Case Study II: SARS-CoV-2 Main Protease The main protease (M pro ) of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is an attractive target for the development of antiviral agents. The Jorgensen lab has focused on the development of drug-like, non-covalent inhibitors of the protease through lead optimisation of virtual screening hits. In particular, starting from the anti-epileptic drug, perampanel, researchers combined model building with the BOMB software, with free energy calculations, to rapidly yield potent antiviral compounds. Figure shows the structures of the two main series of cyanophenyl-and uracil-based compounds investigated. A high-resolution x-ray crystal structure of 4 with M pro confirmed binding to the S1, S1' and S2 pockets, with space to grow into the S3-S4 region. 24 Turning attention to the uracil series, the core molecule was again built from the crystal structure of 4, by removing the cyanophenyl group. The added uracil group has three low energy conformations, and in this case we retained the second lowest energy structure, which forms key hydrogen bonding interactions with the backbone of Thr26 and the catalytic Cys145. In agreement with the original modelling, performed using the BOMB software, we find that again a range of substituents are permitted in the S3/S4 pocket, including substituted benzyloxy side chains (Figure ). Figure (c) shows that the modelled uracil group in the S1' pocket is in good agreement with the corresponding crystal structure (7L12).