Simple Predictive Models of Passive Membrane Permeability Incorporating Size-Dependent Membrane-Water Partition

We
investigate the relationship between passive permeability and
molecular size, in the context of solubility-diffusion theory, using
a diverse compound set with molecular weights ranging from 151 to
828, which have all been characterized in a consistent manner using
the RRCK cell monolayer assay. Computationally, each compound was
subjected to extensive conformational search and physics-based permeability
prediction, and multiple linear regression analyses were subsequently
performed to determine, empirically, the relative contributions of
hydrophobicity and molecular size to passive permeation in the RRCK
assay. Additional analyses of Log D and PAMPA data
suggest that these measurements are not size selective, a possible
reason for their sometimes weak correlation with cell-based permeability.