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**Harvard**

Lüder, K., Lindfors, L., Westergren, J., Nordholm, S., Persson, R. och Pedersen, M. (2009) *In Silico Prediction of Drug Solubility: 4. Will Simple Potentials Suffice?*.

** BibTeX **

@article{

Lüder2009,

author={Lüder, Kai and Lindfors, Lennart and Westergren, Jan and Nordholm, Sture and Persson, Rasmus and Pedersen, Mikaela},

title={In Silico Prediction of Drug Solubility: 4. Will Simple Potentials Suffice?},

journal={Journal of Computational Chemistry},

issn={0192-8651},

volume={30},

issue={12},

pages={1859},

abstract={In view of the extreme importance of reliable computational prediction of aqueous drug solubility, we
have established a Monte Carlo simulation procedure which appears, in principle, to yield reliable solubilities even
for complex drug molecules. A theory based on judicious application of linear response and mean field approximations
has been found to reproduce the computationally demanding free energy determinations by simulation while at
the same time offering mechanistic insight. The focus here is on the suitability of the model of both drug and solvent,
i.e., the force fields. The optimized potentials for liquid simulations all atom (OPLS-AA) force field, either intact or
combined with partial charges determined either by semiempirical AM1/CM1A calculations or taken from the condensed-
phase optimized molecular potentials for atomistic simulation studies (COMPASS) force field has been used.
The results illustrate the crucial role of the force field in determining drug solubilities. The errors in interaction energies
obtained by the simple force fields tested here are still found to be too large for our purpose but if a component
of this error is systematic and readily removed by empirical adjustment the results are significantly improved. In fact,
consistent use of the OPLS-AA Lennard-Jones force field parameters with partial charges from the COMPASS force
field will in this way produce good predictions of amorphous drug solubility within 1 day on a standard desktop PC.
This is shown here by the results of extensive new simulations for a total of 47 drug molecules which were also
improved by increasing the water box in the hydration simulations from 500 to 2000 water molecules.},

year={2009},

keywords={solubility; drug molecule; free energy; Monte-Carlo simulation; crystal energy calculation; amorphous},

}

** RefWorks **

RT Journal Article

SR Electronic

ID 113169

A1 Lüder, Kai

A1 Lindfors, Lennart

A1 Westergren, Jan

A1 Nordholm, Sture

A1 Persson, Rasmus

A1 Pedersen, Mikaela

T1 In Silico Prediction of Drug Solubility: 4. Will Simple Potentials Suffice?

YR 2009

JF Journal of Computational Chemistry

SN 0192-8651

VO 30

IS 12

AB In view of the extreme importance of reliable computational prediction of aqueous drug solubility, we
have established a Monte Carlo simulation procedure which appears, in principle, to yield reliable solubilities even
for complex drug molecules. A theory based on judicious application of linear response and mean field approximations
has been found to reproduce the computationally demanding free energy determinations by simulation while at
the same time offering mechanistic insight. The focus here is on the suitability of the model of both drug and solvent,
i.e., the force fields. The optimized potentials for liquid simulations all atom (OPLS-AA) force field, either intact or
combined with partial charges determined either by semiempirical AM1/CM1A calculations or taken from the condensed-
phase optimized molecular potentials for atomistic simulation studies (COMPASS) force field has been used.
The results illustrate the crucial role of the force field in determining drug solubilities. The errors in interaction energies
obtained by the simple force fields tested here are still found to be too large for our purpose but if a component
of this error is systematic and readily removed by empirical adjustment the results are significantly improved. In fact,
consistent use of the OPLS-AA Lennard-Jones force field parameters with partial charges from the COMPASS force
field will in this way produce good predictions of amorphous drug solubility within 1 day on a standard desktop PC.
This is shown here by the results of extensive new simulations for a total of 47 drug molecules which were also
improved by increasing the water box in the hydration simulations from 500 to 2000 water molecules.

LA eng

DO 10.1002/jcc.21173

LK http://dx.doi.org/10.1002/jcc.21173

OL 30