We next prepare to connect the Thr 304 carbonyl carbon to the newly built CH2 group, and thus cyclize the substrate. In UCSF Chimera, when the new bond is formed, it must not cross other atoms or bonds, otherwise subsequent structural minimization will fail. We rotate the backbone Cα-N bond of Gln 306 to bring the Thr 304 carbonyl carbon close to the CH2 group, to avoid crossing other atoms or bonds when building the new C-C bond (Figure ). We cyclize the substrate by building a C-C bond between the Thr 304 carbonyl carbon and the CH2 carbon. In cyclizing the substrate, we have built an unnatural amino acid residue -[4-(2-aminoethyl)phenyl]-acetic acid (AEPA) -from Phe 309 and Thr 304. The resulting cyclic peptide contains a β-turn comprising Phe 305 and Gln 306 (Figure ). We envision that hydrogen bonding within this β-turn might provide additional conformational rigidity to the cyclic peptide. Geometry optimization of the cyclic peptide inhibitor. At this point, the bond lengths, angles, and dihedral angles of the newly built cyclic peptide are not optimal. We are now ready to allow the cyclic peptide to relax to a low-energy conformation (local minimum) within the active site of the SARS-CoV M pro . We use the "minimize structure" tool to optimize the geometry of the cyclic peptide while holding the structure of M pro fixed. The minimized structure (Figure ) has more reasonable bond lengths, angles, and dihedral angles than the structure prior to minimization (Figure ), with Phe 305 and Gln 306 forming a hydrogen-bonded β-turn. To introduce additional conformational rigidity, we mutate Gly 307 to Ser, which is the most common residue at the P1' position of SARS-CoV-2 M pro substrates (Figure ). UCSF Chimera allows this point mutation to be achieved with a single command. After the point mutation, we perform a second round of geometry optimization to clean up the structure and afford a hypothesized structure of the cyclic peptide inhibitor (Figure ). Figure illustrates the chemical structure of the cyclic peptide inhibitor, which we term UCI-1 (University of California, Irvine Coronavirus Inhibitor-1). Docking the inhibitor to SARS-CoV M pro and SARS-CoV-2 M pro . In structure-based drug design, we would typically now synthesize the cyclic peptide inhibitor and evaluate its activity experimentally through studying its ability to block the cleavage of a fluorogenic peptide substrate by SARS-CoV-2 M pro . We would also attempt to co-crystalize the inhibitor with the M pro to experimentally evaluate the structure hypothesized in Figure . Using the co-crystal structure and additional structureactivity studies, we would then carry out iterative rounds of modification and optimization of the cyclic peptide inhibitor to achieve higher affinity and specificity for SARS-CoV-2 M pro .