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.

Fig. 1

General structure and proposed inhibitory mechanism of Cys enzymes (Enz) by1,2,4-thiadiazoles molecules. R₁ and R₂ are organic substituents

Fig. 2

Chemical structure and isomers of 1,2,4-thiadiazoles drugs and their active metabolites. The approved ceftarolinefosamil and ceftobiprole, and an experimental drug, ceftobiprole medocaril. For ceftarolinefosamil and ceftobiprole medocaril, isomers Z1 and E1 are the most abundant protonation forms, at physiological pH between 7.0 and 7.4, (determined in the Marvin Sketch program). The other forms, and proportions at physiological pH range, are presented in the Supporting Information

Fig. 3

Target cysteinyl residues in the SARS-CoV-2 M^pro active site (Cys145), PL^pro active site (Cys11), and Zn binding site (Cys189, Cys192, Cys224, and Cys226) are depicted in the figure. A M^pro active site (6lu7), B PL^pro active site, and C PL.^pro Zn site (7jn2)

Fig. 4

M^pro docking with 1,2,4-thiadiazole containing drugs and their metabolites. A Ceftaroline fosamil isomer Z1. B Ceftaroline fosamil isomer E1. C Ceftaroline fosamil dephosphorylated metabolite isomer Z. D Ceftaroline fosamil dephosphorylated metabolite isomer E. E Ceftobiprole isomer Z. F Ceftobiprole isomer E. G Ceftobiprole metabolite isomer Z. H Ceftobiprole metabolite isomer E. I Ceftobiprole medocaril isomer Z1. J Ceftobiprole medocaril isomer E1. Distances are shown in Å

Fig. 5

PL^pro docking with 1,2,4-thiadiazole containing drugs and their metabolites. A Ceftaroline fosamil isomer Z1. B Ceftaroline fosamil isomer E1. C Ceftaroline fosamil dephosphorylated metabolite isomer Z. D Ceftaroline fosamil dephosphorylated metabolite isomer E. E Ceftobiprole isomer Z. F Ceftobiprole isomer E. G Ceftobiprole metabolite isomer Z. H Ceftobiprole metabolite isomer E. I Ceftobiprole medocaril isomer Z1. J Ceftobiprolemedocaril isomer E1. Distances are shown in Å

Fig. 6

PL^pro Zn site docking with 1,2,4-thiadiazole containing drugs and their metabolites. A Ceftaroline fosamil isomer Z1. B Ceftaroline fosamil isomer E1. C Ceftaroline fosamil dephosphorylated metabolite isomer Z. D Ceftaroline fosamil dephosphorylated metabolite isomer E. E Ceftobiprole isomer Z. F Ceftobiprole isomer E. G Ceftobiprole metabolite isomer Z. H Ceftobiprole metabolite isomer E. I Ceftobiprole medocaril isomer Z1. J Ceftobiprole medocaril isomer E1. Distances are shown in Å

Fig. 7

A MD structures of PL^pro-ceftaroline fosamil at 0, 100, and 200 ns (top row), RMSD along the dynamics (bottom left), and RMSF by residue (bottom right); B MD structures of PL.^pro- dephosphorylated ceftaroline fosamil metabolite at 0, 100, and 200 ns (top row), RMSD along the dynamics (bottom left), and RMSF by residue (bottom right)