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"Bucket brigade" using lysine residues in RNA-dependent RNA polymerase of SARS-CoV-2.

ABSTRACT: The RNA-dependent RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a promising drug target for coronavirus disease 2019 (COVID-19) because it plays the most important role in the replication of the RNA genome. Nucleotide analogs such as remdesivir and favipiravir are thought to interfere with the RNA replication by RdRp. More specifically, they are expected to compete with nucleoside triphosphates, such as ATP. However, the process in which these drug molecules and nucleoside triphosphates are taken up by RdRp remains unknown. In this study, we performed all-atom molecular dynamics simulations to clarify the recognition mechanism of RdRp for these drug molecules and ATP that were at a distance. The ligand recognition ability of RdRp decreased in the order of remdesivir, favipiravir, and ATP. We also identified six recognition paths. Three of them were commonly found in all ligands, and the remaining three paths were ligand-dependent ones. In the common two paths, it was observed that the multiple lysine residues of RdRp carried the ligands to the binding site like a "bucket brigade." In the remaining common path, the ligands directly reached the binding site. Our findings contribute to the understanding of the efficient ligand recognition by RdRp at the atomic level.

SUBMITTER: Tanimoto S

PROVIDER: S-EPMC8324383 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction. The emergence of SARS-CoV-2 has taken humanity off guard. Following an outbreak of SARS-CoV in 2002, and MERS-CoV about 10?years later, SARS-CoV-2 is the third coronavirus in less than 20?years to cross the species barrier and start spreading by human-to-human transmission. It is the most infectious of the three, currently causing the COVID-19 pandemic. No treatment has been approved for COVID-19. We previously proposed targets that can serve as binding sites for antiviral drugs for multiple coronaviruses, and here we set out to find current drugs that can be repurposed as COVID-19 therapeutics.Aim. To identify drugs against COVID-19, we performed an in silico virtual screen with the US Food and Drug Administration (FDA)-approved drugs targeting the RNA-dependent RNA polymerase (RdRP), a critical enzyme for coronavirus replication.Methodology. Initially, no RdRP structure of SARS-CoV-2 was available. We performed basic sequence and structural analysis to determine if RdRP from SARS-CoV was a suitable replacement. We performed molecular dynamics simulations to generate multiple starting conformations that were used for the in silico virtual screen. During this work, a structure of RdRP from SARS-CoV-2 became available and was also included in the in silico virtual screen.Results. The virtual screen identified several drugs predicted to bind in the conserved RNA tunnel of RdRP, where many of the proposed targets were located. Among these candidates, quinupristin is particularly interesting because it is expected to bind across the RNA tunnel, blocking access from both sides and suggesting that it has the potential to arrest viral replication by preventing viral RNA synthesis. Quinupristin is an antibiotic that has been in clinical use for two decades and is known to cause relatively minor side effects.Conclusion. Quinupristin represents a potential anti-SARS-CoV-2 therapeutic. At present, we have no evidence that this drug is effective against SARS-CoV-2 but expect that the biomedical community will expeditiously follow up on our in silico findings.

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"Bucket brigade" using lysine residues in RNA-dependent RNA polymerase of SARS-CoV-2.

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