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A new topological descriptors based model for pbkp_redicting intestinal epithelial transport of drugs in caco-2 cell culture

Abstract:

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 pbkp_redict 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 pbkp_redictability. Furthermore, others 18 drugs were selected as a test set in order to assess the pbkp_redictive power of the models and the accuracy of the final pbkp_rediction was similar to achieve for the data set. Besides, the use of both regression models, in a combinative way, is possible to pbkp_redict 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 pbkp_redict the P values and it proved to be a good tool for studying the oral absorption of drug candidates during the drug development process.