CSP plots of Z604 (purple), 30b (light blue), 30c (red), 31c (green), 32a (orange),
and 35b (pink) (a). The light-pink shade shows the active
site amino acids with the indication of the subpockets (exemplary
amino acids for S1’: T24, T25, T26, L27, S1: F140, L141, N142,
G143, S144, C145, H163, H164, S2: C44, T45, S46, E47, M49, S3: L167,
P168, G170, T190, Q192). Exemplary CSPs of V42 and G174 in the absence
(black) and presence of ligands are shown in (b). See also Figures S9–S10 for the reference compounds.
Modeling of each ligand within the active site pocket of Mpro ((c) left column: noncovalent; right column: covalent binding).
Amino acids N142 and Q189 are removed for visibility of the active
site pockets (see Figure S11 for the same
structures with all amino acids). The cocrystal structure of Mpro with two 35b binding sites (PDB: 8PH4) shown as a dimer
with indication of first (black rectangle) and second binding sites
(red). A section of the active site is shown in the same position
as in (c) and when tilted to show all moieties within the pocket (d).
Overlay of all modeled ligands with the indication of subpockets (e). KD determination derived from combined CSPs for
the first (left) and second binding sites of 35b (right)
(f).