The compound S08 consists of a nitrile group of which the nitrogen is highly electronegative. Although the negatively charged residues at the R2 pocket are unfavourable for the presentence of the nitrile group, the positively charged residue LYS329 and the relatively spacious pocket appear to be able to tolerate the group. The detailed analyses of the simulation trajectories do not provide more insights. Further searching in the experimental data set has identified another compound which is very similar to S08 and shares the same nitrile group at the R2. The compound also does not show any activities at the highest concentration tested in the assay (data not shown). Although it could be an experimental issue, it is more likely to be a force field or possibly sampling issue. As there are no satisfactory explanations for the disagreement between the experiments and the calculations, S08 remains as an unexplained outlier. Such unexplained outliers are not unusual in drug discovery and development projects. Machinelearning approaches have been proposed to identify the differences between the calculations and the experimental data, and to provide empirical correction terms to the predictions from the alchemical approaches but these too depend on assumptions which are rarely articulated concerning the way in which the data are distributed .