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

Palmer, David and McDonagh, James L and Mitchell, John B.O. and van Mourik, Tanja and Fedorov, Maxim (2012) First principles calculation of the intrinsic aqueous solubility of crystalline druglike molecules. Journal of Chemical Theory and Computation, 8 (9). 3322–3337. ISSN 1549-9618

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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.

Item type: Article
ID code: 40594
Keywords: solubility, RISM, hydration, sublimation, crystal, first-principles, ab initio, drug discovery, bioavailability, pharmacokinetics, first principles, calculation, intrinsic aqueous solubility, crystalline, druglike molecules, Physics, Physical and Theoretical Chemistry, Computer Science Applications
Subjects: Science > Physics
Department: Faculty of Science > Physics
Technology and Innovation Centre > Bionanotechnology
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Depositing user: Pure Administrator
Date Deposited: 30 Jul 2012 13:45
Last modified: 27 Mar 2014 10:22
URI: http://strathprints.strath.ac.uk/id/eprint/40594

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