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Abstract
Accurate computational methods to predict the solubility of crystalline organic molecules in water are highly sought after in many fields of the biomolecular sciences. For example, predictions of solubility are used in the agrochemical and pharmaceutical industries to assess the environmental fate of potential pollutants and the bioavailability of de novo designed drugs, respectively. While a number of statistical Quantitative StructureProperty Relationship (QSPR) solubility models have been built by many groups, including ourselves, development of a method based on chemical theory and molecular simulation has proved challenging. Successful construction of a fully theoretical method would bring both greater insight and systematic improvability, with physically meaningful component effects becoming quantifiable.
Here we show that reasonably accurate values for the intrinsic aqueous solubility of druglike organic molecules are obtainable from theory. We combine sublimation free energies calculated using the crystal lattice minimisation program DMACRYS with hydration free energies calculated using the 3D Reference Interaction Site Model (3DRISM) of the Integral Equation Theory of Molecular Liquids (IET). Intrinsic solubilities of 25 diverse crystalline druglike molecules are computed by our method, obtaining R=0.85 and RMSE =1.45 log10 S units. This is considerably better than results from implicit continuum solvent models such as the polarizable continuum model (PCM). We can fully computationally describe the thermodynamics of the transfer of a druglike molecule from the crystalline solid phase via the gas phase to dilute aqueous solution. Although the 3D RISM free energy functional that we use contains some parameters, our approach is not parameterized against experimentally measured solubilities. Ongoing work to improve the accuracy of the calculated sublimation thermodynamic parameters will also be discussed.
Here we show that reasonably accurate values for the intrinsic aqueous solubility of druglike organic molecules are obtainable from theory. We combine sublimation free energies calculated using the crystal lattice minimisation program DMACRYS with hydration free energies calculated using the 3D Reference Interaction Site Model (3DRISM) of the Integral Equation Theory of Molecular Liquids (IET). Intrinsic solubilities of 25 diverse crystalline druglike molecules are computed by our method, obtaining R=0.85 and RMSE =1.45 log10 S units. This is considerably better than results from implicit continuum solvent models such as the polarizable continuum model (PCM). We can fully computationally describe the thermodynamics of the transfer of a druglike molecule from the crystalline solid phase via the gas phase to dilute aqueous solution. Although the 3D RISM free energy functional that we use contains some parameters, our approach is not parameterized against experimentally measured solubilities. Ongoing work to improve the accuracy of the calculated sublimation thermodynamic parameters will also be discussed.
Original language  English 

Publication status  Published  4 Sept 2013 
Event  International Conference on the Properties of Water and Steam (ICPWS16)  London, United Kingdom Duration: 1 Sept 2013 → 5 Sept 2013 
Conference
Conference  International Conference on the Properties of Water and Steam (ICPWS16) 

Country/Territory  United Kingdom 
City  London 
Period  1/09/13 → 5/09/13 
Keywords
 solubility
 solvation
 druglike
 pharmaceutical
 in silico screening
 physicochemical properties
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Investigating the accuracy of sublimation free energy prediction by ab initio and semiempirical methods.
Palmer, D., Fedorov, M., Mitchell, J., van Mourik, T. & McDonagh, J.
1/01/13 → …
Project: Research

IETSOL: CALCULATION OF PHARMACOKINETIC PROPERTIES OF DRUGLIKE MOLECULES USING INTEGRAL EQUATION THEORY
Palmer, D. & Fedorov, M.
1/02/12 → 31/01/14
Project: Research Fellowship

Novel Methods to Calculate Hydration Thermodynamic Parameters for Pharmaceutical and Pollutant Molecules
Palmer, D. & Fedorov, M.
1/01/11 → 31/10/11
Project: Internally funded project
Research output
 2 Article

First principles calculation of the intrinsic aqueous solubility of crystalline druglike molecules
Palmer, D., McDonagh, J. L., Mitchell, J. B. O., van Mourik, T. & Fedorov, M., 11 Sept 2012, In: Journal of Chemical Theory and Computation . 8, 9, p. 3322–3337 16 p.Research output: Contribution to journal › Article › peerreview
77 Citations (Scopus) 
In silico screening of bioactive and biomimetic solutes using Integral Equation Theory
Palmer, D. S., Chuev, G. N., Ratkova, E. L. & Fedorov, M. V., Jun 2011, In: Current Pharmaceutical Design. 17, 17, p. 16951708 14 p.Research output: Contribution to journal › Article › peerreview
19 Citations (Scopus)