scholarly journals Norovirus RNA-dependent RNA polymerase: A computational study of metal-binding preferences

2017 ◽  
Vol 85 (8) ◽  
pp. 1435-1445 ◽  
Author(s):  
Md Munan Shaik ◽  
Nicholus Bhattacharjee ◽  
Mikolaj Feliks ◽  
Kenneth K.-S. Ng ◽  
Martin J. Field
Keyword(s):  
Rna Polymerase ◽  
Metal Binding ◽  
Computational Study ◽  
Rna Dependent Rna Polymerase

scholarly journals Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets

Science ◽  
2021 ◽  
pp. eabi5224
Author(s):  
Nunziata Maio ◽  
Bernard A. P. Lafont ◽  
Debangsu Sil ◽  
Yan Li ◽  
J. Martin Bollinger ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Metal Binding ◽  
Rna Dependent Rna Polymerase ◽  
Iron Sulfur Clusters ◽  
Metal Binding Sites ◽  
Iron Sulfur ◽  
Cryo Electron Microscopy ◽  
Metal Cofactors ◽  
Antiviral Targets ◽  
Viral Helicase

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes. We found that the catalytic subunit of the RdRp, nsp12, ligates two iron-sulfur metal cofactors in sites that were modeled as zinc centers in the available cryo-electron microscopy structures of the RdRp complex. These metal binding sites are essential for replication and for interaction with the viral helicase. Oxidation of the clusters by the stable nitroxide TEMPOL caused their disassembly, potently inhibited the RdRp, and blocked SARS-CoV-2 replication in cell culture. These iron-sulfur clusters thus serve as cofactors for the SARS-CoV-2 RdRp and are targets for therapy of COVID-19.

scholarly journals Structural Elucidation of SARS-CoV-2 Vital Proteins: Computational Methods Reveal Potential Drug Candidates Against Main Protease, Nsp12 RNA-dependent RNA Polymerase and Nsp13 Helicase

2020 ◽  
Author(s):  
Muhammad Usman Mirza ◽  
Matheus Froeyen
Keyword(s):  
Drug Discovery ◽  
Rna Polymerase ◽  
High Throughput Screening ◽  
Structural Information ◽  
Computational Study ◽  
Antiviral Drug ◽  
Decomposition Analysis ◽  
Energy Decomposition Analysis ◽  
Rna Dependent Rna Polymerase ◽  
Main Protease

The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a major outbreak of coronavirus disease 2019 (COVID-19) and instigated a widespread fear and has threatened global health security. Although phenomenal efforts are in progress to effectively combat this COVID-19 outbreak. Still, no licensed antiviral drugs or vaccines are available, and treatment is limited to supportive care and few repurposed drugs. In this urgency situation, computational drug discovery methods provide both an alternative and a supplement to tiresome high-throughput screening, particularly in the hit-to-lead-optimization stage. Identification of small molecules that specifically target viral replication apparatus has shown the most successful strategy in antiviral drug discovery. The present study deals with the identification of potential compounds that specifically interact with SARS-CoV-2 vital proteins, including main protease (Mpro), Nsp12 RNA-dependent-RNA-polymerase (RdRp) and Nsp13 helicase. A constructive and integrated virtual screening efforts together with molecular dynamics simulations identified potential binding modes and favourable molecular interaction profile of corresponding compounds. Moreover, structurally important binding site residues in conserved motifs located inside the active site are elucidated, which displayed relative importance in ligand binding based on residual energy decomposition analysis. Although the current study lacks experimental validation, the structural information obtained from this computational study paved the way to identify and design specific targeted inhibitors to combat COVID-19 outbreak.

scholarly journals In-Silico Drug Designing of Novel Morpholino Based Physcion Drug Candidate and Investigation of Inhibition Effects on Covid-19 RNA Dependent - RNA Polymerase Non Structural Protein 12 (Nsp 12) with ADMET Study

2020 ◽  
Author(s):  
Poojasri Sargunam ◽  
Sribal Sridharan
Keyword(s):  
Binding Energy ◽  
Rna Polymerase ◽  
Computational Study ◽  
Positive Control ◽  
New Drugs ◽  
Dimensional Structure ◽  
Drug Candidate ◽  
Genome Replication ◽  
Structural Protein ◽  
Rna Dependent Rna Polymerase

<p>Recent explosion of highly fatal pandemic corona virus <i>C</i><i>ovid</i><i>-19</i> in human population. The <i>C</i><i>ovid</i><i>-19</i> is a positive sense single stranded enveloped virus which belongs to the <i>Coronaviridae family</i> required non-structural proteins 12 (nsp12), a RNA dependent-RNA polymerase as an important machinery for the viral genome replication and transcription processes. There are various RNA polymerase inhibitors are currently using in clinical activities to treat <i>Covid-19</i> infections but their treating efficacy is not up to much impressive particularly in aged people. In this study, we docked Morpholino based physcion drug candidate against RNA polymerase target (<i>PDB ID : 6NUR</i>). We designed drug candidate using Chemsketch software and further it was proceeded to molecular docking using AutoDock Vina 4.0 software. UCSF Chimera software was used for visualization of 3-Dimensional structure of ligand - protein docked pose. Moreover the docked drug candidate was checked for ADMET properties. Hence, this study supports the emergence of developing an efficient new drugs to combat Covid-19 infections. From this computational study we identified the designed drug candidate have high potential of inhibition of virus RNA Dependent - RNA polymerase minimum binding energy of <i>- 8.76</i>. To identify the inhibition potential of designed ligand, we used Remdesivir resulted minimum binding energy of <i>- 7.25</i> as a positive control. These findings supports emergency discovery of anti-viral drug candidate to combat <i>Covid-19</i> infections all over the world.</p>

scholarly journals Computational Study of SARS-CoV-2 RNA Dependent RNA Polymerase Allosteric Site Inhibition

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 223
Author(s):  
Shah Faisal ◽  
Syed Lal Badshah ◽  
Bibi Kubra ◽  
Mohamed Sharaf ◽  
Abdul-Hamid Emwas ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Active Sites ◽  
Time Course ◽  
Computational Study ◽  
Strong Association ◽  
Allosteric Site ◽  
Rna Dependent Rna Polymerase ◽  
Computational Screening ◽  
Virus Rna ◽  
New Information

The COVID-19 pandemic has caused millions of fatalities since 2019. Despite the availability of vaccines for this disease, new strains are causing rapid ailment and are a continuous threat to vaccine efficacy. Here, molecular docking and simulations identify strong inhibitors of the allosteric site of the SARS-CoV-2 virus RNA dependent RNA polymerase (RdRp). More than one hundred different flavonoids were docked with the SARS-CoV-2 RdRp allosteric site through computational screening. The three top hits were Naringoside, Myricetin and Aureusidin 4,6-diglucoside. Simulation analyses confirmed that they are in constant contact during the simulation time course and have strong association with the enzyme’s allosteric site. Absorption, distribution, metabolism, excretion and toxicity (ADMET) data provided medicinal information of these top three hits. They had good human intestinal absorption (HIA) concentrations and were non-toxic. Due to high mutation rates in the active sites of the viral enzyme, these new allosteric site inhibitors offer opportunities to drug SARS-CoV-2 RdRp. These results provide new information for the design of novel allosteric inhibitors against SARS-CoV-2 RdRp.

scholarly journals In-Silico Drug Designing of Novel Morpholino Based Physcion Drug Candidate and Investigation of Inhibition Effects on Covid-19 RNA Dependent - RNA Polymerase Non Structural Protein 12 (Nsp 12) with ADMET Study

2020 ◽  
Author(s):  
Poojasri Sargunam ◽  
Sribal Sridharan
Keyword(s):  
Binding Energy ◽  
Rna Polymerase ◽  
Computational Study ◽  
Positive Control ◽  
New Drugs ◽  
Dimensional Structure ◽  
Drug Candidate ◽  
Genome Replication ◽  
Structural Protein ◽  
Rna Dependent Rna Polymerase

<p>Recent explosion of highly fatal pandemic corona virus <i>C</i><i>ovid</i><i>-19</i> in human population. The <i>C</i><i>ovid</i><i>-19</i> is a positive sense single stranded enveloped virus which belongs to the <i>Coronaviridae family</i> required non-structural proteins 12 (nsp12), a RNA dependent-RNA polymerase as an important machinery for the viral genome replication and transcription processes. There are various RNA polymerase inhibitors are currently using in clinical activities to treat <i>Covid-19</i> infections but their treating efficacy is not up to much impressive particularly in aged people. In this study, we docked Morpholino based physcion drug candidate against RNA polymerase target (<i>PDB ID : 6NUR</i>). We designed drug candidate using Chemsketch software and further it was proceeded to molecular docking using AutoDock Vina 4.0 software. UCSF Chimera software was used for visualization of 3-Dimensional structure of ligand - protein docked pose. Moreover the docked drug candidate was checked for ADMET properties. Hence, this study supports the emergence of developing an efficient new drugs to combat Covid-19 infections. From this computational study we identified the designed drug candidate have high potential of inhibition of virus RNA Dependent - RNA polymerase minimum binding energy of <i>- 8.76</i>. To identify the inhibition potential of designed ligand, we used Remdesivir resulted minimum binding energy of <i>- 7.25</i> as a positive control. These findings supports emergency discovery of anti-viral drug candidate to combat <i>Covid-19</i> infections all over the world.</p>

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