Predicting drug absorption from molecular surface properties based on molecular dynamics simulations

To develop an efficient method for generating representative conformations for calculation of the conformationally dependent molecular surface area, and to investigate the relation between this parameter and the permeability in Caco-2 cells.

High temperature molecular dynamics (MD) simulations were used to obtain 1000 conformations of six beta-blocking agents and their prodrugs. The Boltzmann averaged (B.a.) polar surface area of the 1000 conformations was correlated to the apparent permeability coefficients (Papp) for transport across filter-grown Caco-2 cells.

Sampling of 1000 conformations during the MD simulations was sufficient for obtaining a representative set of conformations. The B.a. polar water accessible surface area (PWASA) yielded an excellent linear correlation with Papp for both series of compounds under study (R2 = 0.98). Thus, the improved permeability of the prodrugs could be explained by a reduced PWASA. The improvement of permeability after derivatization correlated positively with the size of the non-polar water accessible surface area-suggesting a synergistic effect of the cyclopropyl and the non-polar parts of the molecule to shield the polar parts from contact with water.

An efficient method for generating the representative conformations for calculation of the B.a. polar surface area has been established. An excellent linear correlation explaining the improved permeability of the prodrugs was obtained.