Hand-engineered poses performed better compared to those from pose prediction protocol for ligands with high similarity Some of the reference structures that we used in our docking protocol were very similar to the target ligands. For example, BACE_3 and the ligand co-crystallized with BACE-1 in the PDB structure 3DV5 differ only by a single hydroxyl group. For such simple cases, we directly made the structural changes using Chimera (listed in Table ) and submitted the binding pose to evaluate how well docking search algorithms perform compared to educated human guesses. However, human guesses were not always possible, especially when the changes involved adding or modifying nonaromatic rings (BACE_2 and BACE_7) or macrocycles with different ring sizes (BACE_19 and 3DV1).