In addition, since some compounds showed major variation in substituent size when compared to the starting scaffold and explicit water molecules are treated as frozen in the standard SP/XP docking, additional studies allowing protein side chain and water reorganization in response to ligand binding were performed using the standard protocol for the IF workflow implemented in Maestro. The planarity of conjugated πgroups was enhanced, and a Prime refinement was performed for residue side chains within 5 Å of ligand atoms. XP redocking was done as previously described, yielding up to 20 receptor-ligand complexes per compound. The validation of the docking protocol is presented in the SI.