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

David Palmer; James L  McDonagh; John B.O.  Mitchell; Tanja  van Mourik; Maxim Fedorov

doi:10.1021/ct300345m

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

David Palmer, James L McDonagh, John B.O. Mitchell, Tanja van Mourik, Maxim Fedorov

Research output: Contribution to journal › Article › peer-review

56 Citations (Scopus)

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.

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	https://doi.org/10.1021/ct300345m
Publication status	Published - 11 Sep 2012

Keywords

solubility
RISM
hydration
sublimation
crystal
first-principles
ab initio
drug discovery
bioavailability
pharmacokinetics
first principles
calculation
intrinsic aqueous solubility
crystalline
druglike molecules

Access to Document

10.1021/ct300345m

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1 Active

Investigating the accuracy of sublimation free energy prediction by ab initio and semi-empirical methods.
Palmer, D., Fedorov, M., Mitchell, J., van Mourik, T. & McDonagh, J.
1/01/13 → …
Project: Research

ARCHIE-WeSt (UOSHPC)
Richard Martin (Manager)
University Of Strathclyde
Facility/equipment: Facility

56 Citations
3 Speech

Computational biomolecular design using the integral equation theory of molecular liquids: from drug discovery to bionanotechnology
Palmer, D., 4 Mar 2015.
Research output: Contribution to conference › Speech
Solvation thermodynamics of biomolecules from the integral equation theory of molecular liquids
Palmer, D., Misin, M. & Fedorov, M., 20 Aug 2014, (Unpublished).
Research output: Contribution to conference › Speech
Computing intrinsic aqueous solubility of crystalline organic molecules
Palmer, D. & Fedorov, M., 4 Sep 2013.
Research output: Contribution to conference › Speech

1 Participation in conference
1 Invited talk

Computational Biomolecular Design using the Integral Equation Theory of Molecular Liquids: from Drug Discovery to Bionanotechnology
David Palmer (Contributor)
27 Apr 2015
Activity: Talk or presentation types › Invited talk
WE-Heraeus Seminar on "Exploring Solvation Science"
David Palmer (Participant)
27 Oct 2014 → 30 Oct 2014
Activity: Participating in or organising an event types › Participation in conference

Cite this

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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 (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. ",

keywords = "solubility, RISM, hydration, sublimation, crystal, first-principles, ab initio, drug discovery, bioavailability, pharmacokinetics, first principles, calculation, intrinsic aqueous solubility, crystalline, druglike molecules",

author = "David Palmer and McDonagh, {James L} and Mitchell, {John B.O.} and {van Mourik}, Tanja and Maxim Fedorov",

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doi = "10.1021/ct300345m",

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AU - Palmer, David

AU - McDonagh, James L

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AU - van Mourik, Tanja

AU - Fedorov, Maxim

PY - 2012/9/11

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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.

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KW - first-principles

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KW - bioavailability

KW - pharmacokinetics

KW - first principles

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KW - druglike molecules

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

Abstract

Keywords

Access to Document

Investigating the accuracy of sublimation free energy prediction by ab initio and semi-empirical methods.

ARCHIE-WeSt (UOSHPC)

Computational biomolecular design using the integral equation theory of molecular liquids: from drug discovery to bionanotechnology

Solvation thermodynamics of biomolecules from the integral equation theory of molecular liquids

Computing intrinsic aqueous solubility of crystalline organic molecules

Computational Biomolecular Design using the Integral Equation Theory of Molecular Liquids: from Drug Discovery to Bionanotechnology

WE-Heraeus Seminar on "Exploring Solvation Science"

Cite this