ADME Evaluation in Drug Discovery. 2. Prediction of Partition Coefficient by
Atom-Additive Approach Based on Atom-Weighted Solvent Accessible Surface Areas
posted on 2003-04-11, 00:00authored byT. J. Hou, X. J. Xu
A novel method for the calculations of 1-octanol/water partition coefficient (log P) of organic molecules
has been presented here. The method, SLOGP v1.0, estimates the log P values by summing the contribution
of atom-weighted solvent accessible surface areas (SASA) and correction factors. Altogether 100 atom/group types were used to classify atoms with different chemical environments, and two correlation factors
were used to consider the intermolecular hydrophobic interactions and intramolecular hydrogen bonds.
Coefficient values for 100 atom/group and two correction factors have been derived from a training set of
1850 compounds. The parametrization procedure for different kinds of atoms was performed as follows:
first, the atoms in a molecule were defined to different atom/group types based on SMARTS language, and
the correction factors were determined by substructure searching; then, SASA for each atom/group type was
calculated and added; finally, multivariate linear regression analysis was applied to optimize the hydrophobic
parameters for different atom/group types and correction factors in order to reproduce the experimental log
P. The correlation based on the training set gives a model with the correlation coefficient (r) of 0.988, the
standard deviation (SD) of 0.368 log units, and the absolute unsigned mean error of 0.261. Comparison of
various procedures of log P calculations for the external test set of 138 organic compounds demonstrates
that our method bears very good accuracy and is comparable or even better than the fragment-based
approaches. Moreover, the atom-additive approach based on SASA was compared with the simple atom-additive approach based on the number of atoms. The calculated results show that the atom-additive approach
based on SASA gives better predictions than the simple atom-additive one. Due to the connection between
the molecular conformation and the molecular surface areas, the atom-additive model based on SASA may
be a more universal model for log P estimation especially for large molecules.