Challenges in the use of atomistic simulations to predict solubilities of drug-like molecules

Abstract: Molecular simulations begin with an underlying energy model or force field and from this can predict diverse physical properties. However, force fields were often developed with relatively limited data sets, yet accuracy for diverse properties across a broad chemical space is desirable; therefore, tests of such accuracy are particularly important. Here, to this end, we calculated 237 infinite dilution activity coefficients (IDACs), comparing with experimental values from NIST’s ThermoML database. We found that calculated IDAC values correlate strongly with experiment (Pearson R of 0.92 $\pm$ 0.01) and allow us to identify specific functional groups that appear to present challenges to the force field employed. One potentially valuable aspect of IDACs, as compared to solvation free energies, which have been frequently employed as force field tests, is that the same molecules serve both as solutes and solvents in different cases, allowing us to ensure that force fields are not overly tuned to one particular environment or solvent.

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Recommended citation: G. Duarte Ramos Matos, et al. (2019). “Infinite Dilution Activity Coefficients as Constraints for Force Field Parametrization and Method Development”; J. Chem. Theory Comput.. 15 (5), 3066-3074.