As suggested by molecular modeling, the S2 site appears to accommodate a variety of linear, branched, and cyclic alkyl moieties (entries 36 and 39–41). Interestingly, the P2 Phe derivative 42 displayed less potent inhibition of the SARS CoV-1 3CLpro than the corresponding saturated analogue 41. Also noteworthy is the large attenuation in enzyme inhibition seen with P2-N-methyl-Leu inhibitor 38 (IC50 = 83 nM) as compared to 4 (Ki = 4 nM). This loss of potency is consistent with the inhibitor ligand interactions observed with 2 and 4 that show the P2 NH involved in a hydrogen bond with the side-chain amide of Gln189. Additionally, the methyl substitution in 38 would be expected to alter the conformation of the 4-methoxy indole cap and perturb the observed ligand–enzyme hydrogen bond network present in 2 and 4.