Abstract
In order for computer-aided drug design to fulfil its long held promise of delivering new medicines faster and cheaper, extensive development and validation work must be done first. This pertains particularly to molecular dynamics force fields where one important aspect-the hydration free energy (HFE) of small molecules-is often insufficiently analyzed. While most benchmarking studies report excellent accuracies of calculated hydration free energies-usually within 2 kcal/mol of experimental values-we find that deeper analysis reveals significant shortcomings. Herein, we report a dependence of HFE prediction errors on ligand molecular weight-the higher the weight, the bigger the prediction error and the higher the probability the calculated result is erroneous by a large amount. We show that in the drug-like molecular weight region, HFE predictions can easily be off by 5 kcal/mol or more. This is likely to be highly problematic in a drug discovery and development setting. We make our HFE results and molecular descriptors freely and fully available in order to encourage deeper analysis of future molecular dynamics results and facilitate development of the next generation of force fields.