Next, we look at a fragment elaboration study by Murray et al. elaborating 17 ligands from an initial fragment hit (ligand 3, SI Fig. , SI Table ). Whilst the original study does outline two separate fragment elaboration campaigns, we specifically looked at the second elaboration set which involved a larger number of ligands. As shown in Fig. , the free energy estimates correlate very well with the experimental values with a Pearson r of 0.96 ± 0.03 and a Kendall 𝜏 of 0.73 ± 0.12. However, we do see a progressive deviation from experiment as the affinity of the ligands increases leading to a RMSE of 3.82 ± 0.33 kcal/mol. This difference between calculated and experimental values has been observed by other free energy studies of HSP90 and as detailed by Baumann et al. , is possibly explained by several slow degrees of freedom associated with HSP90 binding. These include; the presence of varying waters in the binding site, ligand re-orientation, and side-chain motions.