Development and test of highly accurate endpoint free energy methods. 2: Prediction of logarithm of n‐octanol–water partition coefficient (logP) for druglike molecules using MM‐PBSA method

Abstract

AbstractThe logarithm of n‐octanol–water partition coefficient (logP) is frequently used as an indicator of lipophilicity in drug discovery, which has substantial impacts on the absorption, distribution, metabolism, excretion, and toxicity of a drug candidate. Considering that the experimental measurement of the property is costly and time‐consuming, it is of great importance to develop reliable prediction models for logP. In this study, we developed a transfer free energy‐based logP prediction model‐FElogP. FElogP is based on the simple principle that logP is determined by the free energy change of transferring a molecule from water to n‐octanol. The underlying physical method to calculate transfer free energy is the molecular mechanics‐Poisson Boltzmann surface area (MM‐PBSA), thus this method is named as free energy‐based logP (FElogP). The superiority of FElogP model was validated by a large set of 707 structurally diverse molecules in the ZINC database for which the measurement was of high quality. Encouragingly, FElogP outperformed several commonly‐used QSPR or machine learning‐based logP models, as well as some continuum solvation model‐based methods. The root‐mean‐square error (RMSE) and Pearson correlation coefficient (R) between the predicted and measured values are 0.91 log units and 0.71, respectively, while the runner‐up, the logP model implemented in OpenBabel had an RMSE of 1.13 log units and R of 0.67. Given the fact that FElogP was not parameterized against experimental logP directly, its excellent performance is likely to be expanded to arbitrary organic molecules covered by the general AMBER force fields.