There are 2 sets of parameters, from Ligand GA and from CCDC GOLD. The GOLD parameters during the iterations were chosen with mostly auto default: 15 identical docking jobs were run in each GOLD molecular docking, an autoscale=1.1, early termination was turned on, and a cavity.atoms file was used with a radius of 20 Angstroms centered about. After the ranked set of non-isomeric files was obtained after 4 or 5 iterations using Ligand_GA_Output_Analysis, Ligand GA was restarted with the 30 top scoring non-isomeric molecules. This continued until 33 iterations were completed. Then the net set of the result from the total collection was ranked and ordered using Ligand_GA_Output_Analysis. A truncated list of 76 molecules was selected based on any GOLD PLP score greater than 79; this cutoff was chosen because the highest score of any of Nirmatrelvir's stereoisomers is 78. Then this list of 76 non-isomeric molecules was fully post-processed with an extensive set of GOLD parameters: 30 repeated docking calculations per ligand, pop_size=75, n_islands=10, max_ops=300000, early_termination=0 (off). The set 76 non-isomeric molecules is given in the Supplementary Information. The resulting number of molecules is 15922, coming from 76 non-isomeric molecules (average 260 stereoisomers). The total number of post-processing GOLD runs is ~600,000.