Please use this identifier to cite or link to this item:
|Scopus||Web of Science®||Altmetric|
|Title:||The Pthaladyns : GTP competitive inhibitors of dynamin I and II GTPase derived from virtual screening|
|Citation:||Journal of Medicinal Chemistry, 2010; 53(14):5267-5280|
|Publisher:||Amer Chemical Soc|
|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|
|Appears in Collections:||Paediatrics publications|
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.