A new

Purpose: Quantitative Structure–Permeability Relationships (QSPerR) of the intestinal permeability across the (Caco-2) cells monolayer could be obtained by the application of new molecular descriptors. Method: A novel topologic-molecular approach to computer molecular design (TOMOCOMDCARDD) has been used to estimate the intestinal-epithelial transport of drug in Caco-2 cell culture. Results: The Permeability Coefficients in Caco-2 cells (P) for 33 structurally diverse drugs were well described using quadratic indices of the molecular pseudograph’s atom adjacency matrix as molecular descriptors. A quantitative model that discriminates the high-absorption compounds from those with moderate-poor absorption was obtained for the training data set, showing a global classification of 87.87%. In addition, two QSPerR models, through a multiple linear regression, were obtained to predict the P [apical to basolateral (AP→BL) and basolateral to apical (BL→AP)]. A leave-n-out and leave-one-out cross-validation procedure revealed that the discriminant and regression models respectively, had a good predictability. Furthermore, others 18 drugs were selected as a test set in order to assess the predictive power of the models and the accuracy of the final prediction was similar to achieve for the data set. Besides, the use of both regression models, in a combinative way, is possible to predict the Permeability Directional Ratio (PDR, BL→AP/AP→BL) value. The found models were used in virtual screening of drug intestinal permeability and a relationship between calculated P and percentage of human intestinal absorption for several compounds was established. Furthermore, this approximation permits us to obtain a good explanation of the experiment based on the molecular structural features. Conclusions: These results suggest that the proposed method is able to predict the P values and it proved to be a good tool for studying the oral absorption of drug candidates during the drug development process.