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The Pthaladyns :
The Pthaladyns : GTP Competitive Inhibitors of Dynamin I and II GTPase Derived from Virtual Screening
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- Odell, Luke R (author)
- Chemistry, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia
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Howan, Dian (author)
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Gordon, Christopher P. (author)
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Robertson, Mark J. (author)
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Chau, Ngoc (author)
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Mariana, Anna (author)
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Whiting, Ainslie E. (author)
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Abagyan, Ruben (author)
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Daniel, James A. (author)
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Gorgani, Nick N. (author)
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Robinson, Phillip J. (author)
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McCluskey, Adam (author)
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(creator_code:org_t)
- 2010-06-24
- 2010
- English.
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:14, s. 5267-5280
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- PHARMACY
- FARMACI
- Organic Pharmaceutical Chemistry
- Organisk farmaceutisk kemi
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Odell, Luke R
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Howan, Dian
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Gordon, Christop ...
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Robertson, Mark ...
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Chau, Ngoc
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Mariana, Anna
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show more...
-
Whiting, Ainslie ...
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Abagyan, Ruben
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Daniel, James A.
-
Gorgani, Nick N.
-
Robinson, Philli ...
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McCluskey, Adam
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmaceutical S ...
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Journal of Medic ...
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Uppsala University