Macrocycle Cell Permeability Measured by Solvation Free Energies in Polar and Apolar Environments.

ABSTRACT: The relation of surface polarity and conformational preferences is decisive for cell permeability and thus bioavailability of macrocyclic drugs. Here, we employ grid inhomogeneous solvation theory (GIST) to calculate solvation free energies for a series of six macrocycles in water and chloroform as a measure of passive membrane permeability. We perform accelerated molecular dynamics simulations to capture a diverse structural ensemble in water and chloroform, allowing for a direct profiling of solvent-dependent conformational preferences. Subsequent GIST calculations facilitate a quantitative measure of solvent preference in the form of a transfer free energy, calculated from the ensemble-averaged solvation free energies in water and chloroform. Hence, the proposed method considers how the

SUBMITTER: Kamenik AS 

PROVIDER: S-EPMC7388155 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature