Show simple item record

dc.contributor.authorArchontis, Georgios Z.en
dc.contributor.authorWatson, K. A.en
dc.contributor.authorXie, Q.en
dc.contributor.authorAndreou, Georgiaen
dc.contributor.authorChrysina, Evangelia D.en
dc.contributor.authorZographos, Spyros E.en
dc.contributor.authorOikonomakos, Nikos G.en
dc.contributor.authorKarplus, M.en
dc.creatorArchontis, Georgios Z.en
dc.creatorWatson, K. A.en
dc.creatorXie, Q.en
dc.creatorAndreou, Georgiaen
dc.creatorChrysina, Evangelia D.en
dc.creatorZographos, Spyros E.en
dc.creatorOikonomakos, Nikos G.en
dc.creatorKarplus, M.en
dc.description.abstractGP catalyzes the phosphorylation of glycogen to Glc-1-P. Because of its fundamental role in the metabolism of glycogen, GP has been the target for a systematic structure-assisted design of inhibitory compounds, which could be of value in the therapeutic treatment of type 2 diabetes mellitus. The most potent catalytic-site inhibitor of GP identified to date is spirohydantoin of glucopyranose (hydan). In this work, we employ MD free energy simulations to calculate the relative binding affinities for GP of hydan and two spirohydantoin analogues, methyl-hydan and n-hydan, in which a hydrogen atom is replaced by a methyl- or amino group, respectively. The results are compared with the experimental relative affinities of these ligands, estimated by kinetic measurements of the ligand inhibition constants. The calculated binding affinity for methyl-hydan (relative to hydan) is 3.75 ± 1.4 kcal/mol, in excellent agreement with the experimental value (3.6 ± 0.2 kcal/mol). For n-hydan, the calculated value is 1.0 ± 1.1 kcal/mol, somewhat smaller than the experimental result (2.3 ± 0.1 kcal/mol). A free energy decomposition analysis shows that hydan makes optimum interactions with protein residues and specific water molecules in the catalytic site. In the other two ligands, structural perturbations of the active site by the additional methyl- or amino group reduce the corresponding binding affinities. The computed binding free energies are sensitive to the preference of a specific water molecule for two well-defined positions in the catalytic site. The behavior of this water is analyzed in detail, and the free energy profile for the translocation of the water between the two positions is evaluated. The results provide insights into the role of water molecules in modulating ligand binding affinities. A comparison of the interactions between a set of ligands and their surrounding groups in X-ray structures is often used in the interpretation of binding free energy differences and in guiding the design of new ligands. For the systems in this work, such an approach fails to estimate the order of relative binding strengths, in contrast to the rigorous free energy treatment. © 2005 Wiley-Liss, Inc.en
dc.sourceProteins: Structure, Function and Geneticsen
dc.subjectComputer Simulationen
dc.subjectpriority journalen
dc.subjectunclassified drugen
dc.subjectbinding affinityen
dc.subjectdrug targetingen
dc.subjectEnzyme Inhibitorsen
dc.subjectnon insulin dependent diabetes mellitusen
dc.subjectStructure-Activity Relationshipen
dc.subjectenzyme inhibitionen
dc.subjectmolecular interactionen
dc.subjectdrug designen
dc.subjectcomplex formationen
dc.subjectMolecular dynamics simulationsen
dc.subjectmolecular dynamicsen
dc.subjectenzyme active siteen
dc.subjectCrystallography, X-Rayen
dc.subjectligand bindingen
dc.subjectenzyme inhibitoren
dc.subjectGlycogen phosphorylaseen
dc.subjectFree energy calculationsen
dc.subjectglycogen metabolismen
dc.subjectglycogen phosphorylase inhibitoren
dc.subjectProtein-ligand interactionsen
dc.subjectSpirohydantoin analoguesen
dc.subjectspirohydantoin derivativeen
dc.titleGlycogen phosphorylase inhibitors: A free energy perturbation analysis of glucopyranose spirohydantoin analoguesen
dc.description.endingpage998Σχολή Θετικών και Εφαρμοσμένων Επιστημών / Faculty of Pure and Applied SciencesΤμήμα Φυσικής / Department of Physics
dc.description.notes<p>Cited By :24</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.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