Odell, Luke R., Howan, Dian, Gordon, Christopher P., Robertson, Mark J., Chau, Ngoc, Mariana, Anna, Whiting, Ainslie E., Abagyan, Ruben, Daniel, James A., Gorgani, Nick N., Robinson, Phillip J., and McCluskey, Adam (2010) The Pthaladyns: GTP competitive inhibitors of dynamin I and II GTPase derived from virtual screening. Journal of Medicinal Chemistry, 53 (14). pp. 5267-5280.

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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.

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