Journal
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
Volume 8, Issue 9, Pages 3322-3337Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ct300345m
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Funding
- Scottish Universities Physics Alliance (SUPA)
- Deutsche Forschungsgemeinschaft (DFG)-German Research Foundation [FE 1156/ 2-1]
- Forschungszentrum Juelich GmbH, Germany [HLZ18, HLZ16]
- European Commission [FP7-PEOPLE-2010-1EF]
- Scottish Universities Life Sciences Alliance (SULSA)
- Engineering and Physical Sciences Research Council [EP/K000195/1] Funding Source: researchfish
- EPSRC [EP/K000195/1] Funding Source: UKRI
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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 (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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