TY - JOUR
T1 - Attacking the SARS-CoV-2 Replication Machinery with the Pathogen Box’s Molecules
AU - Mogolón, Cleidy Osorio
AU - Ramírez, Gustavo E.Olivos
AU - Otazu, Kewin
AU - Chenet-Zuta, Manuel E.
AU - Palacios, Georcki Ropón
AU - Das Dores Aguiar, Cinthia
AU - Camps, Ihosvany
AU - Jimenez-Avalos, Gabriel M.
AU - Apari-Cossio, Eduardo
AU - Torres Moreira, Natalia E.
AU - Cárdenas-Cárdenas, Reyna G.
N1 - Publisher Copyright:
© 2023 Bentham Science Publishers.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - RNA polymerase
KW - SARS-CoV-2
KW - drug repurposing
KW - molecular docking
KW - nsp12
KW - pandemic
UR - http://www.scopus.com/inward/record.url?scp=85159812022&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/bde17267-96f7-3262-9729-6bd32cc7eb5c/
U2 - 10.2174/1570180819666220622085659
DO - 10.2174/1570180819666220622085659
M3 - Artículo
AN - SCOPUS:85159812022
SN - 1570-1808
VL - 20
SP - 808
EP - 820
JO - Letters in Drug Design and Discovery
JF - Letters in Drug Design and Discovery
IS - 7
ER -