However, the predicted conformation of the unsubstituted benzyloxy side chain is at odds with the crystal structure (7L12). The correct conformer is output as an alternative low energy conformer and, interestingly, the majority of the modelled larger, substituted benzyloxy groups adopt the crystal conformation. This is exemplified by 21 in Figure (d), which also correctly orients the ortho-Cl down into the S4 pocket. The uracil series comprises a set of 13 analogs, spanning around 2.5 kcal/mol in binding free energy, and as such provides a useful benchmark for demonstrating the next stage of the workflow. Although the gnina CNN affinities for these compounds are reasonably well correlated with experimental IC50 measurements in a kinetic assay (Figure ), it is desirable to investigate whether more rigorous free energy methods can be used to improve accuracy. Hence, relative binding free energies were computed using the SOMD software, starting from the structures output by the FEgrow workflow in complex with the receptor (see Computational Methods). Note that we have used the lowest energy structures as input to the free energy calculations (using instead the structure of e.g. 14 that corresponds most closely to the crystal structure can introduce differences of up to 0.4 kcal/mol in free energies in our tests, but this information would not be available for prospective studies).