Prediction Methods Based on 3-D Molecular Structure

These methods were developed to avoid the definition and parameterization of numerous fragments or atomic types and to allow the prediction of lipophilicity for stereoisomers or conformers. Only a selection of methods are highlighted here, since an excellent extensive review was recently published [34]. 

Use of Modified Atomic Contributions Some variations were made on the atom- 

Villar et al. developed an atomic hydrophobicity contribution that depends on the molecular conformation. The hydrophobicity parameters were calculated by including charge densities, atomic contributions to the total molecular surface area and the molecular dipole moment [47, 48]. This method is implemented in the SPARTAN software. 

A modification of the atomic approach was also proposed by Gaillard et al. using molecular lipophilicity potential (MLP) as a 3D source of two lipophilicity parameters calculated from the water-accessible surface, namely a hydrophobic parameter expressed as the sum ofthe positive lipophilicity potential (EM LP+) and a polar parameter expressed as the sum of the negative lipophilicity potential (EMLP—) 

Cruciani et al., used a dynamic physicochemical interaction model to evaluate the interaction energies between a water probe and the hydrophilic and hydrophobic regions of the solute with the GRID force field. The VolSurf program was used to generate a PLS model able to predict log Poet [51] from the 3D molecular structure. 

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