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In vitro and in silico studies of interaction of synthetic 2,6,9-trisubstituted purine kinase inhibitors BPA-302, BP-21 and BP-117 with liver drug-metabolizing cytochromes P45
A. Špičáková, P. Kraus, T. Gucký, V. Kryštof, M. Strnad, V. Bazgier, M. Otyepka, V. Kubíčková, M. Poruba, Z. Rácová, I. Zapletalová, P. Anzenbacher
Language English Country Czech Republic
Document type Journal Article
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- MeSH
- Cytochrome P-450 Enzyme Inhibitors chemistry pharmacology MeSH
- Protein Kinase Inhibitors chemistry pharmacology MeSH
- Isoenzymes MeSH
- Microsomes, Liver drug effects enzymology MeSH
- Kinetics MeSH
- Protein Conformation MeSH
- Drug Interactions MeSH
- Humans MeSH
- Purines chemistry pharmacology MeSH
- Molecular Docking Simulation MeSH
- Cytochrome P-450 Enzyme System chemistry metabolism MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
An evaluation of possible interactions with enzymes of drug metabolism (cytochromes P450, CYP) is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. The article is focused on the preliminary metabolic study of selected 2,6,9-trisubstituted purine kinase inhibitors with significant anticancer activities which we have developed. The compounds BP-21 and BP-117 represent strong CDK inhibitors and the compound BPA-302 was developed as selective FLT3-ITD kinase inhibitor. Here, emphasis is placed on interactions of these compounds with the nine most important forms of CYP to evaluate the possibility of inhibition of these enzymes. The possibility of their inhibitory effect was studied in vitro on selected human liver microsomal CYP enzymes. The most affected enzyme was CYP2C19. Its activity dropped to 22 % of its original value by BPA 302, to 13 % by BP-21 and to 6 % by BP-117 at the highest concentration tested (250 µmol·l(-1)). The results suggest that the metabolism of concomitantly administered drugs should not be significantly affected at lower doses. Molecular docking of BPA-302 indicated that it can bind to active site of both CYP2C19 and CYP2D6 enzymes above the heme cofactor corroborating the experimental data.
Department of Pharmacology Faculty of Medicine Palacký University Olomouc Czech Republic
Department of Pharmacology Faculty of Medicine Palacký University Olomouc Olomouc Czech Republic
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