Selective binding of imatinib to the genetic variants of human alpha1-acid glycoprotein.

@article{citeulike:2449749, abstract = {Imatinib is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia. Its strong plasma protein binding referred to alpha1-acid glycoprotein (AGP) component was found to inhibit the pharmacological activity. AGP shows genetic polymorphism and the two main genetic variants have different drug binding properties. The binding characteristics of imatinib to AGP genetic variants and the possibility of its binding interactions were investigated by various methods. The results proved that binding of imatinib to the two main genetic variants is very different, the high affinity binding belongs dominantly to the F1-S variant. This interaction is accompanied with specific spectral changes (induced circular dichroism, UV change, intrinsic fluorescence quenching), suggesting that the bound ligand has chiral conformation that would largely overlap with other ligands inside the protein cavity. Binding parameters of Ka=1.7(+/-0.2)x10(6)M(-1) and n=0.94 could be determined for the binding on the F1-S variant at 37 degrees . Imatinib binding on the A variant is weaker and less specific. The binding affinity of imatinib to human serum albumin (nKa approximately 3 x 10(4)M(-1)) is low. Pharmacologically relevant binding interactions with other drugs can be expected on the F1-S variant of AGP.}, address = {Department of Molecular Pharmacology, Institute of Biomolecular Chemistry Chemical Research Center, Hungarian Academy of Sciences, Budapest, POB 17, H-1525, Hungary. fitosi@chemres.hu}, author = {Fitos, I. and Visy, J. and Zsila, F. and M\'{a}dy, G. and Simonyi, M. }, citeulike-article-id = {2449749}, doi = {http://dx.doi.org/10.1016/j.bbagen.2006.08.015}, issn = {0006-3002}, journal = {Biochim Biophys Acta}, month = {November}, number = {11}, pages = {1704--1712}, posted-at = {2008-03-01 00:53:03}, priority = {0}, title = {Selective binding of imatinib to the genetic variants of human alpha1-acid glycoprotein.}, url = {http://dx.doi.org/10.1016/j.bbagen.2006.08.015}, volume = {1760}, year = {2006} }

TY - JOUR ID - citeulike:2449749 L3 - citeulike-article-id:2449749 TI - Selective binding of imatinib to the genetic variants of human alpha1-acid glycoprotein. JF - Biochim Biophys Acta VL - 1760 IS - 11 SP - 1704 EP - 1712 AD - Department of Molecular Pharmacology, Institute of Biomolecular Chemistry Chemical Research Center, Hungarian Academy of Sciences, Budapest, POB 17, H-1525, Hungary. fitosi@chemres.hu SN - 0006-3002 N2 - Imatinib is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia. Its strong plasma protein binding referred to alpha1-acid glycoprotein (AGP) component was found to inhibit the pharmacological activity. AGP shows genetic polymorphism and the two main genetic variants have different drug binding properties. The binding characteristics of imatinib to AGP genetic variants and the possibility of its binding interactions were investigated by various methods. The results proved that binding of imatinib to the two main genetic variants is very different, the high affinity binding belongs dominantly to the F1-S variant. This interaction is accompanied with specific spectral changes (induced circular dichroism, UV change, intrinsic fluorescence quenching), suggesting that the bound ligand has chiral conformation that would largely overlap with other ligands inside the protein cavity. Binding parameters of Ka=1.7(+/-0.2)x10(6)M(-1) and n=0.94 could be determined for the binding on the F1-S variant at 37 degrees . Imatinib binding on the A variant is weaker and less specific. The binding affinity of imatinib to human serum albumin (nKa approximately 3 x 10(4)M(-1)) is low. Pharmacologically relevant binding interactions with other drugs can be expected on the F1-S variant of AGP. AU - Fitos, I AU - Visy, J AU - Zsila, F AU - Mády, G AU - Simonyi, M PY - 2006/11// UR - http://dx.doi.org/10.1016/j.bbagen.2006.08.015 ER -