PREDICTING DRUG ABSORPTION FROM MOLECULAR-SURFACE PROPERTIES BASED ONMOLECULAR-DYNAMICS SIMULATIONS

be explained by a reduced PWASA. The improvement of permeability Purpo se. To develop an efficient method for generating representative confo rmations for calculation of the conformationally dependent molecular s urface area, and to investigate the relation between this parameter an d the permeability in Caco-2 cells. Methods, High temperature molecula r dynamics (MD) simulations were used lo 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 th e apparent permeability coefficients (P-app) for transport across filt er-grown Caco-2 cells. Results. Sampling of 1000 conformations during the MD simulations was sufficient for obtaining a representative set o f conformations. The B.a. polar water accessible surface area (PWASA) yielded an excellent linear correlation with P-app for both series of compounds under study (R-2 = 0.98). Thus, the improved permeability of the prodrugs could after derivatization correlated positively with th e size of the non-polar water accessible surface area-suggesting a syn ergistic effect of the cyclopropyl and the non-polar parts of the mole cule to shield the polar parts from contact with water. Conclusions. A n efficient method for generating the representative conformations for calculation of the B.a, polar surface area has been established. An e xcellent linear correlation explaining the improved permeability of th e prodrugs was obtained.