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dc.contributor.authorBischler, N.de
dc.contributor.authorHayes, Joseph M.en
dc.contributor.authorSkamnaki, Vicky T.en
dc.contributor.authorArchontis, Georgios Z.en
dc.contributor.authorLamprakis, Christosen
dc.contributor.authorSarrou, Josephineen
dc.contributor.authorSkaltsounis, Alexios Leandrosen
dc.contributor.authorZographos, Spyros E.en
dc.contributor.authorOikonomakos, Nikos G.en
dc.creatorBischler, N.de
dc.creatorHayes, Joseph M.en
dc.creatorSkamnaki, Vicky T.en
dc.creatorArchontis, Georgios Z.en
dc.creatorLamprakis, Christosen
dc.creatorSarrou, Josephineen
dc.creatorSkaltsounis, Alexios Leandrosen
dc.creatorZographos, Spyros E.en
dc.creatorOikonomakos, Nikos G.en
dc.date.accessioned2019-12-02T15:30:30Z
dc.date.available2019-12-02T15:30:30Z
dc.date.issued2011
dc.identifier.urihttp://gnosis.library.ucy.ac.cy/handle/7/58717
dc.description.abstractWith an aim toward glycogenolysis control in Type 2 diabetes, we have investigated via kinetic experiments and computation the potential of indirubin (IC 50 > 50 μM), indirubin-3'-oxime (IC 50 = 144 nM), KT5720 (K i = 18.4 nM) and staurosporine (K i = 0.37 nM) as phosphorylase kinase (PhKγtrnc) ATP-binding site inhibitors, with the latter two revealed as potent inhibitors in the low nM range. Because of lack of structural information, we have exploited information from homologous kinase complexes to direct in silico calculations (docking, molecular dynamics, and MM-GBSA) to predict the binding characteristics of the four ligands. All inhibitors are predicted to bind in the same active site area as the ATP adenine ring, with binding dominated by hinge region hydrogen bonds to Asp104:O and Met106:O (all four ligands) and also Met106:NH (for the indirubins). The PhKγtrnc-staurosporine complex has the greatest number of receptor-ligand hydrogen bonds, while for the indirubin-3'-oxime and KT5720 complexes there is an important network of interchanging water molecules bridging inhibitor-enzyme contacts. The MM-GBSA results revealed the source of staurosporine's low nM potency to be favorable electrostatic interactions, while KT5720 has strong van der Waals contributions. KT5720 interacts with the greatest number of protein residues either by direct or 1-water bridged hydrogen bond interactions, and the potential for more selective PhK inhibition based on a KT5720 analogue has been established. Including receptor flexibility in Schrödinger induced-fit docking calculations in most cases correctly predicted the binding modes as compared with the molecular dynamics structuresen
dc.description.abstractthe algorithm was less effective when there were key structural waters bridging receptor-ligand contacts. © 2010 Wiley-Liss, Inc.en
dc.sourceProteins: Structure, Function and Bioinformaticsen
dc.source.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-79551492697&doi=10.1002%2fprot.22890&partnerID=40&md5=23d8ba65590565d2d125dec532da30b1
dc.subjectarticleen
dc.subjectpriority journalen
dc.subjectadenineen
dc.subjectunclassified drugen
dc.subjectIndolesen
dc.subjectBase Sequenceen
dc.subjectMolecular Sequence Dataen
dc.subjectDNA Primersen
dc.subjectPyrrolesen
dc.subjectKineticsen
dc.subjectprotein bindingen
dc.subjectnon insulin dependent diabetes mellitusen
dc.subjectType 2 diabetesen
dc.subjectstatic electricityen
dc.subjectwateren
dc.subjecthydrogen bonden
dc.subjectsequence homologyen
dc.subjectSequence Homology, Amino Aciden
dc.subjectmolecular dockingen
dc.subjectAmino Acid Sequenceen
dc.subjectadenosine triphosphateen
dc.subjectIC 50en
dc.subjectdrug structureen
dc.subjectindirubinen
dc.subjectstaurosporineen
dc.subjectMolecular Dynamics Simulationen
dc.subjectCarbazolesen
dc.subjectDesmond molecular dynamicsen
dc.subjectglycogenolysisen
dc.subjectindirubin 3' oximeen
dc.subjectInduced-fit dockingen
dc.subjectkt 5720en
dc.subjectphosphorylase kinaseen
dc.subjectProtein kinase inhibitorsen
dc.subjectReceptor flexibilityen
dc.titleKinetics, in silico docking, molecular dynamics, and MM-GBSA binding studies on prototype indirubins, KT5720, and staurosporine as phosphorylase kinase ATP-binding site inhibitors: The role of water molecules examineden
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1002/prot.22890
dc.description.volume79
dc.description.issue3
dc.description.startingpage703
dc.description.endingpage719
dc.author.facultyΣχολή Θετικών και Εφαρμοσμένων Επιστημών / Faculty of Pure and Applied Sciences
dc.author.departmentΤμήμα Φυσικής / Department of Physics
dc.type.uhtypeArticleen
dc.description.notes<p>Tradenames: kt 5720en
dc.description.notesCited By :37</p>en
dc.source.abbreviationProteins Struct.Funct.Bioinformaticsen
dc.contributor.orcidZographos, Spyros E. [0000-0001-8455-2352]
dc.contributor.orcidSkaltsounis, Alexios Leandros [0000-0002-8458-3180]
dc.contributor.orcidArchontis, Georgios Z. [0000-0002-7750-8641]
dc.gnosis.orcid0000-0001-8455-2352
dc.gnosis.orcid0000-0002-8458-3180
dc.gnosis.orcid0000-0002-7750-8641


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