Compound 67 was cocrystallized with the enzyme in two different forms at 1.95 and 2.20 Å (Figure 21). The key feature observed from this crystal structure was that the inhibitor binds to the shallow substrate‐binding site at the surface of each protomer, between domains I and II. The thioketal that resulted from the nucleophilic Cys145 attacking the inhibitor, is stabilized by a H‐bond from His41, whereas the amide oxygen of 67 accepts a H‐bond from the main‐chain amides of Gly143, Cys145, and in part, Ser144 that make up the cysteine protease's canonical oxyanion hole. 157  The P1 lactam moiety is deeply embedded in the S1 pocket where the lactam nitrogen donates a three‐center H‐bond to the main chain oxygen of the Phe140 and the carboxylate of Glu166. The carbonyl oxygen forms a H‐bond to His163. The P2‐cyclopropyl moiety fits into the S2 subsite. The P3‐P2 pyridone moiety occupies the space normally filled by the substrate's main chain. The Boc group is not situated in the canonical S4 site, rather it is located near Pro168, which explains why the removal of the Boc group as in 68 weakened the inhibitory activity.