The x-ray crystal structure PDB ID 7SI9 of Nirmatrelvir bound to the SARS-Cov-2 was used for docking and also in validating the docked poses; the x-ray protein structures were fully protonated in GOLD/HERMES before docking calculations. The computational docked pose is close to that of the complete x-ray structure, including the eclipsed trifluoromethyl group. The non-covalent and covalently docked pose overlayed with the 7SI9 ligand is illustrated in Figure , and these will be discussed. The trifluoromethyl is in an eclipsed position which is unusual because typically this is higher in energy than non-eclipsed; Studies of these groups have been done with this eclipsed position and found to be more stable in classes of compounds . In both (a,b) and (c,d) 2 conformations are presented, the highest scoring docked Nirmatrelvir/Mpro pose and a pose at the start of the continuous set of scored poses, generated by CCDC GOLD out of multiple runs. The RMSDs are given in the caption and are comparable to the PDB 7SI9 2.0 x-ray resolution . The SARS-Cov-2 3CL protease (Mpro) binding site is an X-shaped cavity which can be described as: 3 ends are caves and the fourth is an exit valley. This is the region of the Mpro relevant to viral replication which is targeted and partly blocked by Nirmatrelvir or other inhibitors. This molecule, when bound, primarily fills in 2 caves. In Figure (a) the blue-to-white-to-orange coloring are hydrophilic to hydrophobic amino acids. Note: In this image of Nirmatrelvir bound to Mpro, the solvent accessible protein surface (SAS) is displayed. This has the advantage of clearly showing the binding cavity. However, in this image and in general there could be a hydrogen appearing to penetrate the surface. This is the case with Nirmatrelvir and Mpro in the atoms N19, N36 farthest, nearest nitrogens from the trifluoromethyl group. These both are hydrogen bond donors (info on next page) with Mpro atoms 1315, 1112 in hydrophilic GLU 166, hydrophobic PHE 140. There is no structural clash or overlap, and this is common in ligand-protein Chimera images.