Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 3322–3337 |
| Number of pages | 16 |
| Journal | Journal of Chemical Theory and Computation |
| Volume | 8 |
| Issue number | 9 |
| Early online date | 25 Jul 2012 |
| DOIs | |
| Publication status | Published - 11 Sep 2012 |
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Keywords
- solubility
- RISM
- hydration
- sublimation
- crystal
- first-principles
- ab initio
- drug discovery
- bioavailability
- pharmacokinetics
- first principles
- calculation
- intrinsic aqueous solubility
- crystalline
- druglike molecules
Cite this
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First principles calculation of the intrinsic aqueous solubility of crystalline druglike molecules. / Palmer, David; McDonagh, James L ; Mitchell, John B.O. ; van Mourik, Tanja ; Fedorov, Maxim.
In: Journal of Chemical Theory and Computation , Vol. 8, No. 9, 11.09.2012, p. 3322–3337.Research output: Contribution to journal › Article
TY - JOUR
T1 - First principles calculation of the intrinsic aqueous solubility of crystalline druglike molecules
AU - Palmer, David
AU - McDonagh, James L
AU - Mitchell, John B.O.
AU - van Mourik, Tanja
AU - Fedorov, Maxim
PY - 2012/9/11
Y1 - 2012/9/11
N2 - 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.
AB - 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.
KW - solubility
KW - RISM
KW - hydration
KW - sublimation
KW - crystal
KW - first-principles
KW - ab initio
KW - drug discovery
KW - bioavailability
KW - pharmacokinetics
KW - first principles
KW - calculation
KW - intrinsic aqueous solubility
KW - crystalline
KW - druglike molecules
UR - http://www.scopus.com/inward/record.url?scp=84866162469&partnerID=8YFLogxK
U2 - 10.1021/ct300345m
DO - 10.1021/ct300345m
M3 - Article
VL - 8
SP - 3322
EP - 3337
JO - Journal of Chemical Theory and Computation
JF - Journal of Chemical Theory and Computation
SN - 1549-9618
IS - 9
ER -