tetano
Editor, Senior Moderator
Gene Rep
. 2020 Dec;21:100860.
doi: 10.1016/j.genrep.2020.100860. Epub 2020 Aug 28.
In silico structure modelling of SARS-CoV-2 Nsp13 helicase and Nsp14 and repurposing of FDA approved antiviral drugs as dual inhibitors
Arun Bahadur Gurung[SUP] 1 [/SUP]
Affiliations
Abstract
The high mortality rate from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in humans and the lack of effective therapeutic regime for its treatment necessitates the identification of new antivirals. SARS-CoV-2 relies on non-structural proteins such as Nsp13 helicase and nsp14 which are the key components of the replication-transcription complex (RTC) to complete its infectious life cycle. Therefore, targeting these essential viral proteins with small molecules will most likely to halt the disease pathogenesis. The lack of experimental structures of these proteins deters the process of structure-based identification of their specific inhibitors. In the present study, the in silico models of SARS-CoV-2 nsp13 helicase and nsp14 protein were elucidated using a comparative homology modelling approach. These in silico model structures were validated using various parameters such as Ramachandran plot, Verify 3D score, ERRAT score, knowledge-based energy and Z-score. The in silico models were further used for virtual screening of the Food and Drug Administration (FDA) approved antiviral drugs. Simeprevir (SMV), Paritaprevir (PTV) and Grazoprevir (GZR) were the common leads identified which show higher binding affinity to both nsp13 helicase and nsp14 as compared to the control inhibitors and therefore, they might be potential dual-target inhibitors. The leads also establish a network of hydrogen bonds and hydrophobic interactions with the key residues lining the active site pockets. The present findings suggest that these FDA approved antiviral drugs can be subjected to repurposing against SARS-CoV-2 infection after verifying the in silico results through in vitro and in vivo studies.
Keywords: 3CLpro, 3C-like proteinase; COVID-19; COVID-19, coronavirus disease 2019; DOPE, discrete optimized protein energy; FDA approved antiviral drugs; FDA, Food and Drug Administration; GRAVY, grand average of hydropathicity; GZR, Grazoprevir; GpppA, Guanosine-P3-adenosine-5′,5′-triphosphate; Homology modelling; MERS-CoV, Middle East respiratory syndrome coronavirus; Molecular docking; N7-MTase, S-adenosyl methionine (SAM)-dependent (guanine-N7) methyltransferase; Nsp13 helicase; Nsp14; Nsps, non-structural proteins; PDB, protein data bank; PLpro, papain-like proteinase; PTV, Paritaprevir; RMSD, root mean square deviation; RTC, replication-transcription complex; RdRp, RNA-dependent RNA polymerase; SAH, S-adenosyl homocysteine; SARS-CoV, severe acute respiratory syndrome coronavirus; SARS-CoV-2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SAVES, Structure Analysis and Verification Server; SF, Sinefungin; SMV, Simeprevir; TMHs, transmembrane helices; ZBD, zinc binding domain.
. 2020 Dec;21:100860.
doi: 10.1016/j.genrep.2020.100860. Epub 2020 Aug 28.
In silico structure modelling of SARS-CoV-2 Nsp13 helicase and Nsp14 and repurposing of FDA approved antiviral drugs as dual inhibitors
Arun Bahadur Gurung[SUP] 1 [/SUP]
Affiliations
- PMID: 32875166
- PMCID: PMC7452913
- DOI: 10.1016/j.genrep.2020.100860
Abstract
The high mortality rate from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in humans and the lack of effective therapeutic regime for its treatment necessitates the identification of new antivirals. SARS-CoV-2 relies on non-structural proteins such as Nsp13 helicase and nsp14 which are the key components of the replication-transcription complex (RTC) to complete its infectious life cycle. Therefore, targeting these essential viral proteins with small molecules will most likely to halt the disease pathogenesis. The lack of experimental structures of these proteins deters the process of structure-based identification of their specific inhibitors. In the present study, the in silico models of SARS-CoV-2 nsp13 helicase and nsp14 protein were elucidated using a comparative homology modelling approach. These in silico model structures were validated using various parameters such as Ramachandran plot, Verify 3D score, ERRAT score, knowledge-based energy and Z-score. The in silico models were further used for virtual screening of the Food and Drug Administration (FDA) approved antiviral drugs. Simeprevir (SMV), Paritaprevir (PTV) and Grazoprevir (GZR) were the common leads identified which show higher binding affinity to both nsp13 helicase and nsp14 as compared to the control inhibitors and therefore, they might be potential dual-target inhibitors. The leads also establish a network of hydrogen bonds and hydrophobic interactions with the key residues lining the active site pockets. The present findings suggest that these FDA approved antiviral drugs can be subjected to repurposing against SARS-CoV-2 infection after verifying the in silico results through in vitro and in vivo studies.
Keywords: 3CLpro, 3C-like proteinase; COVID-19; COVID-19, coronavirus disease 2019; DOPE, discrete optimized protein energy; FDA approved antiviral drugs; FDA, Food and Drug Administration; GRAVY, grand average of hydropathicity; GZR, Grazoprevir; GpppA, Guanosine-P3-adenosine-5′,5′-triphosphate; Homology modelling; MERS-CoV, Middle East respiratory syndrome coronavirus; Molecular docking; N7-MTase, S-adenosyl methionine (SAM)-dependent (guanine-N7) methyltransferase; Nsp13 helicase; Nsp14; Nsps, non-structural proteins; PDB, protein data bank; PLpro, papain-like proteinase; PTV, Paritaprevir; RMSD, root mean square deviation; RTC, replication-transcription complex; RdRp, RNA-dependent RNA polymerase; SAH, S-adenosyl homocysteine; SARS-CoV, severe acute respiratory syndrome coronavirus; SARS-CoV-2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SAVES, Structure Analysis and Verification Server; SF, Sinefungin; SMV, Simeprevir; TMHs, transmembrane helices; ZBD, zinc binding domain.