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Modeling the Effect of Solvation on Structure, Reactivity, and Partitioning of Organic Solutes: Utility in Drug Design

Chambers, C. C.; Giesen, D. J.; Hawkins, G. D.; Vaes, W. H. J.; Cramer, C. J.; Truhlar, D. G.
in Rational Drug Design, Truhlar, D. G., Howe, W. J., Hopfinger, A. J., Blaney, J. M., Dammkoehler, R. A., Eds.; Springer: New York, 1999, 51.

The SMx family of quantum mechanical solvation models accounts for electric and electronic polarization via the generalized Born model and for non-electrostatic components of solvation by microscopic surface tensions. The SM5.4 model, which is the most physical member of the SMx family, has been parameterized using two electronic Hamiltonians, AM1 and PM3. For both Hamiltonians, solvation parameters are obtained for water and for any organic solvent for which certain macroscopic data are available, in particular, the index of refraction, bulk surface tension, dielectric constant, and hydrogen bonding acidity and basicity as measured by the Abraham empirical alpha2 and beta2 scales. For neutral solutes, the mean unsigned errors for aqueous and non-aqueous free energies of solvation are 0.5 kcal/mol (215 data points) and 0.4 kcal/mol (1784 data points), respectively (for either Hamiltonian). By adding solvation effects to gas-phase calculations, it is possible to model the effects of solvent on conformational analysis, molecular recognition, reaction kinetics, etc. The SM5.4 model is also useful for the calculation of solute partitioning between two solvents. Moreover, it is possible to generalize the SM5.4 model to media that are less well characterized than homogeneous solvents--an example is presented here for the case of bilayers of phosphatidyl choline--in order to model partitioning between biophases.

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