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https://hdl.handle.net/2440/62382
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Type: | Journal article |
Title: | The Pthaladyns : GTP competitive inhibitors of dynamin I and II GTPase derived from virtual screening |
Author: | Odell, L. Howan, D. Gordon, C. Robertson, M. Chau, N. Mariana, A. Whiting, A. Abagyan, R. Daniel, J. Gorgani, N. Robinson, P. McCluskey, A. |
Citation: | Journal of Medicinal Chemistry, 2010; 53(14):5267-5280 |
Publisher: | Amer Chemical Soc |
Issue Date: | 2010 |
ISSN: | 0022-2623 1520-4804 |
Statement of Responsibility: | 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 and Adam McCluskey |
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 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. |
Keywords: | Brain Synaptosomes Humans Dictyostelium Benzoates Phthalimides Dynamins Dynamin I Dynamin II Protozoan Proteins Guanosine Triphosphate Ligands Endocytosis Binding Sites Protein Conformation Protein Structure, Tertiary Structure-Activity Relationship Kinetics Models, Molecular Isoindoles ortho-Aminobenzoates |
Rights: | Copyright © 2010 American Chemical Society |
DOI: | 10.1021/jm100442u |
Published version: | http://dx.doi.org/10.1021/jm100442u |
Appears in Collections: | Aurora harvest Paediatrics publications |
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