Single conformer PSAs

The polar surface area of a single conformer PSAs is calculated from the global minimum conformation of the molecule (van de Waterbeemd et al. 1996, Clark 1999a). Alternatively the 3D structure of the molecule could be generated by 2D/3D converters like CONCORD (Pearlman 1987 Balducci et al.), or CORINA (Sadowski et al. 1992,1994), followed by energy minimization. Finally, the PSA of the minimized conformation is calculated for example by MOLVOL (Dodd and Theodorou 1991) or other approaches. 

This equation relies on a PSA value generated from a single conformer. More recent methods include variations from Feher et al, and Kelder et al, the latter group proposed a more direct correlation between Log BB and a so-called dynamic PSA (dPSA). The dPSA is challenging to obtain, since it is determined from a Boltzmann-weighted ensemble of molecular conformations. Note that, in Kelder et al. s formulation of Log BB, c Log P is not considered at all ... 

Figure 9.3 Observed correlation between human fractional absorption and PSA calculated using dynamic (red) and single conformer (green) methods for 20 drugs utilizing passive absorption. (Reprinted with permission from Clark, D.E., Pickett, S.D. Computational methods for the prediction of drug likeness . Drug Discov. Today 2000, 5, 49-58, cop5right 2000, Elsevier).

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