for PWWP1 Böttcher et al . This was easily done for HSP90 41 and PWWP1 39 but was more complex for MCL-1 and Cyclophilin D . Indeed, for MCL-1 we opted to group the decisions into three sets of various substitutions, each for a specific fragment core, and one fragment merging decision. For Cyclophilin D, five clear fragment merging cases could be identified from the simulated ligands and these were used as the synthetic decisions. It is worth noting that the non-equal number of syntheses per decision, combined with our assessment that a failed decision occurs when in that set has an insufficiently estimated ΔΔG, makes it such that some decisions have a much higher predictive difficulty than others.