Study of the binding affinity between imatinib and α-1 glycoprotein using nuclear spin relaxation and isothermal titration calorimetry.

Imatinib is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia and gastrointestinal stromal tumors. Binding of drugs to proteins influence their pharmacokinetic and pharmacodynamics action. In the blood, the drug is distributed in the body in the free form or bound to plasma protein. Albumin and α-1 glycoprotein (AGP) are plasma proteins with the highest affinity for drug substances. Drugs which are weak acids mainly bind to plasma albumin, while drugs that are bases have affinity for α-1 glycoprotein. The main goal of this study is to quantitatively evaluate the interaction between imatinib mesylate (IMT) and α-1 glycoprotein to characterize the nature and forces underlying the formation of a molecular complex. Relaxation experiments provide quantitative information about the relationship between the binding affinity and structure of IMT. Thus, association constant was determined as K a = 873.36 M−1. The ITC data revealed that the binding was an entropy driven process and the association constant K a = 3.22 × 103 M−1, with a 1:1 stoichiometry. The results obtained by NMR and ITC were complemented with a molecular docking study. • Quantitatively evaluate the interaction between imatinib mesylate (IMT) and α-1 glycoprotein (AGP) • The energetics of binding of IMT to AGP was assessed by ITC, NMR and molecular docking. • 1:1 binding stoichiometry • Structure of the conformation with the highest binding energy of IMT:AGP complex. [ABSTRACT FROM AUTHOR]