In S1, the lactam carbonyl of 4 forms a strong hydrogen bond with the side chain of His163, while the lactam NH is within the hydrogen-bonding distance but poorly aligned with the side-chain oxygen of Glu166 and the backbone oxygen of Phe140. These three residues partially define the bottom and edge of the S1 pocket. Additionally, the backbone carbonyl and NH of Glu166 form β-sheet-like hydrogen-bonding interactions with the NH and C2-carbonyl of the indole fragment of 4. The NH of the P2 Leu of inhibitor 4 and the side chain of Gln189 form a hydrogen bond, while the carbonyl of P2 Leu is exposed to the solvent. The inhibitor P1 NH forms a strong hydrogen bond with the backbone carbonyl of His164. The inhibitor’s lipophilic leucine residue is bound to the SARS 3CLpro in the hydrophobic S2 pocket formed by residues Asp187, Arg188, Gln189, Met49, and His41. The indole portion of 4 does not protrude into the S3 pocket but rather rests across a partially collapsed S3, making extended van der Waals interactions across the 189–191 residue backbone atoms. The closed S3 is the only significant conformational difference compared to a recently reported structure of SARS CoV-2 3CLpro inhibited by α-ketoamides.8 The energetics of this extended interaction, the associated protein conformation stabilities, or warhead difference may contribute to the 3-order-of-magnitude increased SARS CoV-2 3CLpro potency of HMK 4 (see below) compared to that of the referenced ketoamides.