Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties

Molecular polar surface area (PSA), i.e., surface belonging to polar atoms, is a descriptor that was shown to correlate well with passive-molecular tr ansport through membranes and, therefore, allows prediction of transport pr operties of drugs. The calculation of PSA, however, is rather time-consumin g because of the necessity to generate a reasonable 3D molecular geometry a nd the calculation of the surface itself. A new approach for the calculatio n of the PSA is presented here, based on the summation of tabulated surface contributions of polar fragments. The method, termed topological PSA (TPSA ), provides results which are practically identical with the 3D PSA (the co rrelation coefficient between 3D PSA and fragment-based TPSA for 34 810 mol ecules from the World Drug Index is 0.99), while the computation speed is 2 -3 orders of magnitude faster. The new methodology may, therefore, be used for fast bioavailability screening of virtual libraries having millions of molecules. This article describes the new methodology and shows the results of validation studies based on sets of published absorption data, includin g intestinal absorption, Caco-2 monolayer penetration, and blood-brain barr ier penetration.