Transferability of fragmental contributions to the octanol/water partition coefficient: An NDDO‐based MST study

AbstractThis study examines the transferability of fragmental contributions to the octanol/water partition coefficient. As a previous step, we report the parameterization of the AM1 and PM3 versions of the MST model for n‐octanol. The final AM1 and PM3 MST models reproduce the experimental free energy of solvation and the octanol/water partition coefficient (log Pow) with a root‐mean‐square deviation of around 0.7 kcal/mol and 0.5 (in units of log P), respectively. Based on this parameterization, an NNDO‐based procedure is presented to dissect the free energy of transfer between octanol and water in contributions directly associated with specific atoms or functional groups. The application of this procedure to a set of representative molecular systems illustrates the dependence of the log Pow fragmental contribution due to electronic, hydrogen bonding, and steric effects, which cannot be easily accounted for in simple additive‐based empirical schemes. The results point out the potential use of theoretical methods to refine the fragmental contributions in empirical methods. © 2002 Wiley Periodicals, Inc. J Comput Chem 24: 32–45, 2003