RESUMO
Responsible for COVID-19, SARS-CoV-2 is a coronavirus in which contagious variants continue to appear. Therefore, some population groups have demonstrated greater susceptibility to contagion and disease progression. For these reasons, several researchers have been studying the SARS-CoV-2/human interactome to understand the pathophysiology of COVID-19 and develop new pharmacological strategies. D. melanogaster is a versatile animal model with approximately 90 % human protein orthology related to SARS-CoV-2/human interactome and is widely used in metabolic studies. In this context, our work assessed the potential interaction between human proteins (ZNF10, NUP88, BCL2L1, UBC9, and RBX1) and their orthologous proteins in D. melanogaster (gl, Nup88, Buffy, ubc9, and Rbx1a) with proteins from SARS-CoV-2 (nsp3, nsp9, E, ORF7a, N, and ORF10) using computational approaches. Our results demonstrated that all the proteins have the potential to interact, and we compared the binding sites between humans and fruit flies. The stability and consistency in the structure of the gl_nsp3 complex, specifically, could be crucial for its specific biological functions. Lastly, to enhance the understanding of the influence of host factors on coronavirus infection, we also analyse the mRNA expression of the five genes (mbo, gl, lwr, Buffy, and Roc1a) responsible for encoding the fruit fly proteins. Briefly, we demonstrated that those genes were differentially regulated according to diets, sex, and age. Two groups showed higher positive gene regulation than others: females in the HSD group and males in the aging group, which could imply a higher virus-host susceptibility. Overall, while preliminary, our work contributes to the understanding of host defense mechanisms and potentially identifies candidate proteins and genes for in vivo viral studies against SARS-CoV-2.
RESUMO
The main protease (Mpro) of the novel coronavirus SARS-CoV-2 is a key target for developing antiviral drugs. Ebselen (EbSe) is a selenium-containing compound that has been shown to inhibit Mpro in vitro by forming a covalent bond with the cysteine (Cys) residue in the active site of the enzyme. However, EbSe can also bind to other proteins, like albumin, and low molecular weight compounds that have free thiol groups, such as Cys and glutathione (GSH), which may affect its availability and activity. In this study, we analyzed the Mpro interaction with EbSe, its analogues, and its metabolites with Cys, GSH, and albumin by molecular docking. We also simulated the electronic structure of the generated molecules by density functional theory (DFT) and explored the stability of EbSe and one of its best derivatives, EbSe-2,5-MeClPh, in the catalytic pocket of Mpro through covalent docking and molecular dynamics. Our results show that EbSe and its analogues bound to GSH/albumin have larger distance between the selenium atom of the ligands and the sulfur atom of Cys145 of Mpro than the other compounds. This suggests that EbSe and its GSH/albumin-analogues may have less affinity for the active site of Mpro. EbSe-2,5-MeClPh was found one of the best molecules, and in molecular dynamics simulations, it showed to undergo more conformational changes in the active site of Mpro, in relation to EbSe, which remained stable in the catalytic pocket. Moreover, this study also reveals that all compounds have the potential to interact closely with the active site of Mpro, providing us with a concept of which derivatives may be promising for in vitro analysis in the future. We propose that these compounds are potential covalent inhibitors of Mpro and that organoselenium compounds are molecules that should be studied for their antiviral properties.
