In a recent study by our group, 14 compounds of interest, each of which bind to one of three sites (the substrate binding site, allosteric site I, and allosteric site II) on the surface of 3CLpro, were identified from a previously conducted high-throughput crystallographic screen of repurposed drug molecules. Based on the results derived in that study, we selected 3 ligands of interest, MUT056399 (RQN), AT7519 (LZE) and pelitinib (93J) for the current study covering all three binding sites and a wide range of EC50 values (Table ). Furthermore, by building the system containing both RQN (which binds to the substrate binding site) and LZE (which binds to allosteric site 2), we aim to capture whether or not the binding of RQN is affected by the binding of LZE, and if so then determine the allosteric mechanism involved in the process. For the PLpro system we decided to focus on the ligand GRL0617 as it showed strong antiviral activity using NMR data and a promising value of EC50. Tofacitinib, which is a FDA approved pharmaceutical that is used to treat rheumatoid arthritis and ulcerative colitis was chosen as the ligand for the ADRP system.