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The Pthaladyns: GTP Competitive Inhibitors of Dynamin I and II GTPase Derived from Virtual Screening
Chemistry, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
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2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 14, 5267-5280 p.Article in journal (Refereed) Published
Abstract [en]

We 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 170 μM 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 μM dynamin I GTPase inhibitor. Pthaladyn-29 displays borderline selectivity for dynamin I relative to dynamin II (5−10 fold). Only pthaladyn-23 (dynamin I IC50 17.4 ± 5.8 μM) was an effective inhibitor of dynamin I mediated synaptic vesicle endocytosis in brain synaptosomes with an IC50 of 12.9 ± 5.9 μM. This compound was also competitive with respect to Mg2+·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.

Place, publisher, year, edition, pages
2010. Vol. 53, no 14, 5267-5280 p.
National Category
Pharmaceutical Sciences
Research subject
Organic Pharmaceutical Chemistry
URN: urn:nbn:se:uu:diva-142213DOI: 10.1021/jm100442uPubMedID: 20575553OAI: oai:DiVA.org:uu-142213DiVA: diva2:387114
Available from: 2011-01-13 Created: 2011-01-13 Last updated: 2013-11-22Bibliographically approved

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Odell, Luke R
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