In this study, two fragment series are grown in parallel, with an eventual merge to form a nanomolar compound (SI Fig S3, Table ). Here we have one of the lowest correlations between calculated and experimental ΔG values with a Pearson r of 0.81 ± 0.08 and a Kendall 𝜏 of 0.56 ± 0.15. We also see a shift from experiment in the absolute values, with an RMSE of 2.33 ± 0.24 kcal/mol. It should also be noted that in this series only an upper bound Ki of > 1000 µM was assigned for three of the ligands (ligands 1, 6, and 12, SI Table ).