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 log10S 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.
authors.affiliation: Department of Physics, University of Strathclyde , John Anderson Building, 107 Rottenrow, Glasgow, Scotland G4 0NG, United Kingdom.|Max Planck Institute for Mathematics in the Sciences , Inselstrasse 22, DE-04103 Leipzig, Germany.
authors.forename: David S
authors.initials: DS
authors.lastname: Palmer
authors.affiliation: Biomedical Sciences Research Complex and EaStCHEM School of Chemistry, University of St. Andrews , Purdie Building, North Haugh, St. Andrews, Scotland KY16 9ST, United Kingdom.
authors.forename: James L
authors.initials: JL
authors.lastname: McDonagh
authors.affiliation: Biomedical Sciences Research Complex and EaStCHEM School of Chemistry, University of St. Andrews , Purdie Building, North Haugh, St. Andrews, Scotland KY16 9ST, United Kingdom.
authors.forename: John B O
authors.initials: JB
authors.lastname: Mitchell
authors.affiliation: Biomedical Sciences Research Complex and EaStCHEM School of Chemistry, University of St. Andrews , Purdie Building, North Haugh, St. Andrews, Scotland KY16 9ST, United Kingdom.
authors.forename: Tanja
authors.initials: T
authors.lastname: van Mourik
authors.affiliation: Department of Physics, University of Strathclyde , John Anderson Building, 107 Rottenrow, Glasgow, Scotland G4 0NG, United Kingdom.|Max Planck Institute for Mathematics in the Sciences , Inselstrasse 22, DE-04103 Leipzig, Germany.
authors.forename: Maxim V
authors.initials: MV
authors.lastname: Fedorov