The Pthaladyns: GTP competitive inhibitors of dynamin I and II GTPase derived from virtual screening

Odell, Luke R., Howan, Dian, Gordon, Christopher P., Robertson, Mark J., Chau, Ngoc, Mariana, Anna, Whiting, Ainslie E., Abagyan, Ruben, Daniel, James A., Gorgani, Nick N., Robinson, Phillip J., and McCluskey, Adam (2010) The Pthaladyns: GTP competitive inhibitors of dynamin I and II GTPase derived from virtual screening. Journal of Medicinal Chemistry, 53 (14). pp. 5267-5280.

[img] PDF (Published Version) - Published Version
Restricted to Repository staff only

View at Publisher Website: http://dx.doi.org/10.1021/jm100442u
33


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 ∼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.

Item ID: 36826
Item Type: Article (Research - C1)
ISSN: 1520-4804
Funders: National Health and Medical Research Council (NHMRC), Children's Medical Research Institute (CMRI), University of Newcastle (UoN), AusAid
Date Deposited: 10 Dec 2014 07:31
FoR Codes: 03 CHEMICAL SCIENCES > 0305 Organic Chemistry > 030503 Organic Chemical Synthesis @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 100%
More Statistics

Actions (Repository Staff Only)

Item Control Page Item Control Page