First-principles calculation of the intrinsic aqueous solubility of crystalline druglike molecules

David S. Palmer; James L. McDonagh; John B. O. Mitchell; Tanja van Mourik; Maxim V. Fedorov

doi:10.1021/ct300345m

First-principles calculation of the intrinsic aqueous solubility of crystalline druglike molecules

David S. Palmer, James L. McDonagh, John B. O. Mitchell, Tanja van Mourik, Maxim V. Fedorov

Research output: Contribution to journal › Article › peer-review

Abstract

We demonstrate that the intrinsic aqueous solubility of crystalline druglike molecules can be estimated with reasonable accuracy from sublimation free energies calculated using crystal lattice simulations and hydration free energies calculated using the 3D Reference Interaction Site Model (3D-RISM) of the Integral Equation Theory of Molecular Liquids (IET). The solubilities of 25 crystalline druglike molecules taken from different chemical classes are predicted by the model with a correlation coefficient of R = 0.85 and a root mean square error (RMSE) equal to 1.45 log(10) S units, which is significantly more accurate than results obtained using implicit continuum solvent models. The method is not directly parametrized against experimental solubility data, and it offers a full computational characterization of the thermodynamics of transfer of the drug molecule from crystal phase to gas phase to dilute aqueous solution.

Original language	English
Pages (from-to)	3322-3337
Number of pages	16
Journal	Journal of Chemical Theory and Computation
Volume	8
Issue number	9
Early online date	9 Aug 2012
DOIs	https://doi.org/10.1021/ct300345m
Publication status	Published - 11 Sept 2012

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Copyright © 2012 American Chemical Society. This work has been made available online in accordance with publisher policies or with permission. Permission for further reuse of this content should be sought from the publisher or the rights holder. This is the author created accepted manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1021/ct300345m
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title = "First-principles calculation of the intrinsic aqueous solubility of crystalline druglike molecules",

abstract = "We demonstrate that the intrinsic aqueous solubility of crystalline druglike molecules can be estimated with reasonable accuracy from sublimation free energies calculated using crystal lattice simulations and hydration free energies calculated using the 3D Reference Interaction Site Model (3D-RISM) of the Integral Equation Theory of Molecular Liquids (IET). The solubilities of 25 crystalline druglike molecules taken from different chemical classes are predicted by the model with a correlation coefficient of R = 0.85 and a root mean square error (RMSE) equal to 1.45 log(10) S units, which is significantly more accurate than results obtained using implicit continuum solvent models. The method is not directly parametrized against experimental solubility data, and it offers a full computational characterization of the thermodynamics of transfer of the drug molecule from crystal phase to gas phase to dilute aqueous solution.",

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T1 - First-principles calculation of the intrinsic aqueous solubility of crystalline druglike molecules

AU - Palmer, David S.

AU - McDonagh, James L.

AU - Mitchell, John B. O.

AU - van Mourik, Tanja

AU - Fedorov, Maxim V.

PY - 2012/9/11

Y1 - 2012/9/11

N2 - We demonstrate that the intrinsic aqueous solubility of crystalline druglike molecules can be estimated with reasonable accuracy from sublimation free energies calculated using crystal lattice simulations and hydration free energies calculated using the 3D Reference Interaction Site Model (3D-RISM) of the Integral Equation Theory of Molecular Liquids (IET). The solubilities of 25 crystalline druglike molecules taken from different chemical classes are predicted by the model with a correlation coefficient of R = 0.85 and a root mean square error (RMSE) equal to 1.45 log(10) S units, which is significantly more accurate than results obtained using implicit continuum solvent models. The method is not directly parametrized against experimental solubility data, and it offers a full computational characterization of the thermodynamics of transfer of the drug molecule from crystal phase to gas phase to dilute aqueous solution.

AB - We demonstrate that the intrinsic aqueous solubility of crystalline druglike molecules can be estimated with reasonable accuracy from sublimation free energies calculated using crystal lattice simulations and hydration free energies calculated using the 3D Reference Interaction Site Model (3D-RISM) of the Integral Equation Theory of Molecular Liquids (IET). The solubilities of 25 crystalline druglike molecules taken from different chemical classes are predicted by the model with a correlation coefficient of R = 0.85 and a root mean square error (RMSE) equal to 1.45 log(10) S units, which is significantly more accurate than results obtained using implicit continuum solvent models. The method is not directly parametrized against experimental solubility data, and it offers a full computational characterization of the thermodynamics of transfer of the drug molecule from crystal phase to gas phase to dilute aqueous solution.

U2 - 10.1021/ct300345m

DO - 10.1021/ct300345m

M3 - Article

SN - 1549-9618

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EP - 3337

JO - Journal of Chemical Theory and Computation

JF - Journal of Chemical Theory and Computation

IS - 9

ER -

First-principles calculation of the intrinsic aqueous solubility of crystalline druglike molecules

Abstract

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