Highly Selective Phosphatidylinositol 4-Kinase IIIβ Inhibitors and Structural Insight into Their Mode of Action
| Autor: | Milan Dejmek, Michal Šála, Eliška Procházková, Ivana Mejdrová, Pavla Plačková, Gabriel Birkus, Martin Kögler, Radim Nencka, Evzen Boura, Hubert Hřebabecký, Adriana Baumlova, Gary Lee, Jan Weber, Dominika Chalupska, Helena Mertlíková-Kaiserová, Rémi Guillon, Dmytro Strunin |
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| Rok vydání: | 2015 |
| Předmět: |
Protein Conformation
Pyridines Crystallography X-Ray Antiviral Agents 01 natural sciences Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Adenosine Triphosphate Drug Discovery Humans RNA Viruses Phosphatidylinositol Binding site Mode of action 030304 developmental biology chemistry.chemical_classification 0303 health sciences Binding Sites Triazines 010405 organic chemistry Chemistry Kinase Imidazoles RNA Ethylenediamines 0104 chemical sciences 3. Good health Isoenzymes Molecular Docking Simulation Phosphotransferases (Alcohol Group Acceptor) Pyrimidines Enzyme Biochemistry Pyrazoles Molecular Medicine Phosphorylation HeLa Cells PI4KB |
| Zdroj: | Journal of Medicinal Chemistry. 58:3767-3793 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Phosphatidylinositol 4-kinase IIIβ is a cellular lipid kinase pivotal to pathogenesis of various RNA viruses. These viruses hijack the enzyme in order to modify the structure of intracellular membranes and use them for the construction of functional replication machinery. Selective inhibitors of this enzyme are potential broad-spectrum antiviral agents, as inhibition of this enzyme results in the arrest of replication of PI4K IIIβ-dependent viruses. Herein, we report a detailed study of novel selective inhibitors of PI4K IIIβ, which exert antiviral activity against a panel of single-stranded positive-sense RNA viruses. Our crystallographic data show that the inhibitors occupy the binding site for the adenine ring of the ATP molecule and therefore prevent the phosphorylation reaction. |
| Databáze: | OpenAIRE |
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