The Pthaladyns: GTP Competitive Inhibitors of Dynamin I and II GTPase Derived from Virtual Screening

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• 作者：Luke R. Odell ; Dian Howan ; Christopher P. Gordon ; Mark J. Robertson ; Ngoc Chau ; Anna Mariana ; Ainslie E. Whiting ; Ruben Abagyan ; James A. Daniel ; Nick N. Gorgani ; Phillip J. Robinson ; Adam McCluskey
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：July 22, 2010
• 年：2010
• 卷：53
• 期：14
• 页码：5267-5280
• 全文大小：1120K
• 年卷期：v.53,no.14(July 22, 2010)
• ISSN：1520-4804

文摘

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.