The Binding of Drug Molecules to Serum Albumin: The Effect of Drug Hydrophobicity on Binding Strength and Protein Desolvation

In this work, dual polarization interferometry (DPI) and quartz crystal microgravimetry with dissipation monitoring (QCM-D) were used to examine the binding characteristics and structure–activity relationships of 12 common drugs on a model bovine serum albumin (BSA) film. By taking advantage of the different hydration sensitivities of DPI and QCM-D, we were able to quantify changes in the solvent state upon drug binding to BSA. Quantifying the changes in water mass within binding pockets and upon drug–protein binding allows for a more complete understanding of binding phenomena between drug molecules and serum proteins. For the drugs tested, a quantitative structure–activity relationship (QSAR) was used to establish a correlation between drug binding (KD) and hydrophobicity (ClogP), with the latter being related to the drug's ability to desolvate the BSA upon binding. Understanding these relationships provides insight into the role of water at the protein–ligand interface and is of particular importance in the area of ligand binding within the field of drug design. This study underscores the importance of hydrophobicity to drug binding kinetics and may be used to further understand and improve drug design and delivery protocols.