The complexity as well as the flexibility of the Plpro binding pocket, made this test case particularly challenging. The binding site contains of a highly flexible loop named the "Ploop" that is found in different conformations in the crystal structures. Two crystal structures were chosen for the purpose of including different states of SARS-Cov-2 PL-pro binding site conformation; chain A from the apo-form (PDB ID: 6WUU), and the GRL0617-bound Holoform (PDB ID: 7JRN). Structural information of the holo-form GRL0617-bound Pl-pro (PDB ID :7JRN), revealed that the catalytic site is formed of a P-loop composed of TYR-268 and GLN-269, forming Pi-Pi stacking and hydrogen bond interactions with the bound ligand respectively. This conformation of the P-loop bound to the ligand is named a "holo-closed conformation" (Figure ).