Advanced Analytical Tools for the Estimation of Gut Permeability of Compounds of Pharmaceutical Interest

Featured Application QSAR model for the determination of gut permeability of 228 pharmacological drugs at different pH conditions. The present study aims at developing a quantitative structure-activity relationship (QSAR) model for the determination of gut permeability of 228 pharmacological drugs at different pH conditions (3, 5, 7.4, 9, intrinsic). As a consequence, five different datasets (according to the diverse permeability shown by the compounds at the different pH values) were handled, with the aim of discriminating compounds as low-permeable or high-permeable. In order to achieve this goal, molecular descriptors for all the investigated compounds were computed and then classification models calculated by means of partial least squares discriminant analysis (PLS-DA). A high predictive capability was achieved for all models, providing correct classification rates in external validation between 80% and 96%. In order to test whether a reduction in the molecular descriptors would improve predictions and provide information about the most relevant variables, a feature selection approach, covariance selection, was used to select the most relevant subsets of predictors. This led to a slight improvement in the predictive accuracies, and it has indicated that the most relevant descriptors for the discrimination of the investigated compounds into low- and high-permeable were associated with the 2D and 3D structures.

Automated summary

A QSAR model was developed to determine gut permeability of 228 pharmacological drugs under different pH conditions. Molecular descriptors were computed and classification models were calculated using PLS-DA. The models showed high predictive capability with correct classification rates between 80% and 96% in external validation. A feature selection approach, covariance selection, was used to improve predictions and identify the most relevant descriptors for discrimination, which were associated with 2D and 3D structures.