Design Objective: explore modifications to x1093 to increase affinity in S1 binding pocket In a previous submission, SID-ELM-b65, I proposed adding a fluoro- substituent ortho to the attachment point of the pyridine ring of x0434 and x0678. I am proposing a similar modification to the 7-azaindole moiety of fragment x1093. In addition to proposing a fluoro- substituent at the ortho position to the attachment point of the 7-azaindole ring, I am also proposing a chloro- substituent at the same location. I am also proposing some nitrogen replacements in the 7-azaindole ring to modulate electronic interactions with the binding pocket, slightly adjust angles for h-bonding interactions, and/or provide additional polar interactions with nearby polar side chains, e.g. ASN142. Finally, I am also proposing changing the linker to a carbamate analogous to x0434. The attached PDB file contains QM/MM energy minimized structures for all 18 of these candidates along with the dimer of the Mpro enzyme to see how these ligands interact with the SER1 N-terminal ammonium group.