Selective binding of imatinib to the genetic variants of human α1-acid glycoprotein

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Abstract

Imatinib is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia. Its strong plasma protein binding referred to α1-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) × 106 M- 1 and n = 0.94 could be determined for the binding on the F1-S variant at 37°. Imatinib binding on the A variant is weaker and less specific. The binding affinity of imatinib to human serum albumin (nKa ≈ 3 × 104 M- 1) is low. Pharmacologically relevant binding interactions with other drugs can be expected on the F1-S variant of AGP.

Original languageEnglish
Pages (from-to)1704-1712
Number of pages9
JournalBBA - General Subjects
Volume1760
Issue number11
DOIs
Publication statusPublished - Nov 2006

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Medical Genetics
Glycoproteins
Acids
Ligands
Dichroism
Genetic Polymorphisms
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Circular Dichroism
Polymorphism
Protein Binding
Serum Albumin
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Conformations
Blood Proteins
Quenching
Fluorescence
Imatinib Mesylate
Pharmacology
Proteins

Keywords

  • α-Acid glycoprotein
  • Drug binding interaction
  • Fluorescence quenching
  • Genetic variants
  • Imatinib
  • Induced circular dichroism

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

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title = "Selective binding of imatinib to the genetic variants of human α1-acid glycoprotein",
abstract = "Imatinib is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia. Its strong plasma protein binding referred to α1-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) × 106 M- 1 and n = 0.94 could be determined for the binding on the F1-S variant at 37°. Imatinib binding on the A variant is weaker and less specific. The binding affinity of imatinib to human serum albumin (nKa ≈ 3 × 104 M- 1) is low. Pharmacologically relevant binding interactions with other drugs can be expected on the F1-S variant of AGP.",
keywords = "α-Acid glycoprotein, Drug binding interaction, Fluorescence quenching, Genetic variants, Imatinib, Induced circular dichroism",
author = "I. Fitos and J. Visy and F. Zsila and G. M{\'a}dy and M. Simonyi",
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T1 - Selective binding of imatinib to the genetic variants of human α1-acid glycoprotein

AU - Fitos, I.

AU - Visy, J.

AU - Zsila, F.

AU - Mády, G.

AU - Simonyi, M.

PY - 2006/11

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N2 - Imatinib is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia. Its strong plasma protein binding referred to α1-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) × 106 M- 1 and n = 0.94 could be determined for the binding on the F1-S variant at 37°. Imatinib binding on the A variant is weaker and less specific. The binding affinity of imatinib to human serum albumin (nKa ≈ 3 × 104 M- 1) is low. Pharmacologically relevant binding interactions with other drugs can be expected on the F1-S variant of AGP.

AB - Imatinib is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia. Its strong plasma protein binding referred to α1-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) × 106 M- 1 and n = 0.94 could be determined for the binding on the F1-S variant at 37°. Imatinib binding on the A variant is weaker and less specific. The binding affinity of imatinib to human serum albumin (nKa ≈ 3 × 104 M- 1) is low. Pharmacologically relevant binding interactions with other drugs can be expected on the F1-S variant of AGP.

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KW - Induced circular dichroism

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