CCES Unicamp

In silico study of Casopitant, Stavudine, Grazoprevir, Lamivudine, Rimantadine, Remdesivir and Tenofovir against proteases of the pre and post-fusion phases of the COVID-19 virus in human cells.

Date: July 27, 2022

Candidate:Jorge Maurício da Silva Brito

Prof. Dr. Nelson Morgon – IQ/UNICAMP
The new coronavirus, identified as SARS-CoV-2, has left a huge burden of death worldwide since December 2019, when the COVID-19 pandemic was declared. And according to authorities, SARS-CoV-2 is a highly virulence and pathogenic virus that is transmitted mainly through spittle droplets or secretions expelled by coughing or sneezing. The impact of this disease on the economy of countries can be verified by the large volume of financial resources that have already been mobilized to care for infected people. However, despite the existence of several vaccines that target SARS-CoV-2, as their function is to stimulate our immune system to produce the antibodies necessary to fight the virus; on the other hand, the pathology (the disease) still remains without an objective therapeutic solution. In other words, vaccines work until the disease does not exist, after which it is necessary to “cure the disease” with medication. Thus, what motivated us to do this research was the possibility of collaborating for the solution of the disease, trying to envision drugs capable of preventing the progress of the infection. For this reason, we carried out an in silico study of the antivirals Casopitant, Stavudine, Grazoprevir, Lamivudine, Remdesivir, Rimantadine and Tenofovir in order to verify their biological potentials in the pre- and post-cellular fusion phases of SARS-CoV-2. All already have proven efficacy and safety for other pathologies, especially against hepatitis B and C viruses, and HIV. Furthermore, both have inhibitory potential against some proteases that SARS-Cov-2 also uses in the infection process, a fact that was considered in the selection of each one. We did a molecular docking against the Spike protein in closed conformation (PDB ID: 6VXX) and the angiotensin 2 converting enzyme, ACE-2 (PDB ID: 1R42) that work in the pre-fusion phase of the virus; and against the open conformation Spike protein (PDB ID: 6VYB), the 3-chymotrypsin-like protease, 3CLpro (PDB ID: 6LU7) and the RNA-dependent RNA polymerase, RdRp (PDB ID: 6M71), which function in phase of post-merger. The results of binding affinities show that only the antivirals Casopitant, Grazoprevir, Remdesivir and Rimantadine have potent activities against both phases of the viral cycle, ranging from -17.19 to 28.72 kcal/mol (pre-fusion), and of -16.25 to -48.96 kcal/mol (post fusion). Furthermore, an HCA of theoretical affinities applied to the complete set of researched drugs shows that the probable mode of action of these four drugs is very similar, being quite different from the others. Likewise, HCA shows that the proteases in the pre- and post-fusion phases are quite distinct, being governed by different metabolic processes, an experimental evidence that has already been widely proven and that authenticated the protocol and method used in this research. The predicted interaction residues in the complexes of the four selected antivirals match the binding residues reported in the literature. And these residues are crucial in the interaction of protein S with the ACE-2 cell receptor, including residues GlyB339, AsnB343, ValB512, ProB426, CysB432, HisA195 and TyrA196 that were conserved in all SARS-CoV-2 complexes. And related to the inhibition of viral RNA synthesis (RdRp), residues LysA621, ArgA553 and AspA623 were conserved. Finally, for the pre-fusion phase, the results show the power to block the snap of the virus in human cells and inhibit membrane fusion, which, in the worst case, significantly reduces the viral load of contagion and virions in the cells , favoring a lighter clinical picture. In post-fusion, 3CLpro and RdRp proteases are responsible for proteolysis, replication and production of new virions; and the results were extremely robust for this phase, according to the affinities already mentioned, indicating a high potential against the production of proteins and self-assembly of the viral genome. The results produced in this research deserve in vitro and in vivo analysis, as well as the possibility of emergency use.

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