Analysis of Drug–Protein Binding Using Nuclear Magnetic Resonance Based Molecular Diffusion Measurements

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Abstract
1 H and 19 F NMR spectroscopic approaches are presented for investigation of protein–ligand binding using the measurement of molecular diffusion coefficients. This has been exemplified by investigation of the binding of 4-trifluoromethylbenzoic acid (TFBA), and the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen to human serum albumin (HSA). To avoid the need to define the number of independent binding sites and their individual dissociation constants, the relative binding of the ligands to HSA was quantified using a binding capacity, defined as log (ratio of ligand to HSA) required to give 50% of the ligand bound. The diffusion-based approach to the study of protein–ligand binding offers a number of advantages over previous NMR methods, which rely on the error-prone determination of bound-ligand chemical shifts, relaxation times or linewidths. The comparative simplicity of the diffusion method may allow its widespread use in the investigation of drug–macromolecule interactions, particularly for the weak but extensive binding of drugs to HSA in blood, which can affect biological activity in vivo.

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