Development of quinone analogues as dynamin GTPase inhibitors
| Autor: | Mohammed K. Abdel-Hamid, Adam McCluskey, Ainslie Whiting, Kylie A. MacGregor, Ngoc Chau, Phillip J. Robinson, Luke R. Odell |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
GTP'
Stereochemistry Protein Conformation Drug Evaluation Preclinical GTPase Endocytosis Cell Line GTP Phosphohydrolases chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Animals Humans Binding site Enzyme Inhibitors Dynamin I Dynamin Pharmacology Chemistry Organic Chemistry Quinones General Medicine Benzoquinone Naphthoquinone Clathrin Quinone Molecular Docking Simulation |
| Zdroj: | European journal of medicinal chemistry. 85 |
| ISSN: | 1768-3254 |
| Popis: | Virtual screening of the ChemDiversity and ChemBridge compound databases against dynamin I (dynI) GTPase activity identified 2,5-bis-(benzylamino)-1,4-benzoquinone 1 as a 273 ± 106 μM inhibitor. In silico lead optimization and focused library-led synthesis resulted in the development of four discrete benzoquinone/naphthoquinone based compound libraries comprising 54 compounds in total. Sixteen analogues were more potent than lead 1, with 2,5-bis-(4-hydroxyanilino)-1,4-benzoquinone (45) and 2,5-bis(4-carboxyanilino)-1,4-benzoquinone (49) the most active with IC50 values of 11.1 ± 3.6 and 10.6 ± 1.6 μM respectively. Molecular modelling suggested a number of hydrogen bonding and hydrophobic interactions were involved in stabilization of 49 within the dynI GTP binding site. Six of the most active inhibitors were evaluated for potential inhibition of clathrin-mediated endocytosis (CME). Quinone 45 was the most effective CME inhibitor with an IC50(CME) of 36 ± 16 μM. |
| Databáze: | OpenAIRE |
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