Prediction of the intestinal absorption of endothelin receptor antagonistsusing three theoretical methods of increasing complexity

Purpose. Three new computational strategies have been evaluated for their a bility to predict intestinal membrane permeability to a series of endotheli n receptor antagonists. Methods. The three methods were evaluated using a set of ten non-peptide en dothelin receptor antagonists. The simplest method, "the rule of five", is based on 2D parameters such as the number of potential hydrogen bonds, mole cular weight and calculated lipophilicity. A method based on molecular mech anics calculations is used to calculate 3D parameters such as polar and non -polar parts of the molecular surface area. The third method uses quantum m echanics to calculate molecular properties related to the valence region. Results. Descriptors derived by the latter two methods correlated well with permeability coefficients of the endothelin receptor antagonists. On the o ther hand, the rule of five failed to discriminate between drugs with high and low permeability. Conclusions. Molecular surface descriptors and descriptors derived from qua ntum mechanics are potentially useful for the virtual screening of the perm eability of the intestinal membrane to endothelin receptor antagonists.