Prediction of membrane permeability to peptides from calculated dynamic molecular surface properties

Purpose. To develop a theoretical method for prediction of transcellular permeability to peptides. Methods. The dynamic molecular surface properties of 19 oligopeptide derivatives, divided into three homologous series were calculated. The dynamic molecular surface properties were compared with commonly used experimental predictors of membrane permeability such as partition coefficients. Relationships between the dynamic molecular surface properties and intestinal epithelial permeability, as determined in Caco-2 cell monolayers, were used to develop a model for prediction of the transmembrane permeability to the oligopeptide derivatives. Results. A theoretical model was derived which takes both the polar and non-polar pan of the dynamic molecular surface area of the investigated molecule into consideration. The model provided a strong relationship with transepithelial permeability for the oligopeptide derivatives. The predictability of transepithelial permeability from this model was comparable to that from the best experimental descriptor. Conclusions. To our knowledge, this is the first example of a theoretical model that gives a satisfactory relationship between calculated molecular properties and epithelial permeability to peptides by accounting for both the hydrogen bonding capacity and the hydrophobicity of the investigated molecule. This model may be used to differentiate poorly absorbed oligopeptide drugs at an early stage of the drug discovery process.