Abstract
The high interest in the prediction of the intestinal absorption for New Chemical Entities (NCEs) is generated by the increasing rate in the synthesis of compounds by combinatorial chemistry and the extensive cost of the traditional evaluation methods. Quantitative Structure–Permeability Relationships (QSPerR) of the intestinal permeability across the Caco-2 cells monolayer (PCaco-2) could be obtained by the application of new molecular descriptors. In this sense, quadratic indices of the “molecular pseudograph’s atom adjacency matrix” and multiple linear regression analysis were used to obtain good quantitative models to determine the PCaco-2. QSPerR models found are significant from a statistical point of view. The total and local quadratic indices were calculated with the TOMO-COMD software. A leave-one-out cross-validation procedure (internal validation) and the evaluation of external test set of 20 drugs (external validation) revealed that regression models had a good predictive power. A comparison with results derived from other theoretical studies shown a quite satisfactory behavior of the present method. The descriptors included in the prediction models permitted the interpretation in structural terms of the permeability process, evidencing the main role of H-bonding and size properties. The models found were used in virtual screening of drug intestinal permeability and a relationship between PCaco-2 calculated and percentage of human intestinal absorption for the 72 compounds was established. These results suggest that the proposed method is able to predict PCaco-2, being a good tool for screening of PCaco-2 for large sets of NCEs synthesized via combinatorial chemistry approach.
Highlights
The oral administration is one of the most important routes due to its convenience, low cost and high patient compliance rates
Sci. 2003, 4 models found were used in virtual screening of drug intestinal permeability and a relationship between permeability across the Caco-2 cells monolayer (PCaco-2) calculated and percentage of human intestinal absorption for the 72 compounds was established. These results suggest that the proposed method is able to predict PCaco-2, being a good tool for screening of PCaco-2 for large sets of New Chemical Entities (NCEs) synthesized via combinatorial chemistry approach
Artursson and Karlsson have obtained a good correlation between human oral drug absorption and permeability coefficient, determined through the Caco-2 cell monolayer, which suggest that the human absorption can be predicted by this in vitro model [7]
Summary
The oral administration is one of the most important routes due to its convenience, low cost and high patient compliance rates. As a rapid way to predict the human intestinal absorption during the high throughput screening (HTS) [3], many in vitro cell culture models, has been investigated as potential tool for drug absorption and metabolism studies [4,5]. The permeability coefficient across Caco-2 cell monolayer (Pcaco-2) has been used to estimate oral absorption of New Chemical Entities (NCEs) [6,7,8,9]. Artursson and Karlsson have obtained a good correlation between human oral drug absorption and permeability coefficient, determined through the Caco-2 cell monolayer, which suggest that the human absorption can be predicted by this in vitro model [7]. Inter-laboratory differences of Caco-2 cell permeability have been demonstrated by several researchers [10, 11]
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