Assessing the Accuracy and Performance of Implicit Solvent Models for Drug Molecules: Conformational Ensemble Approaches

The accuracy and performance of implicit
solvent methods for solvation
free energy calculations were assessed on a set of 20 neutral drug
molecules. Molecular dynamics (MD) provided ensembles of conformations
in water and water-saturated octanol. The solvation free energies
were calculated by popular implicit solvent models based on quantum
mechanical (QM) electronic densities (COSMO-RS, MST, SMD) as well
as on molecular mechanical (MM) point-charge models (GB, PB). The
performance of the implicit models was tested by a comparison with
experimental water–octanol transfer free energies (ΔGow) by using single- and multiconformation approaches.
MD simulations revealed difficulties in a priori estimation of the
flexibility features of the solutes from simple structural descriptors,
such as the number of rotatable bonds. An increasing accuracy of the
calculated ΔGow was observed in
the following order: GB1 ∼ PB < GB7 ≪ MST < SMD
∼ COSMO-RS with a clear distinction identified between MM-
and QM-based models, although for the set excluding three largest
molecules, the differences among COSMO-RS, MST, and SMD were negligible.
It was shown that the single-conformation approach applied to crystal
geometries provides a rather accurate estimate of ΔGow for rigid molecules yet fails completely for the flexible
ones. The multiconformation approaches improved the performance, but
only when the deformation contribution was ignored. It was revealed
that for large-scale calculations on small molecules a recent GB model,
GB7, provided a reasonable accuracy/speed ratio. In conclusion, the
study contributes to the understanding of solvation free energy calculations
for physical and medicinal chemistry applications.