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

Cleidy Osorio Mogolón, Gustavo E.Olivos Ramírez, Kewin Otazu, Manuel E. Chenet-Zuta, Georcki Ropón Palacios, Cinthia Das Dores Aguiar, Ihosvany Camps, Gabriel M. Jimenez-Avalos, Eduardo Apari-Cossio, Natalia E. Torres Moreira, Reyna G. Cárdenas-Cárdenas

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

Resumen

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 synthesisbrof 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 RNAbrpolymerase (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 drugbrsearch, 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 isbrconsidered 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'sbrRule of Five. At the same time, the Remdesivir, Beclabuvir and Sofosbuvir drug, previously used in iin 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 bebrconsidered as drugs for the development of effective treatments against this new pandemic.
Idioma originalInglés
Páginas (desde-hasta)808-820
Número de páginas13
PublicaciónLetters in Drug Design and Discovery
Volumen20
N.º7
DOI
EstadoPublicada - 2023

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