Estimation of ADME properties in drug discovery: Predicting Caco-2 cell permeability using atom-based stochastic and non-stochastic linear indices

The in vitro determination of the permeability through cultured Caco-2 cells is the most often-used in vitro model for drug absorption. In this report, we use the largest data set of measured P_caco-2, consisting of 157 structurally diverse compounds. Linear discriminant analysis (LDA) was used to obtain quantitative models that discriminate higher absorption compounds from those with moderate-poorer absorption. The best LDA model has an accuracy of 90.58% and 84.21% for training and test set. The percentage of good correlation, in the virtual screening of 241 drugs with the reported values of the percentage of human intestinal absorption (HIA), was greater than 81%. In addition, multiple linear regression models were developed to predict Caco-2 perme ability with determination coefficients of 0.71 and 0.72. Our method compares favorably with other approaches implemented in the Dragon software, as well as other methods from the international literature. These results suggest that the proposed method is a good tool for studying the oral absorption of drug candidates.