title: The pthaladyns: GTP competitive inhibitors of dynamin I and II GTPase derived from virtual screening.
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.
authors.affiliation: Chemistry, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
authors.forename: Luke R
authors.initials: LR
authors.lastname: Odell
authors.forename: Dian
authors.initials: D
authors.lastname: Howan
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Gordon
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Robertson
authors.forename: Ngoc
authors.initials: N
authors.lastname: Chau
authors.forename: Anna
authors.initials: A
authors.lastname: Mariana
authors.forename: Ainslie E
authors.initials: AE
authors.lastname: Whiting
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: James A
authors.initials: JA
authors.lastname: Daniel
authors.forename: Nick N
authors.initials: NN
authors.lastname: Gorgani
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Robinson
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
mesh_terms: D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004023:Dictyostelium; D034284:Dynamin I / Q000037:antagonists & inhibitors*; D034285:Dynamin II / Q000037:antagonists & inhibitors*; D034281:Dynamins / Q000737:chemistry*; D004705:Endocytosis / Q000187:drug effects; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D010797:Phthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C551621:4-chloro-2-(2-(4-(hydroxymethyl)phenyl)-1,3-dioxoisoindoline-5-carboxamido)benzoic acid; D001565:Benzoates; D054833:Isoindoles; D008024:Ligands; D010797:Phthalimides; D015800:Protozoan Proteins; D062367:ortho-Aminobenzoates; D006160:Guanosine Triphosphate; D034284:Dynamin I; D034285:Dynamin II; D034281:Dynamins; C117420:dynamin A protein, Dictyostelium discoideum