title: Interaction of imatinib mesylate with human serum transferrin: The comparative spectroscopic studies.
abstract: Imatinib mesylate (Imt) is a tyrosine kinase inhibitor mainly used in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+CML). Human serum transferrin is the most abundant serum protein responsible for the transport of iron ions and many endogenous and exogenous ligands. In this study the mechanism of interactions between the imatinib mesylate and all states of transferrin (apo-Tf, Htf and holo-Tf) has been investigated by fluorescence, ultraviolet-visible (UV-vis), circular dichroism (CD) and zeta potential spectroscopic methods. Based on the experimental results it was proved that under physiological conditions the imatinib mesylate binds to the each form of transferrin with a binding constant c.a. 105M-1. The thermodynamic parameters indicate that hydrogen bonds and van der Waals were involved in the interaction of apo-Tf with the drug and hydrophobic and ionic strength participate in the reaction of Htf and holo-Tf with imatinib mesylate. Moreover, it was shown that common metal ions, Zn2+and Ca2+strongly influenced apo-Tf-Imt binding constant. The CD studies showed that there are no conformational changes in the secondary structure of the proteins. No significant changes in secondary structure of the proteins upon binding with the drug and instability of apo-Tf-Imt system are the desirable effects from pharmacological point of view.
authors.affiliation: Department of Analytical Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211 A, 50-566 Wrocław, Poland. Electronic address: urszula.sliwinska-hill@umed.wroc.pl.
authors.forename: Urszula
authors.initials: U
authors.lastname: Śliwińska-Hill
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002942:Circular Dichroism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000068877:Imatinib Mesylate / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D055550:Protein Stability; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D014168:Transferrin; D000068877:Imatinib Mesylate; D015032:Zinc; D002118:Calcium
keywords: Circular dichroism; Fluorescence quenching; Human serum transferrin; Imatinib mesylate; Tyrosine kinase inhibitors; Zeta potential