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

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

Research output: Contribution to journalArticle

46 Citations (Scopus)

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 (3DRISM) 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 R = 0.85 and RMSE = 1.45 log10 S units, which is significantly more accurate than results obtained using implicit continuum solvent models. The method is not directly parameterized 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.
LanguageEnglish
Pages3322–3337
Number of pages16
JournalJournal of Chemical Theory and Computation
Volume8
Issue number9
Early online date25 Jul 2012
DOIs
Publication statusPublished - 11 Sep 2012

Fingerprint

solubility
Solubility
Crystalline materials
Free energy
Molecules
free energy
molecules
Sublimation
sublimation
crystal lattices
Crystal lattices
Hydration
Integral equations
hydration
integral equations
drugs
Gases
Thermodynamics
vapor phases
continuums

Keywords

  • solubility
  • RISM
  • hydration
  • sublimation
  • crystal
  • first-principles
  • ab initio
  • drug discovery
  • bioavailability
  • pharmacokinetics
  • first principles
  • calculation
  • intrinsic aqueous solubility
  • crystalline
  • druglike molecules

Cite this

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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 (3DRISM) 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 R = 0.85 and RMSE = 1.45 log10 S units, which is significantly more accurate than results obtained using implicit continuum solvent models. The method is not directly parameterized 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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First principles calculation of the intrinsic aqueous solubility of crystalline druglike molecules. / Palmer, David; McDonagh, James L ; Mitchell, John B.O. ; van Mourik, Tanja ; Fedorov, Maxim.

In: Journal of Chemical Theory and Computation , Vol. 8, No. 9, 11.09.2012, p. 3322–3337.

Research output: Contribution to journalArticle

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