Quantitative Structure-Activity Relationships Using Hydrophobicity Constants Measured by High-Pressure Liquid Chromatography: A Comparison with Octanol-Water Partition Coefficients

Abstract

Capacity ratios (k') for a set of small organic compounds of miscellaneous structure were measured under a variety of reversed-phase liquid chromatoghraphic conditions. The capacity ratios from these experiments were correlated with the binding of these solutes to bovine serum albumin (BSA). Hydrophobic binding of small molecules to BSA is considered to be a nonspecific process (i.e., requiring no special orientation or restriction of movement of the solute molecules) and serves as a model for the hydrophobic binding of small molecules to other macromolecules, such as hemoglobin and ribonuclease. Standard deviations from these correlations were compared using the null hypothesis to determine the set of chromatographic conditions giving the best correlation with the binding constants. The null hypothesis was again applied to compare the correlation of the best chromatographic data with binding to the correlation of the binding data with the octanol-water partition coefficients of these compounds. For the chromatographic parameters varied here, the statistical differences between these methods are generally nonsignificant. However, the correlation involving partition coefficients is shown to be statistically better at the 99% confidence level than those involving capacity ratios.