- Title
- The Pthaladyns: GTP competitive inhibitors of Dynamin I and II GTPase derived from virtual screening
- 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.
- Relation
- Journal of Medicinal Chemistry Vol. 53, Issue 14, p. 5267-5280
- Publisher Link
- http://dx.doi.org/10.1021/jm100442u
- Publisher
- American Chemical Society
- Resource Type
- journal article
- Date
- 2010
- 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.
- Subject
- virtual screening; pthaladyns; GTPase; competitive inhibitors
- Identifier
- http://hdl.handle.net/1959.13/927810
- Identifier
- uon:10254
- Identifier
- ISSN:0022-2623
- Language
- eng
- Full Text
- Reviewed
- Hits: 10942
- Visitors: 10660
- Downloads: 1
| Thumbnail | File | Description | Size | Format |
|---|