Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/62382
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dc.contributor.authorOdell, L.-
dc.contributor.authorHowan, D.-
dc.contributor.authorGordon, C.-
dc.contributor.authorRobertson, M.-
dc.contributor.authorChau, N.-
dc.contributor.authorMariana, A.-
dc.contributor.authorWhiting, A.-
dc.contributor.authorAbagyan, R.-
dc.contributor.authorDaniel, J.-
dc.contributor.authorGorgani, N.-
dc.contributor.authorRobinson, P.-
dc.contributor.authorMcCluskey, A.-
dc.date.issued2010-
dc.identifier.citationJournal of Medicinal Chemistry, 2010; 53(14):5267-5280-
dc.identifier.issn0022-2623-
dc.identifier.issn1520-4804-
dc.identifier.urihttp://hdl.handle.net/2440/62382-
dc.description.abstractWe report the development of a homology model for the GTP binding domain of human dynamin I based on the corresponding crystal structure of Dictyostelium discoidum dynamin A. Virtual screening identified 2-[(2-biphenyl-2-yl-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonyl)amino]-4-chlorobenzoic acid (1) as a approximately 170 microM potent inhibitor. Homology modeling- and focused library-led synthesis resulted in development of a series of active compounds (the "pthaladyns") with 4-chloro-2-(2-(4-(hydroxymethyl)phenyl)-1,3-dioxoisoindoline-5-carboxamido)benzoic acid (29), a 4.58 +/- 0.06 microM dynamin I GTPase inhibitor. Pthaladyn-29 displays borderline selectivity for dynamin I relative to dynamin II ( approximately 5-10 fold). Only pthaladyn-23 (dynamin I IC(50) 17.4 +/- 5.8 microM) was an effective inhibitor of dynamin I mediated synaptic vesicle endocytosis in brain synaptosomes with an IC(50) of 12.9 +/- 5.9 microM. This compound was also competitive with respect to Mg(2+).GTP. Thus the pthaladyns are the first GTP competitive inhibitors of dynamin I and II GTPase and may be effective new tools for the study of neuronal endocytosis.-
dc.description.statementofresponsibilityLuke R. Odell, Dian Howan, Christopher P. Gordon, Mark J. Robertson, Ngoc Chau, Anna Mariana, Ainslie E. Whiting, Ruben Abagyan, James A. Daniel, Nick N. Gorgani, Phillip J. Robinson and Adam McCluskey-
dc.language.isoen-
dc.publisherAmer Chemical Soc-
dc.rightsCopyright © 2010 American Chemical Society-
dc.subjectBrain-
dc.subjectSynaptosomes-
dc.subjectHumans-
dc.subjectDictyostelium-
dc.subjectBenzoates-
dc.subjectPhthalimides-
dc.subjectDynamins-
dc.subjectDynamin I-
dc.subjectDynamin II-
dc.subjectProtozoan Proteins-
dc.subjectGuanosine Triphosphate-
dc.subjectLigands-
dc.subjectEndocytosis-
dc.subjectBinding Sites-
dc.subjectProtein Conformation-
dc.subjectProtein Structure, Tertiary-
dc.subjectStructure-Activity Relationship-
dc.subjectKinetics-
dc.subjectModels, Molecular-
dc.subjectIsoindoles-
dc.subjectortho-Aminobenzoates-
dc.titleThe Pthaladyns : GTP competitive inhibitors of dynamin I and II GTPase derived from virtual screening-
dc.typeJournal article-
dc.identifier.doi10.1021/jm100442u-
pubs.publication-statusPublished-
Appears in Collections:Aurora harvest
Paediatrics publications

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