Molecular Lipophilicity Calculations of Chemically Heterogeneous Chemicals and Drugs on the Basis of Structural Similarity and Physicochemical Parameters

Abstract

QSARs based on molecular polarizability (α) and H-bond acceptor factors (∑C_a) as independent variables provided good predictability of octanol/water partition coefficients (P) for chemicals and drugs. However, for some molecules containing few functional groups, the calculated values deviated 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 closely related to the compound-of-interest. The most successful of these variations took the mean log P value of few most closely related compounds after each was adjusted for differences between their and the compound-of-interest's polarizabilities (α) and H-bond acceptor capacities (∑C_a).

Key Words:

• Lipophilicity
• Polarizability
• H-bond acceptor factors
• Similarity