In silico prediction of blood-brain barrier permeation using the calculated molecular cross-sectional area as main parameter

The cross-sectional area, AD, of a compound oriented in an amphiphilic gradient such as the air−water or lipid−water interface has previously been shown to be crucial for membrane partitioning and permeation, respectively. Here, we developed an algorithm that determines the molecular axis of amphiphilicity and the cross-sectional area, ADcalc, perpendicular to this axis. Starting from the conformational ensemble of each molecule, the three-dimensional conformation selected as the membrane-binding conformation was the one with the smallest cross-sectional area, ADcalcM, and the strongest amphiphilicity. The calculated, ADcalcM, and the measured, AD, cross-sectional areas correlated linearly (n = 55, slope, m = 1.04, determination coefficient, r2 = 0.95). The calculated cross-sectional areas, ADcalcM, were then used together with the calculated octanol−water distribution coefficients, log D7.4, of the 55 compounds (with a known ability to permeate the blood−brain barrier) to establish a calibration diagram ...