The computational cost of ABFEs is not insignificant, being easily orders of magnitude higher than cheaper endpoint methods. Previous works Additionally, for MCL-1 whilst the fragment optimisation activity cliffs for decision 1 cannot be clearly distinguished due to large uncertainties, the optimisation of ligand 12 into ligand 13 (decision 3), which could not be supported by the ABFE results can be clearly identified using Nwat-MM/GBSA. We can also compare some of the results with previously published RBFE data. Specifically, a subset of the MCL-1 dataset investigated here was also calculated using FEP+ in