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Abstract
The P-glycoprotein transporter is important for drug disposition because it effluxes a wide variety of chemicals from cells via conformational changes and ATP hydrolysis. A variety of medicines have been shown to stimulate Pgp ATP hydrolysis, although the relationship between ATP and drug binding is unclear. This work focuses on investigating the structural differences between three anticancer drugs, ceritinib, crizotinib and alectinib with Pgp. Results of this research demonstrated that these drugs stimulated the ATPase activity with mouse Pgp, alectinib has a much lower Km of the Pgp-mediated ATP hydrolysis than both crizotinib and ceritinib. However the KDs (dissociation constants) of ceritinib and crizotinib determined by fluorescence did not have a significant difference and they were relatively similar. These anticancer drugs move Pgp to an "open" conformation, however in the presence of AMP-PNP ceritinib and alectinib shifted towards a “intermediate” confirmation whereas crizotinib had little effect according to acrylamide quenching.