Toward the elucidation of the mechanism for passive membrane permeability of cyclic peptides

The combination of solubility-diffusion theory with a kinetic model for permeation based on MD simulations of spontaneous partitioning improved the agreement between calculated and experimental permeability coefficients substantially for six known drug molecules, identifying the ‘flip-flopping’ across the membrane interior as the rate-limiting step for drug-like compounds (12). [...]the adoption of a permeable conformation and partitioning to the membrane (potentially occurring concertedly) may become rate-limiting for this class of compounds. [...]a future challenge for the computational chemistry community is to develop efficient search strategies to identify the closed conformation of new cyclic peptides in a reliable and robust manner. First steps have been made into this direction by exhaustive MD simulations combined with kinetic models.