A computational study of the inhibition mechanisms of P-glycoprotein mediated paclitaxel efflux by kinase inhibitors
| العنوان: | A computational study of the inhibition mechanisms of P-glycoprotein mediated paclitaxel efflux by kinase inhibitors |
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| المؤلفون: | Jianwen Fang, Richard Simon, Joe Bender |
| المصدر: | BMC Systems Biology, Vol 11, Iss 1, Pp 1-10 (2017) BMC Systems Biology |
| بيانات النشر: | BMC, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Paclitaxel, medicine.drug_class, Drug resistance, Pharmacology, Biology, Tyrosine-kinase inhibitor, Substrate Specificity, Docking, 03 medical and health sciences, chemistry.chemical_compound, Adenosine Triphosphate, 0302 clinical medicine, Structural Biology, medicine, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, Protein Kinase Inhibitors, Molecular Biology, lcsh:QH301-705.5, P-glycoprotein, Kinase, Applied Mathematics, Computational Biology, Cancer drug resistance, Antineoplastic Agents, Phytogenic, Molecular pump, Computer Science Applications, Mass action kinetic modeling, 030104 developmental biology, chemistry, lcsh:Biology (General), Drug Resistance, Neoplasm, Docking (molecular), 030220 oncology & carcinogenesis, Modeling and Simulation, biology.protein, Efflux, Simulation, Research Article, Binding domain |
| الوصف: | Background Drug resistance mediated by P-glycoprotein (P-gp) renders many cancer therapies ineffective. One P-gp substrate is the widely used chemotherapy drug paclitaxel. Co-administration of paclitaxel and another drug that inhibits P-gp may enhance the therapeutic effectiveness of paclitaxel by preventing its efflux from tumor cells. Results Here we present a computational approach that combines docking studies with mass action kinetic modeling to investigate how kinase inhibitors may inhibit P-gp mediated paclitaxel efflux. The results show that the inhibition can be attributed to competition between paclitaxel and a tyrosine kinase inhibitor (TKI) for the substrate binding domain (SBD) as well as competition between the kinase inhibitor and ATP for the nuclear (ATP) binding domain (NBD). The relative scales of these two competitions are TKI dependent and determined by the relative affinities of paclitaxel and TKIs to the SBD and NBD of P-gp, and their membrane partition coefficients. Additional simulations suggested that there is no single strategy to further improve the ability of TKIs to inhibit paclitaxel efflux and the most efficient way likely depends on the properties of the TKIs. Conclusions The developed model fits existing experimental results well and thus detailed analyses of isolated parameters provide insight into the mechanisms of rather important drug efflux. It can be used to guide how to design better TKIs or develop feasible drug combination strategies for targeting P-gp induced drug resistance. Electronic supplementary material The online version of this article (10.1186/s12918-017-0498-x) contains supplementary material, which is available to authorized users. |
| اللغة: | English |
| تدمد: | 1752-0509 |
| DOI: | 10.1186/s12918-017-0498-x |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::abe726113e51c8479627b93aeff08945 http://link.springer.com/article/10.1186/s12918-017-0498-x |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....abe726113e51c8479627b93aeff08945 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17520509 |
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| DOI: | 10.1186/s12918-017-0498-x |