High Throughput Computational Deconvolutional Screening: Finally, we sought to investigate the potential of our "Swiss Cheese" framework towards in silico screening. A set of 61,814 amines commercially available from Enamine were initially sourced which were screened for structural alerts. Molecules with more than a single stereocenter were removed to avoid downstream complications in assessing potency. This resulted in 58,082 1˚ and 2˚ amines which were subjected to virtual screening by our trained "Swiss Cheese" framework to identify possible amides with potent M pro inhibition, irrespective of their potential coupling yield. The top 20 compounds predicted by the "Swiss Cheese" to have high M pro inhibition were synthesized and assessed (Figure , Figure ). Of these compounds, 19 were successfully formed in suitable purity, and 7 of them had nanomolar inhibitory activity that ranked them in the 96 th percentile of hits from the initial 300 amine screen. This resulted in an increase of sub 100 nanomolar inhibitors from 12 to 19, a 58% increase with minimal screening and computational cost.