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 SARS-CoV-2 proteases M^pro and PL^pro are important targets for the development of antivirals against COVID-19. The functional group 1,2,4-thiadiazole has been indicated to inhibit cysteinyl proteases, such as papain and cathepsins. Of note, the 1,2,4-thiadiazole moiety is found in a new class of cephalosporin FDA-approved antibiotics: ceftaroline fosamil, ceftobiprole, and ceftobiprole medocaril. Here we investigated the interaction of these new antibiotics and their main metabolites with the SARS-CoV-2 proteases by molecular docking, molecular dynamics (MD), and density functional theory (DFT) calculations. Our results indicated the PL^pro enzyme as a better in silico target for the new antibacterial cephalosporins. The results with ceftaroline fosamil and the dephosphorylate metabolite compounds should be tested as potential inhibitor of PL^pro, M^pro, and SARS-CoV-2 replication in vitro. In addition, the data here reported can help in the design of new potential drugs against COVID-19 by exploiting the S atom reactivity in the 1,2,4-thiadiazole moiety.

Supplementary information: The online version contains supplementary material available at 10.1007/s11224-022-02036-5.

Keywords: 1,2,4 thiadiazoles; Cephalosporins; Computational docking; DFT calculations; Drug repurposing; Molecular dynamics.