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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
Statement of
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
Dynamin I
Dynamin II
Protozoan Proteins
Guanosine Triphosphate
Binding Sites
Protein Conformation
Protein Structure, Tertiary
Structure-Activity Relationship
Models, Molecular
Rights: Copyright © 2010 American Chemical Society
DOI: 10.1021/jm100442u
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