Fig. 17. Docking informs novel inhibitor design. HBs between Mpro (magenta) and the ligands are shown as dotted yellow lines. (a) Overlay of the docked pose of FOC-CAS-e3a94da8-1 (green and greenish-yellow) with the crystal structure of x10789 (pink) on the Mpro surface (PDB entry 5RER; 1.88 Å resolution).35 Derivatisation of x10789 into the oxyanion hole could be achieved by attaching a methylene amide group present in x0830 (highlighted greenish-yellow). (b) Docked pose of Pfizer's Phase I covalent inhibitor PF-07321332, covalently docked into Mpro (PDB entry 6XHM; 1.41 Å resolution).71 PF-07321332 (cyan) is covalently attached to Cys-145. The docked PF-07321332 adopts the same major contacts as the ‘combination’ of x10789 and x0830, namely the double HB to the backbone of Glu-166, the HB to His-163 in the S1 subsite, and a series of hydrophobic interactions in the S2 subsite. (c) Structures of Moonshot designed compound FOC-CAS-e3a94da8-1, crystallographic fragment x10789, and inhibitor PF-07321332.
