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SARS-CoV-2 and SARS-CoV: Virtual screening of potential inhibitors targeting RNA-dependent RNA polymerase activity (NSP12).

ABSTRACT: Since the outbreak of severe acute respiratory syndrome (SARS) in 2003, the harm caused by coronaviruses to the world cannot be underestimated. Recently, a novel coronavirus (severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2]) initially found to trigger human severe respiratory illness in Wuhan City of China in 2019, has infected more than six million people worldwide by 21 June 2020, and which has been recognized as a public health emergency of international concern as well. And the virus has spread to more than 200 countries around the world. However, the effective drug has not yet been officially licensed or approved to treat SARS-Cov-2 and SARS-Cov infection. NSP12-NSP7-NSP8 complex of SARS-CoV-2 or SARS-CoV, essential for viral replication and transcription, is generally regarded as a potential target to fight against the virus. According to the NSP12-NSP7-NSP8 complex (PDB ID: 7BW4) structure of SARS-CoV-2 and the NSP12-NSP7-NSP8 complex (PDB ID: 6NUR) structure of SARS-CoV, NSP12-NSP7 interface model, and NSP12-NSP8 interface model were established for virtual screening in the present study. Eight compounds (Nilotinib, Saquinavir, Tipranavir, Lonafarnib, Tegobuvir, Olysio, Filibuvir, and Cepharanthine) were selected for binding free energy calculations based on virtual screening and docking scores. All eight compounds can combine well with NSP12-NSP7-NSP8 in the crystal structure, providing drug candidates for the treatment and prevention of coronavirus disease 2019 and SARS.

SUBMITTER: Ruan Z

PROVIDER: S-EPMC7361265 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:An outbreak of a cluster of viral pneumonia cases, subsequently identified as coronavirus disease 2019 (COVID-19), due to a novel SARS-CoV-2 necessitates an urgent need for a vaccine to prevent infection or an approved medication for a cure. In our in silico molecular docking study, a total of 173 compounds, including FDA-approved antiviral drugs, with good ADME descriptors, and some other nucleotide analogues were screened. The results show that these compounds demonstrate strong binding affinity for the residues at the active sites of RNA-dependent RNA-polymerase (RdRp) modelled structures and Chymotrypsin-like cysteine protease (3CLpro) of the HCoV proteins. Free energies (ΔG's) of binding for SARS-CoV-2 and SARS-CoV RdRp range from - 5.4 to - 8.8 kcal/mol and - 4.9 to - 8.7 kcal/mol, respectively. Also, SARS-CoV-2 and SARS-CoV 3CLpro gave ΔG values ranging from - 5.1 to - 8.4 kcal/mol and - 5.5 to - 8.6 kcal/mol, respectively. Interesting results are obtained for ivermectin, an antiparasitic agent with broad spectrum activity, which gave the highest binding energy value (- 8.8 kcal/mol) against the 3CLpro of SARS-CoV-2 and RdRps of both SARS-CoV and SARS-CoV-2. The reason for such high binding energy values is probably due to the presence of hydroxy, methoxy and sugar moieties in its structure. The stability of the protein-ligand complexes of polymerase inhibitors considered in this investigation, such as Sofosbuvir, Remdesivir, Tenofovir, Ribavirin, Galidesivir, 5c3, 5h1 and 7a1, show strong to moderate hydrogen bonding and hydrophobic interactions (π-π stacked, π-π T-shaped, π-sigma and π-alkyl). The stability provided from such interactions translate into greater antiviral activity or inhibitory effect of the ligands. Assessment of the average free energies of binding of the FDA approved drugs are highly comparable for conformers of a particular inhibitor, indicating similar modes of binding within the pockets.Supplementary informationThe online version contains supplementary material available at 10.1007/s13721-021-00299-2.

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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SARS-CoV-2 and SARS-CoV: Virtual screening of potential inhibitors targeting RNA-dependent RNA polymerase activity (NSP12).

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