Comparative evaluation of the predictive power of calculation procedures for molecular lipophilicity

The predictive power of four calculation procedures for molecular lipophilicity is checked by comparing with experimental data (log P and chromatographical RMw) taken from the literature. Two sets of test compounds are used: the first comprises simple organic molecules and the second consists of more complicated drug molecules. Our comparative evaluation leads us to conclude that the predictive power is significantly better for not too complicated organic molecules than for drugs with complicated structural pattern. The four investigated calculation procedures should be arranged in two groups with significantly differing predictive power: (a) Rekker and Hansch/Leo and (b) Ghose/Crippen and Suzuki/Kudo. This conclusion is based on a statistical control using log P and RMw as the independent parameters. Correlations have in common: (1) slopes in correlations with calculated data based on fragmental methods are not significantly different from 1; calculations with data from atom-based procedures show up in most cases with slopes below 1. (2) The accompanying overall statistics underline the superiority of the fragmental methods. We think that all four tested calculation procedures have their own restrictions; for future development we would advise a thorough reconsideration of structural effects not fully (or even not at all) incorporated in the data sets. Special attention will have to be paid to the conformational aspects of lipophilic behavior.