Predicting octanol/water partition coefficients for the SAMPL6 challenge using the SM12, SM8, and SMD solvation...

Blind predictions of octanol/water partition coefficients at 298 K for 11 kinase inhibitor fragment like compounds were made for the SAMPL6 challenge. We used the conventional, "untrained", free energy based approach wherein the octanol/water partition coefficient was computed directly as the difference in solvation free energy in water and 1-octanol. We additionally proposed and used two different forms of a "trained" approach. Physically, the goal of the trained approach is to relate the partition coefficient computed using pure 1-octanol to that using water-saturated 1-octanol. In the first case, we assumed the partition coefficient using water-saturated 1-octanol and pure 1-octanol are linearly correlated. In the second approach, we assume the solvation free energy in water-saturated 1-octanol can be written as a linear combination of the solvation free energy in pure water and 1-octanol. In all cases here, the solvation free energies were computed using electronic structure calculations in the SM12, SM8, and SMD universal solvent models. In the context of the present study, our results in general do not support the additional effort of the trained approach.