title: Characterization of binding mode of imatinib to human α1-acid glycoprotein.
abstract: Imatinib (IMT) is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its strong plasma protein binding was found to belong to the F1*S genetic variant of α(1)-acid glycoprotein (AGP). In this work, comparative AGP binding studies were performed with IMT fragment molecules to reveal which parts of the molecule are important in the high-affinity interaction provoking specific spectral changes. Molecular modeling calculations indicated that IMT docked into the X-ray structure of AGP/F1 adopts a bent, compact conformation. This binding mode is similar to those found in its complexes with some low-affinity kinases and a quinone reductase, being strikingly different from the extended conformation of IMT in its high-affinity kinase targets.
authors.affiliation: Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, POB 17, H-1525 Budapest, Hungary. fitosi@chemres.hu
authors.forename: I
authors.initials: I
authors.lastname: Fitos
authors.forename: Á
authors.initials: Á
authors.lastname: Simon
authors.forename: F
authors.initials: F
authors.lastname: Zsila
authors.forename: G
authors.initials: G
authors.lastname: Mády
authors.forename: Á
authors.initials: Á
authors.lastname: Bencsura
authors.forename: Z
authors.initials: Z
authors.lastname: Varga
authors.forename: L
authors.initials: L
authors.lastname: Orfi
authors.forename: G
authors.initials: G
authors.lastname: Kéri
authors.forename: J
authors.initials: J
authors.lastname: Visy
mesh_terms: D001549:Benzamides; D006801:Humans; D000068877:Imatinib Mesylate; D008958:Models, Molecular; D009961:Orosomucoid / Q000737:chemistry / Q000378:metabolism*; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism*; D013057:Spectrum Analysis
chemical_list: D001549:Benzamides; D009961:Orosomucoid; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate