Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.13/927810

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Title
The Pthaladyns: GTP competitive inhibitors of Dynamin I and II GTPase derived from virtual screening
Author/Creator
Odell, Luke R.;  Howan, Dian;  Robinson, Phillip J.;  McCluskey, Adam;  Gordon, Christopher P.;  Robertson, Mark J.;  Chau, Ngoc;  Mariana, Anna;  Whiting, Ainslie E.;  Abagyan, Ruben;  Daniel, James A.;  Gorgani, Nick N.
Institution
The University of Newcastle. Faculty of Science & Information Technology, School of Environmental and Life Sciences
Description
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.
Relation
Journal of Medicinal Chemistry Vol. 53, Issue 14, p. 5267-5280
Publisher Link
http://dx.doi.org/10.1021/jm100442u
Date
2010
Publisher
American Chemical Society
Keyword(s)
virtual screening;  pthaladyns;  GTPase;  competitive inhibitors
Resource Type
journal article
Identifier
http://hdl.handle.net/1959.13/927810
Identifier
ISSN:0022-2623
Reviewed
Reviewed
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Subject
"Journal of Medicinal Chemistry"
 
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