The pthaladyns: GTP competitive inhibitors of dynamin I and II GTPase derived from virtual screening - PubMed (original) (raw)

. 2010 Jul 22;53(14):5267-80.

doi: 10.1021/jm100442u.

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, Adam McCluskey

Affiliations

• PMID: 20575553
• DOI: 10.1021/jm100442u

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

Luke R Odell et al. J Med Chem. 2010.

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.

PubMed Disclaimer

Similar articles

• Iminochromene inhibitors of dynamins I and II GTPase activity and endocytosis.
  Hill TA, Mariana A, Gordon CP, Odell LR, Robertson MJ, McGeachie AB, Chau N, Daniel JA, Gorgani NN, Robinson PJ, McCluskey A. Hill TA, et al. J Med Chem. 2010 May 27;53(10):4094-102. doi: 10.1021/jm100119c. J Med Chem. 2010. PMID: 20426422
• Inhibition of dynamin mediated endocytosis by the dynoles--synthesis and functional activity of a family of indoles.
  Hill TA, Gordon CP, McGeachie AB, Venn-Brown B, Odell LR, Chau N, Quan A, Mariana A, Sakoff JA, Chircop M, Robinson PJ, McCluskey A. Hill TA, et al. J Med Chem. 2009 Jun 25;52(12):3762-73. doi: 10.1021/jm900036m. J Med Chem. 2009. PMID: 19459681
• Increased GTP-binding to dynamin II does not stimulate receptor-mediated endocytosis.
  Jeong MJ, Yoo J, Lee SS, Lee KI, Cho A, Kwon BM, Moon MJ, Park YM, Han MY. Jeong MJ, et al. Biochem Biophys Res Commun. 2001 Apr 27;283(1):136-42. doi: 10.1006/bbrc.2001.4681. Biochem Biophys Res Commun. 2001. PMID: 11322780
• Oligomerization and kinetic mechanism of the dynamin GTPase.
  Eccleston JF, Binns DD, Davis CT, Albanesi JP, Jameson DM. Eccleston JF, et al. Eur Biophys J. 2002 Jul;31(4):275-82. doi: 10.1007/s00249-002-0226-2. Epub 2002 Jun 18. Eur Biophys J. 2002. PMID: 12122474 Review.
• Dynamin GTPase, a force-generating molecular switch.
  Warnock DE, Schmid SL. Warnock DE, et al. Bioessays. 1996 Nov;18(11):885-93. doi: 10.1002/bies.950181107. Bioessays. 1996. PMID: 8939066 Review.

Cited by

• Software and resources for computational medicinal chemistry.
  Liao C, Sitzmann M, Pugliese A, Nicklaus MC. Liao C, et al. Future Med Chem. 2011 Jun;3(8):1057-85. doi: 10.4155/fmc.11.63. Future Med Chem. 2011. PMID: 21707404 Free PMC article. Review.
• The Rhodadyns, a New Class of Small Molecule Inhibitors of Dynamin GTPase Activity.
  Robertson MJ, Hadzic G, Ambrus J, Pomè DY, Hyde E, Whiting A, Mariana A, von Kleist L, Chau N, Haucke V, Robinson PJ, McCluskey A. Robertson MJ, et al. ACS Med Chem Lett. 2012 Mar 26;3(5):352-6. doi: 10.1021/ml200284s. eCollection 2012 May 10. ACS Med Chem Lett. 2012. PMID: 24900478 Free PMC article.
• Sorting nexin 9 recruits clathrin heavy chain to the mitotic spindle for chromosome alignment and segregation.
  Ma MP, Robinson PJ, Chircop M. Ma MP, et al. PLoS One. 2013 Jul 5;8(7):e68387. doi: 10.1371/journal.pone.0068387. Print 2013. PLoS One. 2013. PMID: 23861900 Free PMC article.
• From laptop to benchtop to bedside: structure-based drug design on protein targets.
  Chen L, Morrow JK, Tran HT, Phatak SS, Du-Cuny L, Zhang S. Chen L, et al. Curr Pharm Des. 2012;18(9):1217-39. doi: 10.2174/138161212799436386. Curr Pharm Des. 2012. PMID: 22316152 Free PMC article. Review.
• Synthesis of Phthaladyn-29 and Naphthalimide-10, GTP Site Directed Dynamin GTPase Inhibitors.
  Russell CC, Prichard KL, O'Brien NS, McCluskey A, Robinson PJ, Baker JR. Russell CC, et al. Methods Mol Biol. 2022;2417:239-258. doi: 10.1007/978-1-0716-1916-2_18. Methods Mol Biol. 2022. PMID: 35099804

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • American Chemical Society

• Other Literature Sources

  • The Lens - Patent Citations Database

• Chemical Information

  • BindingDB