It is also worth to notice that our MX results contrast with what found so far in the 500 MX structures, which exhibit double occupation and, in most cases (>98%), cyclic symmetry. This suggests that these studies probably were conducted with 2:1 ligand/monomer stoichiometry or more. The ligands, if in excess, may not be an inhibitor of Mpro even if they form doubly occupied adducts. Indeed, while X77 -an R-enantiomer structure -inhibits Mpro in the μM-high nM range (Fig. ), the correspondent Senantiomer (S-X77) does not exert any inhibitory activity in concentration 20 μM or lower (Fig. ). In excess concentration, however, it does bind the enzyme, as shown by the Xray structure of the S-enantiomer/Mpro adduct (See SI). This may be caused by the wellknown high flexibility of the active site cavities , which allows the distorted second binding site to eventually accommodate the substrate in saturating condition.