Fourth, initially we tried to identify similar ligands in our PDB database using shape and color similarity search. We searched the database using OMEGA and OEShape (Open-Eye Toolkits version 3.0.8, OpenEye Scientific Software) to identify ligands that are similar to the 20 ligands. However, we were unsuccessful in identifying close ligand structures with this approach, probably because the version of OMEGA we were using was not particularly good for macrocycles, resulting in low similarity scores even for macrocycles which in fact were quite similar. As a result, we had to identify similar ligands manually. Additionally other similarity tools like TanimotoCombo similarity or Tversky coefficient, which has been successfully used by Kumar et al. in earlier Grand Challenges could have done a better job at selecting the reference ligands and in turn, automating the process.