Facts, Patterns, and Principles in Drug Discovery: Appraising the Rule of 5 with Measured Physicochemical Data

The rule of 5 was designed to estimate the likelihood of poor absorption or permeation, noting the impact of poor solubility. This Perspective explores the impact of various physicochemical descriptors and contemporary lipophilicity measurements on permeability and solubility, showing that the distribution coefficient log D7.4 (rather than log P) is the most impactful parameter. Molecular weight, almost invariably the defining characteristic of “beyond the rule of 5” compounds, has little impact on solubility when log D7.4 measurements and aromaticity are considered. Predicting permeation is more complex, given passive and carrier transport mechanisms; however, notable patterns of behavior are apparent, giving insight even “beyond the rule of 5”. Recommended best practices should involve using the facts (measurements) and the patterns they reveal to establish informative principles rather than fastidious rules.