Dataset Information

In silico studies of M^pro and PL^pro 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.

SUBMITTER: Delgado CP

PROVIDER: S-EPMC9463509 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Delgado Cássia Pereira CP Rocha João Batista Teixeira JBT Orian Laura L Bortoli Marco M Nogara Pablo Andrei PA

Structural chemistry 20220910 6

The SARS-CoV-2 proteases Mpro and PLpro 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 mai ...[more]

PMID: 36106095

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Project description:Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads. Natural products as sesame were reported to exhibit potential to protect from COVID-19 disease. In our study, the total methanolic extract of Sesamum indicum L. seeds (sesame) were led to isolation of seven known compounds, five lignan; sesamin 1, sesamolin 2, pinoresinol 3, hydroxymatairesinol 6, spicatolignan 7, together with two simple phenolic compounds; ferulic acid 4 and vanillic acid 5. All isolated compounds were evaluated in silico against three important SARS-CoV-2 protein targets; main protease (Mpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp) which possessed crucial role in replication and proliferation of the virus inside the human cell. The results revealed that compound 6 has the high affinity against the three main proteins, specially towards the SARS-CoV-2 Mpro that exceeded the currently used SARS-CoV-2 Mpro inhibitor darunavir as well as, exhibiting a similar binding energy at SARS CoV-2 PLpro when compared with the co-crystallized ligand. This activity continued to include the RdRp as it displayed a comparable docking score with remdesivir. Inferiorly, compounds 1 and 2 showed also similar triple inhibitory effect against the three main proteins while compound 7 exhibited a dual inhibitory effect against SARS CoV-2 PLPro and RdRp. Further molecular dynamic simulation experiments were performed to validate these docking experiments and to calculate their binding free energies (ΔGs). Compounds 1, 2, 3, 6, and 7 showed comparable binding stability inside the active site of each enzyme with ΔG values ranged from -4.9 to -8.8 kcal mol-1. All the compounds were investigated for their ADME and drug likeness properties, which showed acceptable ADME properties and obeying Lipinski's rule of five parameters. It can be concluded that the isolated compounds from sesame lignans could be an alternative source for the development of new natural leads against COVID-19.

Dataset Information

In silico studies of M^pro and PL^pro from SARS-CoV-2 and a new class of cephalosporin drugs containing 1,2,4-thiadiazole.

Supplementary information

Publications

<i>In silico</i> studies of M<sup>pro</sup> and PL<sup>pro</sup> from SARS-CoV-2 and a new class of cephalosporin drugs containing 1,2,4-thiadiazole.

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