INTRODUCTION OF SOLVENT-ACCESSIBLE SURFACE-AREA IN THE CALCULATION OFTHE HYDROPHOBICITY PARAMETER LOG-P FROM AN ATOMISTIC APPROACH

A conventional atomistic approach of estimating molecular hydrophobici ty (log P) was improved by taking into account the proximity effect of substituent groups as well as the importance of solute-solvent intera ction in the partition phenomena. The new method reassigns atomic para meters when the molecule is fully exposed to surrounding solvent. Each atom in a molecule contributes to the log P by an amount of its atomi c parameter multiplied by the degree of exposure to the surrounding so lvent. This degree of exposure is calculated from the solvent-accessib le surface area (SASA). In carrying out actual calculations, the neces sary parameters were determined with the log P values of 500 compounds that were used as training data, This method, which may be called SAS A-scaled atomistic method, gave satisfactory results when compared wit h the original method of estimating log P from atomic parameters. The ability of the new method to predict log P for compounds other than th ose used as the training data was also tested. The newly proposed SASA -scaled atomistic method was also compared with other methods availabl e for the calculation of log P. The SASA-scaled atomistic method gave better estimations from fewer training data. Finally, the ability of t he proposed method to predict differences in log P for steric isomers was tested. The new method was superior to other methods, including CL OGP, a widely accepted method of estimating log P for a variety of com pounds.