### Abstract

Language | English |
---|---|

Pages | 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 |

### Fingerprint

### 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

*Journal of Chemical Theory and Computation*,

*8*(9), 3322–3337. https://doi.org/10.1021/ct300345m

}

*Journal of Chemical Theory and Computation*, vol. 8, no. 9, pp. 3322–3337. https://doi.org/10.1021/ct300345m

**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.

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

T2 - Journal of Chemical Theory and Computation

JF - Journal of Chemical Theory and Computation

SN - 1549-9618

IS - 9

ER -