The world is currently facing a pandemic caused by the new 2019 coronavirus disease (COVID-19), caused by SARS-CoV-2. Among the fundamental processes of this virus are viral transcription and replication. They allow the synthesis<br>of genetic material and the consequent multiplication of the virus to infect other cells or organisms. These are performed by a multi-subunit machinery of various nonstructural proteins (nsp); among which the RNA-dependent RNA<br>polymerase (RdRp or nsp12) is the most important, and, at the same time, conserved among coronaviruses. The structure of this protein (PDB ID: 6M71) was used as a target in the application of computational strategies for drug<br>search, like virtual screening and molecular docking. The region considered for virtual screening has three important amino acids for protein catalysis: T680 (located in Motif A), N691 and D623 (located in Motif B), where a grid box was located. In turn, applying the concept of drug repositioning is<br>considered as a quick response in the treatment of sudden outbreaks of diseases. Here, we used the Pathogen Box, a database of chemical compounds analyzed for the treatment against malaria, which were filtered under the criteria of selecting those that do not present any violation of Lipinski's<br>Rule of Five. At the same time, the Remdesivir, Beclabuvir and Sofosbuvir drug, previously used in <i>in silico</i> and clinical studies for inhibition of nsp12, were used as positive controls. The results showed a Top10 potential target inhibitors, with binding energy higher than those of the positive controls, of which TCMDC-134153 and TCMDC-135052, both with -7.53 kcal/mol, present interactions with the three important residues of the nsp12 catalytic site. These proposed ligands would be used for subsequent validation by molecular dynamics, where they can be<br>considered as drugs for the development of effective treatments against this new pandemic.
Introduction:
The world is currently facing a pandemic caused by the new coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus. Viral transcription and replication are within the fundamental processes of any virus. They allow the synthesis of genetic material and the consequent multiplication of the virus to infect other cells or organisms.
Methods:
The most important protein in SARS-CoV-2 is the RNA polymerase (RdRp or nsp12), responsible for both processes. The structure of this protein (PDB ID: 6M71) was used as a target in the application of computational strategies for drug search, like virtual screening and molecular docking. Here, Pathogen Box database of chemical compounds was used together with Remdesivir, Beclabuvir, and Sofosbuvir drugs as potential inhibitors of nsp12.
Results:
The results showed a Top10 potential target inhibitor, with binding energy (∆G) higher than those of the positive controls, of which TCMDC-134153 and TCMDC-135052, both with ∆G = −7.53 kcal/mol, present interactions with three important residues of the nsp12 catalytic site.
Conclusion:
These proposed ligands would be used for subsequent validation by molecular dynamics, where they can be considered as drugs for the development of effective treatments against this new pandemic.
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