In our study, we apply these statistically robust techniques to three crucial SARS-CoV-2 drug targets: adenosine ribose phosphatase (ADRP), papain-like protease (PLpro) 58 and 3-chymotrypsin-like protease (3CLpro). Each of these are globular, non-structural proteins encoded by SARS-CoV-2 which play key roles in the lifecycle of the virus and serve as important potential targets for SARS-CoV-2. Our findings here shed light on potentially druggable sites on the surface of the proteins, elucidate relative binding free energies between each of the sites, and demonstrate binding mechanisms which may explicitly inform future efforts in SARS-CoV-2 drug discovery. We also compare different free energy protocols and discuss the applicability of each in different scenarios. In addition to these methodological developments, we report new scientific findings on the allosteric effects observed in 3CLPro.