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Modeling free energies of solvation in olive oil.

ABSTRACT: Olive oil partition coefficients are useful for modeling the bioavailability of drug-like compounds. We have recently developed an accurate solvation model called SM8 for aqueous and organic solvents (Marenich, A. V.; Olson, R. M.; Kelly, C. P.; Cramer, C. J.; Truhlar, D. G. J. Chem. Theory Comput. 2007, 3, 2011) and a temperature-dependent solvation model called SM8T for aqueous solution (Chamberlin, A. C.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2008, 112, 3024). Here we describe an extension of SM8T to predict air-olive oil and water-olive oil partitioning for drug-like solutes as functions of temperature. We also describe the database of experimental partition coefficients used to parametrize the model; this database includes 371 entries for 304 compounds spanning the 291-310 K temperature range.

SUBMITTER: Chamberlin AC

PROVIDER: S-EPMC2772112 | biostudies-literature | 2008 Nov-Dec

REPOSITORIES: biostudies-literature

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Modeling free energies of solvation in olive oil.

Chamberlin Adam C AC Levitt David G DG Cramer Christopher J CJ Truhlar Donald G DG

Molecular pharmaceutics 20081101 6

Olive oil partition coefficients are useful for modeling the bioavailability of drug-like compounds. We have recently developed an accurate solvation model called SM8 for aqueous and organic solvents (Marenich, A. V.; Olson, R. M.; Kelly, C. P.; Cramer, C. J.; Truhlar, D. G. J. Chem. Theory Comput. 2007, 3, 2011) and a temperature-dependent solvation model called SM8T for aqueous solution (Chamberlin, A. C.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2008, 112, 3024). Here we describe an ext ...[more]

PMID: 19434923

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Project description:Accurate yet efficient computational models of solvent environment are central for most calculations that rely on atomistic modeling, such as prediction of protein-ligand binding affinities. In this study, we evaluate the accuracy of a recently developed generalized Born implicit solvent model, GBNSR6 (Aguilar et al. J. Chem. Theory Comput. 2010, 6, 3613-3639), in estimating the electrostatic solvation free energies (ΔG(pol)) and binding free energies (ΔΔG(pol)) for small protein-ligand complexes. We also compare estimates based on three different explicit solvent models (TIP3P, TIP4PEw, and OPC). The two main findings are as follows. First, the deviation (RMSD = 7.04 kcal/mol) of GBNSR6 binding affinities from commonly used TIP3P reference values is comparable to the deviations between explicit models themselves, e.g. TIP4PEw vs TIP3P (RMSD = 5.30 kcal/mol). A simple uniform adjustment of the atomic radii by a single scaling factor reduces the RMS deviation of GBNSR6 from TIP3P to within the above "error margin" - differences between ΔΔG(pol) estimated by different common explicit solvent models. The simple radii scaling virtually eliminates the systematic deviation (ΔΔG(pol)) between GBNSR6 and two out of the three explicit water models and significantly reduces the deviation from the third explicit model. Second, the differences between electrostatic binding energy estimates from different explicit models is disturbingly large; for example, the deviation between TIP4PEw and TIP3P estimates of ΔΔG(pol) values can be up to ∼50% or ∼9 kcal/mol, which is significantly larger than the "chemical accuracy" goal of ∼1 kcal/mol. The absolute ΔG(pol) calculated with different explicit models could differ by tens of kcal/mol. These discrepancies point to unacceptably high sensitivity of binding affinity estimates to the choice of common explicit water models. The absence of a clear "gold standard" among these models strengthens the case for the use of accurate implicit solvation models for binding energetics, which may be orders of magnitude faster.

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Modeling free energies of solvation in olive oil.

Publications

Modeling free energies of solvation in olive oil.

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