Development of liposome/water partition coefficients predictive models for neutral and ionogenic organic chemicals.

Membrane/water partition coefficient (Km/w) is a vital parameter used to characterize the membrane permeability of compounds. Considering the Km/w value is difficult to observe experimentally for real biological membranes, liposome/water partition coefficient (Klip/w) is employed to approximate Km/w. Here, quantitative structure property relationship (QSPR) models for logKlip/w of the neutral organic chemicals and the neutral form of ionogenic organic chemicals (IOCs) (logKlip/w-neutral), ionic form of IOCs (logKlip/w-ionic), the speciation-corrected liposome-water distribution ratios at a pH = 7.40 (logDlip/w-(pH=7.40)) were developed. In the modeling, two modeling methods (multiple linear regressions (MLR) and k-nearest neighbor (kNN)) were used. The predictive variables employed here could be calculated from the molecular structure directly. For logKlip/w-neutral and logDlip/w-(pH=7.40), the logKOW and logDOW-based, non-logKOW and non-logDOW-based kNN-QSPR and MLR-QSPR models were developed, respectively. The evaluation results implied that the predictive performance of kNN-QSPR models is better than that of MLR-QSPR models. For logKlip/w-ionic, only one acceptable MLR-QSPR model was developed for cation and anion, respectively. The model quality of the derived models was evaluated following the OECD QSPR models validation guideline. The determination coefficient (R2), leave-one-out cross validation Q2 (Q2LOO) and bootstrapping coefficient (Q2BOOT), the external validation coefficient (Q2EXT) of all the models met the acceptable criteria (Q2 > 0.600, R2 > 0.700); while the root-mean-square error (RMSE) range from 0.351 to 0.857. All the results implied that the models had good goodness-of-fit, robustness and predictive ability. Therefore, the developed models could be used to fill the data gap for substances within the applicability domain on their missing logKlip/w-neutral, logKlip/w-ionic, logDlip/w-(pH=7.40) values.