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Pyrimidine-Based Inhibitors of Dynamin I GTPase Activity: Competitive Inhibition at the Pleckstrin Homology Domain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Univ Newcastle, Sch Environm & Life Sci, Chem, Callaghan, NSW 2308, Australia..
Univ Newcastle, Sch Environm & Life Sci, Chem, Callaghan, NSW 2308, Australia.;Assiut Univ, Fac Pharm, Dept Med Chem, Assiut 71526, Egypt..
Univ Newcastle, Sch Environm & Life Sci, Chem, Callaghan, NSW 2308, Australia..
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2017 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 1, 349-361 p.Article in journal (Refereed) Published
Abstract [en]

The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds, were reported to disrupt clynamin localization to the plasina membrane via the PH domain and,iniplicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC50 = 10.6 +/- 1.3 to 1.6 +/- 0.3 mu M) and CME (IC50(CME) = 65.9 +/- 7.7 to 17 +/- 1.1 mM), which makes this. series among The more potent inhibitors of dynamin.and CME yet reported. In:CME and growth inhibition cell-based assays, the data obtained Was consistent with dynamin inhibition. CEREP ExpresS profiling identified off-.target effects at the cholecystokinin, dopamine D-2, histamine H-1 and H-2, melanocortin, rnelatonin, muscarir* M-1 and M-3 neurokinin, opioid KOP and serotonin receptors.

Place, publisher, year, edition, pages
2017. Vol. 60, no 1, 349-361 p.
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-316033DOI: 10.1021/acs.jmedchem.6b01422ISI: 000392035100023PubMedID: 27997171OAI: oai:DiVA.org:uu-316033DiVA: diva2:1076880
Funder
Australian Research Council
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2017-02-24Bibliographically approved

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