Based on an Ensemble of Conformers

The first method based on an ensemble of conformers was developed by Hopfinger and Battershell in 1976. Using the solvent-dependent conformational analysis procedure (SCAP), which identifies the preferred conformations of a solute in different solvents (water, methanol, ethanol, -octanol), the free energy of the solute at 300 K can be calculated, whereupon the partition coefficients can be obtained by means of Eq. [35]  

It is important to note that in this approach, the computed partition coefficients of flexible solutes depend only on their conformational gas phase energy minima. Thus only one conformational analysis (i.e., in the gas phase) must be performed to predict the global, conformation-dependent log P. In principle, any method of conformational analysis can be selected that is able to determine a distribution of conformers in the gas phase. To study linear, uncharged dipeptides, Richards and Williams used a stochastic sampling technique.Their results (Table 12) illustrate the accuracy of the method and demonstrate that stochastic sampling methods in combination with empirical solvation potentials provide fair estimates of experimental log P values of flexible compounds. 

The pharmacokinetics of flexible drug molecules is markedly influenced by their conformational behavior. As mentioned earlier, flexible compounds with suitable moieties may exhibit hydrophobic collapse in polar solvents, and hydrophilic folding in nonpolar environments. It is postulated that these 

As discussed above, the back-calculation of log P from the MLP opens a new field of investigations, that of modeling the distribution profile of flexible compounds by calculating lipophilicity variations in their conformational space. Two steps are needed to assess conformational effects on lipophilicity  

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