The RMSEs for both the experimental validation ligands (green curve) and those yet to be evaluated via simulations (purple curve) show low RMSE values, by the end of the learning cycle reaching 1.00±0.09 and 1.19±0.08 kcal/mol, respectively (Fig. ). These error magnitudes are already on par with those expected from the reference MD simulations. Furthermore, as the iterations progress and more ligands are added to the training set, model accuracy increases. This can be seen from the decrease in RMSE for ligands that will be evaluated for subsequent iterations (Fig. ). The prediction accuracy for validation ligands (molecules with the experimentally measured affinities) does not change much with every iteration, yet a low RMSE value of ∼1 kcal/mol is retained. As the ligands from the validation set all have fairly low binding affinities, few chemically similar molecules are added to the training, leading to little opportunity for improvement in those regions of chemical space.