In silico studies of Mpro and PLpro from SARS-CoV-2 and a new class of Cephalosporin drugs containing 1,2,4-thiadiazole

Abstract The proteases from SARS-CoV-2, i.e., Mpro and PLpro, are important targets for the development of antivirals against COVID-19. The functional group 1,2,4-thiadiazole was demonstrated to inhibit cysteine proteases, such as papain and Cathepsins, and it is found in a new class of cephalosporin FDA-approved drugs: Ceftaroline Fosamil, Ceftobiprole, and Ceftobiprole Medocaril. In this work, we investigate the interactions of these drugs and their metabolites with the SARS-CoV-2 proteasesby molecular docking and density functional theory (DFT) calculations and propose a mechanism of inhibition as well. Our results indicate that the PLpro enzyme could be a better target for these drugs than the Mpro, suggesting that these compounds and metabolites can be tested inin vitro/vivo assays to confirm their inhibitory action. In addition, the data here reported can help in the design of new potential drugs against COVID-19.