Trivariate Linear Regression and Machine Learning Prediction of Possible Roles of Efflux Transporters in Estimated...

A system for predicting apparent bidirectional permeability (P_app) across Caco-2 cells of diverse chemicals has been reported. The present study aimed to investigate the relationship between in silico-generated P_app (from apical to basal side, P_{app A to B}) for 301 substances with diverse structures and a binary classification of the reported roles of efflux P-glycoprotein or breast cancer resistant protein. The in silico log(P_{app A to B}/P_{app B to A}) values of 70 substances with reported active efflux and 231 substances with no reported active efflux were significantly different (p < 0.01). The probabilities of active efflux transport estimated by trivariate analysis with log MW, log D_{pH 6.0}, and log D_{pH 7.4} for the 70 active-efflux-positive compounds were higher than those of the other 231 substances (p < 0.01); the area under the corresponding receiver operating characteristic (ROC) curve was 0.81. Further probability values estimated using a machine learning algorithm with 30 chemical descriptors as inputs yielded an area under the ROC curve of 0.79. Using a secondary set of 52 efflux-positive and 48 efflux-negative medicines, the final trivariate-generated probabilities resulted in no significant differences between these binary groups (p = 0.09); however, the final machine learning model demonstrated a good area under the ROC curve of 0.79. Consequently, a combination of the previously established system for generating the permeability coefficients across intestinal monolayers (a continuous variable) and the currently proposed system for predicting the roles of additional active efflux (a binary classification) could prove useful; high accuracy was achieved by applying machine learning using in silico-generated chemical descriptors.