In silico prediction of drug solubility: 4. Will simple potentials suffice?

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.

Approaches for Calculating Solvation Free Energies and Enthalpies Demonstrated with an Update of the FreeSolv Database

“…Free energies of solvation in pure melts and pure amorphous matter have been used to find upper bounds for solubilities given that most drug-like compounds have crystal polymorphs. 67–70 Relative solubilities of a given chemical species between different solvents can also be assessed with these calculations. 24,71 Henry’s law solubility constants 72,73 and solubilities in supercritical fluids 74 can also be predicted using solvation free energies.…”

Exploratory analysis of kinetic solubility measurements of a small molecule library

“…Despite imperfect training sets, numerous computational tools (commercial and non-commercial) for solubility prediction exist to help during library design and optimization efforts. 11–15 Solubility measurements from a large compound collection achieved via a common methodology would be useful in terms of validating current dogma and as a relevant training set for advanced computational models. In 2009, Clark and coworkers reported the kinetic solubilities from a drug-like collection of >700 compounds and provided an analysis of the results in terms of selected physical and calculated descriptors of the library members.…”

Thermodynamic aspects of solubility, solvation and partitioning processes of some sulfonamides

“…It is well-known that in order to estimate the solubility of any compound it is necessary to know two molecular properties at the same time: (i) the sublimation Gibbs free energy and (ii) the solvation/hydration Gibbs free energy. There are quite robust calculation methods for estimation of the solvation/hydration Gibbs free energy [25], whereas analogous methods for estimation of the sublimation Gibbs free energy of solid state molecules without knowledge of crystalline structure are absent. The proposed approach provides an opportunity to eliminate this gap and to carry out the estimation of solubility values on the basis of molecular structure information only.…”