Binding mechanism of the tyrosine-kinase inhibitor nilotinib to human serum albumin determined by 1H STD NMR, 19F NMR, and molecular modeling

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Abstract

Drug interaction with albumins significantly affects in vivo drug transport and biological metabolism. To gain insight into the binding mechanisms of tyrosine-kinase inhibitor nilotinib (NIL) to human serum albumin (HSA), an approach combining 1H saturation-transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, 19F NMR spectroscopy, steady-state fluorescence quenching, and molecular modeling was adopted. 19F NMR was used to determine the binding constant, and a value of 4.12 × 103 M−1 was obtained. Fluorescence spectroscopy was also used to determine the binding constant, and the value obtained was within the same order of magnitude. The binding process was mainly driven by hydrogen bonds and van der Waals forces. Displacement experiments further showed that NIL mainly bound to the hydrophobic cavity of HSA’s subdomain IIA, also called Sudlow’s site I. Molecular docking simulation was also used to establish a molecular binding model, and findings were consistent with those of displacement and the 1H STD NMR experiments.

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