Prediction of Phospholipid–Water Partition Coefficients of Ionic Organic Chemicals Using the Mechanistic Model COSMO<i>mic</i>

The partition coefficient of chemicals from water to phospholipid membrane, <i>K</i>_lipw, is of central importance for various fields. For neutral organic molecules, log <i>K</i>_lipw correlates with the log of bulk solvent–water partition coefficients such as the octanol–water partition coefficient. However, this is not the case for charged compounds, for which a mechanistic modeling approach is highly necessary. In this work, we extend the model COSMO<i>mic</i>, which adapts the COSMO-RS theory for anisotropic phases and has been shown to reliably predict <i>K</i>_lipw for neutral compounds, to the use of ionic compounds. To make the COSMO<i>mic</i> model applicable for ionic solutes, we implemented the internal membrane dipole potential in COSMO<i>mic</i>. We empirically optimized the potential with experimental <i>K</i>_lipw data of 161 neutral and 75 ionic compounds, yielding potential shapes that agree well with experimentally determined potentials from the literature. This model refinement has no negative effect on the prediction accuracy of neutral compounds (root-mean-square error, RMSE = 0.62 log units), while it highly improves the prediction of ions (RMSE = 0.70 log units). The refined COSMO<i>mic</i> is, to our knowledge, the first mechanistic model that predicts <i>K</i>_lipw of both ionic and neutral species with accuracies better than 1 log unit