Molecular lipophilicity calculations of chemically heterogeneous chemicalsand drugs on the basis of structural similarity and physicochemical parameters

QSARs based on molecular polarizability (alpha) and H-bond acceptor factors (SigmaC(a)) as independent variables provided good predictability of octan ol/water partition coefficients (P) for chemicals and drugs. However, for s ome molecules containing few functional groups, the calculated values devia ted significantly from those observed. This approach gave good results when applied to a set of 138 chemicals and drugs previously studied by Mannhold and Dross who compared other methods to calculate log P values. At the same time, three variations on a molecular similarity approach were pursued. In this study, a large training set with experimentally determined octanol/water partition coefficients (P) was searched for structures close ly related to the compound-of-interest. The most successful of these variat ions took the mean log P value of few most closely related compounds after each was adjusted for differences between their and the compound-of-interes t's polarizabilities (a) and H-bond acceptor capacities (SigmaC(a)).