The Pthaladyns: GTP Competitive Inhibitors of Dynamin I and II GTPase Derived from Virtual Screening
| Autor: | Mark J. Robertson, Ainslie Whiting, Anna Mariana, Adam McCluskey, Nick N. Gorgani, Ruben Abagyan, Christopher P. Gordon, Dian Herlinda Octorina Howan, Luke R. Odell, Ngoc Chau, Phillip J. Robinson, James A. Daniel |
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| Rok vydání: | 2010 |
| Předmět: |
Dynamins
Models Molecular GTP' Protein Conformation Protozoan Proteins Phthalimides GTPase Isoindoles Ligands Endocytosis Benzoates Dynamin II Structure-Activity Relationship Drug Discovery Humans Dictyostelium ortho-Aminobenzoates Binding site Dynamin I Dynamin Synaptic vesicle endocytosis Binding Sites Chemistry Brain Protein Structure Tertiary Kinetics Biochemistry Molecular Medicine Guanosine Triphosphate Synaptosomes Binding domain |
| Zdroj: | Journal of Medicinal Chemistry. 53:5267-5280 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 approximately 170 microM 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 microM dynamin I GTPase inhibitor. Pthaladyn-29 displays borderline selectivity for dynamin I relative to dynamin II ( approximately 5-10 fold). Only pthaladyn-23 (dynamin I IC(50) 17.4 +/- 5.8 microM) was an effective inhibitor of dynamin I mediated synaptic vesicle endocytosis in brain synaptosomes with an IC(50) of 12.9 +/- 5.9 microM. This compound was also competitive with respect to Mg(2+).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. |
| Databáze: | OpenAIRE |
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