Abstract
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.
Original language | English |
---|---|
Pages (from-to) | 5267-5280 |
Number of pages | 14 |
Journal | Journal of Medicinal Chemistry |
Volume | 53 |
Issue number | 14 |
DOIs | |
Publication status | Published - 2010 |