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

The cross-sectional area, A(D), 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, A(Dcalc), 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, A(DcalcM), and the strongest amphiphilicity. The calculated, A(DcalcM), and the measured, AD, cross-sectional areas correlated linearly (n = 55, slope, m = 1.04, determination coefficient, r(2) = 0.95). The calculated cross-sectional areas, A(DcalcM), were then used together with the calculated octanol-water distribution coefficients, log D-7.4, of the 55 compounds (with a known ability to permeate the blood-brain barrier) to establish a calibration diagram for the prediction of blood-brain barrier permeation. It yielded a limiting cross-sectional area (A(DcalcM) = 70 angstrom(2)) and an optimal range of octanol-water distribution coefficients (-1.4 <= log D-7.4 < 7.0). The calibration diagram was validated with an independent set of 43 compounds with the known ability to permeate the blood-brain barrier, yielding a prediction accuracy of 86%. The incorrectly predicted compounds exhibited log D-7.4 values comprised between -0.6 and -1.4, suggesting that the limitation for log D-7.4 is less rigorous than the limitation for AD. An accuracy of 83% has been obtained for a second validation set of 42 compounds which were previously shown to be difficult to predict. The calculated parameters, A(DcalcM) and log D-7.4, thus allow for a fast and accurate prediction of blood-brain barrier permeation. Analogous calibration diagrams can be established for other membrane barriers.