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Attacking the SARS-CoV-2 Replication Machinery with the Pathogen Box’s Molecules

preprint
submitted on 17.06.2020 and posted on 19.06.2020 by Cleidy Osorio-Mogollon, Gustavo E. Olivos-Ramirez, Kewin Otazu, Manuel E. Chenet-Zuta, Georcki Ropon-Palacios, Ihosvany Camps, Gabriel M. Jimenez-Avalo, Eduardo Apari-Cossio, Natalia E. Torres-Moreira, Reyna G. Cardenas-Cardenas
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
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
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
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
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
Rule of Five. At the same time, the Remdesivir, Beclabuvir and Sofosbuvir drug, previously used in in silico 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
considered as drugs for the development of effective treatments against this new pandemic.

History

Email Address of Submitting Author

icamps@unifal-mg.edu.br

Institution

Physics Department. Federal University of Alfenas

Country

Brazil

ORCID For Submitting Author

0000-0001-5898-1313

Declaration of Conflict of Interest

There is no Conflict of Interest

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