Does the partial molar volume of a solute reflect the free energy of hydrophobic solvation?

Abstract

Halogenated heterocyclic ligands are widely used as the potent and frequently selective inhibitors of protein kinases. However, the exact contribution of the hydrophobic solvation of a free ligand is rarely accounted for the balance of interactions contributing to the free energy of ligand binding. Herein, we propose a new experimental method based on volumetric data to estimate the hydrophobicity of a ligand. We have tested this approach for a series of ten variously halogenated benzotriazoles, the binding affinity of which to the target protein kinase CK2 was assessed with the use of thermal shift assay. According to the hierarchical clustering procedure, the excess volume, defined as the difference between the experimentally determined partial molar volume and the calculated in silico molecular volume, was found to be distant from any commonly used hydrophobicity descriptors of the ligand. The excess volume, however, properly predicts solute binding affinity. On the way, we have proved that the binding of halogenated benzotriazoles to the protein kinase CK2 is driven mostly by hydrophobic interactions.