Introduction of Solvent-Accessible Surface Area in the Calculation of the Hydrophobicity Parameter log P from an Atomistic Approach

Abstract

A conventional atomistic approach of estimating molecular hydrophobicity (log P) was improved by taking into account the proximity effect of substituent groups as well as the importance of solute-solvent interaction in the partition phenomena. The new method reassigns atomic parameters when the molecule is fully exposed to surrounding solvent. Each atom in a molecule contributes to the log P by an amount of its atomic parameter multiplied by the degree of exposure to the surrounding solvent. This degree of exposure is calculated from the solvent-accessible surface area (SASA). In carrying out actual calculations, the necessary parameters were determined with the log P values of 500 compounds that were used as training data. This method, which may be called SASA-scaled atomistic method, gave satisfactory results when compared with the original method of estimating log P from atomic parameters. The ability of the new method to predict log P for compounds other than those used as the training data was also tested. The newly proposed SASA-scaled atomistic method was also compared with other methods available for the calculation of log P. The SASA-scaled atomistic method gave better estimations from fewer training data. Finally, the ability of the proposed method to predict differences in log P for steric isomers was tested. The new method was superior to other methods, including CLOGP, a widely accepted method of estimating log P for a variety of compounds.