Modeling the pharmacodynamics of passive membrane permeability

Abstract

Small molecule permeability through cellular membranes is critical to a better understanding of pharmacodynamics and the drug discovery endeavor. Such permeability may be estimated as a function of the free energy change of barrier crossing by invoking the barrier domain model, which posits that permeation is limited by passage through a single "barrier domain" and assumes diffusivity differences among compounds of similar structure are negligible. Inspired by the work of Rezai and co-workers (JACS 128:14073-14080, 2006), we estimate this free energy change as the difference in implicit solvation free energies in chloroform and water, but extend their model to include solute conformational affects. Using a set of eleven structurally diverse FDA approved compounds and a set of thirteen congeneric molecules, we show that the solvation free energies are dominated by the global minima, which allows solute conformational distributions to be effectively neglected. For the set of tested compounds, the best correlation with experiment is obtained when the implicit chloroform global minimum is used to evaluate the solvation free energy difference.

Fig. 1

Structures and names of the 11 compounds in the FDA set

Fig. 2

Structures and names of the 13 compounds in the congeneric set

Fig. 3

Correlation with experiment for compounds in the FDA set, a the single-state approximation R² = 0.75, b the two-state approximation R² = 0.68, c the predominant-states approximation R² = 0.71, d QSPR R² = 0.75

Fig. 4

Global minima in chloroform and water for representative compounds from the FDA set, a alfentanil, b verapamil

Fig. 5

Correlation with experiment for compounds in the congeneric set, a the single state approximation R² = 0.72, b the two-state approximation, R² = 0.72, c the predominant-states approximation R² = 0.71, d QSPR R² = 0.58