Challenges of the Use of Atomistic Simulations to Predict Solubilities of Drug-like Molecules

<div><b>Background.</b></div><div>Solubility is a physical property of extreme importance to the Pharmaceutical industry whose prediction for potential drugs has so far been a hard task.</div><div>We attempted to predict the solubility of acetylsalicylic acid (ASA) by estimating absolute chemical potentials of its most stable polymorph and of solutions with different concentrations of the drug molecule.</div><div><br></div><div><b>Methods.</b></div><div>Chemical potentials were estimated from all-atom molecular dynamics simulations. </div><div>We used the Einstein Molecule Method to predict the absolute chemical potential of the solid and solvation free energy calculations to predict the excess chemical potentials of the liquid phase systems.</div><div><br></div><div><b>Results.</b></div><div>Reliable estimations of the chemical potentials for the solid and for a single ASA molecule using the Einstein Molecule Method required an extremely large number of intermediate states for the free energy calculations, meaning that the calculations were extremely demanding computationally.</div><div>Despite the computational cost, however, the computed value did not agree well with experiment, potentially due to limitations with the underlying energy model.</div><div>Perhaps better values could be obtained with a better energy model; however, it seems likely computational cost may remain a limiting factor for use of this particular approach to solubility estimation. </div><div><br></div><div><b>Conclusions.</b></div><div>Solubility prediction of drug-like solids still is a challenge on the computational side, and it appears that both the underlying energy model and the computational approach applied may need improvement before the approach is suitable for routine use.</div>