Figure shows a representation of the interaction diagram of the inhibitors in the active site of the M pro . The inhibitors form extensive interactions in the target binding site by engaging in multiple hydrogen bonding interactions with key amino acid residues of the M pro . An example we highlight is Glu166, whose backbone amino acid groups and carboxylate side chain establishes multiple hydrogen bonding contacts with functional groups of the inhibitors (Figure , right panel). Other hydrogen bonding residues include Gly143, His164, Cys145, Gln189, and Ser144. In addition to these hydrogen bond interactions, there are van der Waals and hydrophobic interactions between the M pro residues and the inhibitors. Together, these interactions between the target protein and inhibitors contribute to the binding free energies of the inhibitors to the M pro .