Conformation Dependence of Results

The dependence of the QikProp results on molecular conformation has been studied by performing conformational searches on many molecules using BOSS with the OPLS-AA force field, followed by QikProp calculations for each conformer. The results demonstrate the following points:

1. There is generally modest difference in the QikProp predictions for different conformers. This results because the algorithms for determining the hydrogen-bond counts, which are very important descriptors, are independent of the 3D structure. The surface area and dipole moment terms are affected by conformation, but their variations are generally small. The differences are always negligible for log BB and PCaco. The differences for log Po/w are also small, normally a few tenths of a log unit. The differences can be greater for log S, but rarely cover more than 1 log unit.
2. When there are differences, extended structures give results closer to the experimental data. The QikProp regressions have been developed using extended conformers; standard 2D–3D conversion programs usually generate extended conformers.
3. Boltzmann-weighting of the QikProp results using either the gas-phase conformer energies or the aqueous-phase conformer energies is probably not worth the effort, though it is theoretically desirable.

The results for six drugs are described below. The drugs each have multiple rotatable bonds, which were explored in the conformational searches. Clearly, negligible dependence of the results on conformation is expected for more rigid molecules.

  • acyclovir—43 conformers covering an energy range of 9 kcal/mol were considered. The QPlogS values range from 0.3 to 0.5; the QPlogPo/w values range from −0.2 to −0.4.

  • epinephrine—69 conformers covering an energy range of 14 kcal/mol were considered. The QPlogS values range from 0.3 to 0.6; the QPlogPo/w values range from −0.2 to −0.4.

  • haloperidol—49 conformers covering an energy range of 18 kcal/mol were considered. The QPlogS values fall in two groups, −3 to −4 for very compact conformers with the fluorophenyl ring folded on top of the piperidine, and −4.5 to −5.0 for extended structures. The experimental log S is −4.4. The QPlogPo/w values range from 3.9 to 4.5 for all conformers.

  • linezolid—68 conformers covering an energy range of 9 kcal/mol were considered. The QPlogS values range from −1.7 to −2.3; the QPlogPo/w values range from 0.3 to 0.9.

  • omeprazole—42 conformers covering an energy range of 8 kcal/mol were considered. The QPlogS values range from −2.9 to −3.9 for the first 45 conformers; the QPlogPo/w values range from 1.5 to 2.2 for the first 42 conformers.

  • indinavir—29 conformers covering an energy range of 8 kcal/mol were considered. The QPlogS values range from −2.3 to −0.2; the QP log Po/w values range from 0.8 to 1.4. This is a very flexible molecule with 16 variable dihedral angles included in the conformational search. The more extended structures give lower log S and higher log P values.