia D. [0000-0001-8147-9030]
dc.contributor.orcidLeonidas, Demetres D. [0000-0002-3874-2523]
dc.contributor.orcidArchontis, Georgios Z. [0000-0002-7750-8641]

Files in this item


There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record