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

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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.
Original languageEnglish
Pages (from-to)3322–3337
Number of pages16
JournalJournal of Chemical Theory and Computation
Issue number9
Early online date25 Jul 2012
Publication statusPublished - 11 Sep 2012



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

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