The shared pair of amino acids GLY 143 and GLU 166 by all 3 molecules are in different strands. The remaining amino acids LEU 141, PHE 140, SER 144, and CYS 145 are all adjacent and utilized differently in the 3 molecules in contacts. Although metabolism is generally high within the liver enzyme CYP 3A4 and other CYPs of drug-like molecules, due presumably to the large featureless cavity, higher interacting small molecules can be designed that are more specific to the target, the viral replication activation site of Mpro of SARS-Cov-2. Up to 3 kCal of increased binding energy over dozens of previously proposed inhibitors of SARS-Cov-2 Mpro can be found in these Ligand GA designed molecules. This increase results in large binding activity, e.g. KD,in a molecular on-/off-state of a protein-ligand complex.