Experimental and computational screening models for the prediction of intestinal drug absorption

The aim of this study was to devise experimental protocols and computationa l models for the prediction of intestinal drug permeability. Both the requi red experimental and computational effort and the accuracy and quality of t he resulting predictions were considered. In vitro intestinal Caco-2 cell m onolayer permeabilities were determined both in a highly accurate experimen tal setting (P-c) and in a faster, but less accurate, mode (P-app). Computa tional models were built using four different principles for generation of molecular descriptors (atom counts, molecular mechanics calculations, fragm ental, and quantum mechanics approaches) and were evaluated for their abili ty to predict intestinal membrane permeability. A theoretical deconvolution of the polar molecular surface area (PSA) was also performed to facilitate the interpretation of this composite descriptor and allow the calculation of PSA in a simplified and fast mode. The results indicate that it is possi ble to predict intestinal drug permeability from rather simple models with little or no loss of accuracy. A new, fast computational model, based on pa rtitioned molecular surface areas, that predicts intestinal drug permeabili ty with an accuracy comparable to that of time-consuming quantum mechanics calculations is presented.