Rethinking log P : Lipophilicity = Hydrophobicity

Abstract LogP values have served as cutoffs for hit-, lead-, and drug-likeness as well as thresholds for toxicity and ADME decision-making and are often characterized as lipophilicity. When the properties of octanol and the experimental limitations of logP measurements are considered, it becomes clear that logP > 3 must be due to increased hydrophobicity and not lipophilicity. We propose that the partition coefficient between either octanol or water and “the thermodynamic ideal solution” is a useful reference to separately determine octanol solvation (lipophilicity) and aqueous solvation (hydrophilicity). We further propose that the ideal solubility of solids measures “autophilicity”. Aqueous solvation spans many orders of magnitude, yet octanol solvation is much narrower, and thus lipophilicity is nearly constant. Understanding which molecules are hydrophobic, rather than lipophilic, can be critical in interpreting affinity, PK, ADME, safety, and other behaviors of molecules necessitating these more nuanced definitions.