scholarly journals Susceptibility of spike glycoprotein and RNA-dependent RNA polymerase of SARS-CoV-2 to mutation: in silico structural dynamics study

2021 ◽  
Vol 9 (4) ◽  
pp. 148-152
Author(s):  
Toluwase Hezekiah Fatoki ◽  
Jude Akinyelu ◽  
Oluwafijimi Yomi Adetuyi ◽  
Temitope Olawale Jeje ◽  
Uchechukwu Nebo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rna Polymerase ◽  
In Silico ◽  
Structural Flexibility ◽  
Amino Acid Residues ◽  
Spike Glycoprotein ◽  
Rna Dependent Rna Polymerase ◽  
Evolutionary Changes ◽  
Fast Pace ◽  
Structural Fluctuations

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a microorganism that causes coronavirus disease 2019 (COVID-19). Mutations affect evolutionary conservation of microorganisms. The fast pace evolutionary changes are currently affecting pathogenicity of SARS-CoV-2. In this study, the structural fluctuations of the amino acid residues in the spike glycoprotein and RNA-dependent RNA polymerase (nsp12) of SARS-CoV-2 were investigated by in silico approach using structural flexibility dynamics to decipher susceptibility to mutation. The result of this study implicated key amino acid residues (with rmsf) which could be very susceptible to mutation, which include residues 50 (3.79 Å), 119 (4.56 Å), 120 (3.53 Å), 220 (3.84 Å), 265 (4.31 Å) of RNA-dependent RNA polymerase (nsp12), as well as residues 477 (4.21 Å), 478 (4.82 Å), 479 (5.40 Å), 481 (5.94 Å), 560 (4.63 Å), 704 (4.02 Å), 848 (4.58 Å), 1144 (4.56 Å) and 1147 (4.61 Å) of spike glycoprotein. The SARS-CoV-2 mutations destabilized the overall protein structure in multiples of amino acid residues which could interfere with active site leading to insensitivity or resistance to the inhibitors. Mutation T478K of Spike glycoprotein showed the highest deviation in the structure. Overall, spike glycoprotein has the highest number of mutations, and these variants could increase the risk to human health if not mitigated in the population.

scholarly journals Andrographolide binds to spike glycoprotein and RNA-dependent RNA polymerase (NSP12) of SARS-CoV-2 by in silico approach: a probable molecule in the development of anti-coronaviral drug

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lokanathan Srikanth ◽  
Potukuchi Venkata Gurunadha Krishna Sarma
Keyword(s):  
Rna Polymerase ◽  
In Silico ◽  
Host Cells ◽  
Spike Glycoprotein ◽  
Leaf Extracts ◽  
Rna Dependent Rna Polymerase ◽  
Angiotensin Converting Enzyme 2 ◽  
Naturally Occurring ◽  
The Family ◽  
Inhibitory Molecules

AbstractThe SARS-CoV-2 belongs to Coronaviridae family infects host cells by the interaction of its spike glycoprotein and angiotensin-converting enzyme 2 (ACE 2) of host cells. Upon entry, the virus uses its RNA dependent RNA polymerase (NSP12) for transcribing its genome to survive in the cell and spread its infection. The protein sequences of receptor-binding domain (RBD) of spike glycoprotein, and NSP12 exhibits high homology in the family of Coronoviridae and are ideal candidates for the development of anti-coronaviral drugs. In the quest to identify inhibitory molecules against these proteins, we searched several molecules that are present in naturally occurring medicinal plants database. Andrographolide which is largely present in the leaf extracts of Andrographis paniculata (AP) and is known to exhibit antiviral, antibacterial, and stabilizes Th1/Th2/Th17 responses; taking this clue, we used in silico approaches to see the binding of andrographolide to RBD and NSP12 molecules. Our docking results showed very strong affinity of andrographolide to RBD and NSP12 of the SARS-CoV-2 virus with dock scores of −10.3460 for RBD and −10.7313 for NSP12 indicating andrographolide acts as an inhibitor of RBD and NSP12. These unique properties of andrographolide, AP extract, can be tested as anti-coronaviral drug.

scholarly journals Beclabuvir can Inhibit the RNA-dependent RNA Polymerase of Newly Emerged Novel Coronavirus (SARS-CoV-2)

2020 ◽  
Author(s):  
Kunal Dutta ◽  
Sergey Shityakov ◽  
Olga Morozova ◽  
Ibrahim Khalifa ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rna Polymerase ◽  
Rna Synthesis ◽  
Binding Free Energy ◽  
Polymerase Activity ◽  
Amino Acid Residues ◽  
Rna Dependent Rna Polymerase ◽  
Recent Emergence ◽  
Novel Coronavirus ◽  
Major Amino Acid

Recent emergence of novel coronavirus (SARS-CoV-2) all over the world has resulted more than 33,106 global deaths. To date well-established therapeutics modules for infected patients are unknown. In this present initiative, molecular interactions between FDA-approved antiviral drugs against the Hepatitis-C virus (HCV) have been investigated theoretically against the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. HCV and SARS-CoV-2 are both +ssRNA viruses. At 25o C beclabuvir, a non-nucleoside inhibitor of the RdRpHCV can efficiently bind to RdRp SARS-CoV-2 (ΔGAutoDock = -9.95 kcal mol-1) with an inhibition constant of 51.03 nM. Both the ΔGLondon and ΔGGBVI / WSA values were - 9.06 and - 6.67 kcal mol-1, respectively for binding of beclabuvir to RdRpSARS-CoV-2. In addition, beclabuvir has also shown better binding free energy with RdRpSARS-CoV-2 (ΔGvina = -8.0 kcal mol-1) than that observed with the Thumb 1 domain of RdRpHCV (ΔGvina = -7.1 kcal mol-1). InterProScan has suggested the RNA-directed 5'-3' polymerase activity exists within 549th to 776th amino acid residues of RdRpSARS-CoV, where the major amino acid residues interacting being I591, Y621, C624, D625, A690, N693, L760, D762, D763, and E813-N817. Molecular interaction suggests occupancy of beclabuvir inside the active site environment of the RdRpSARS-CoV-2, the enzyme essential for viral RNA synthesis. In conclusion, results suggest beclabuvir may serve as an anti-SARS-CoV-2 drug.

scholarly journals Beclabuvir can Inhibit the RNA-dependent RNA Polymerase of Newly Emerged Novel Coronavirus (SARS-CoV-2)

2020 ◽  
Author(s):  
Kunal Dutta ◽  
Sergey Shityakov ◽  
Olga Morozova ◽  
Ibrahim Khalifa ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rna Polymerase ◽  
Rna Synthesis ◽  
Therapeutic Potential ◽  
Binding Free Energy ◽  
Polymerase Activity ◽  
Amino Acid Residues ◽  
Rna Dependent Rna Polymerase ◽  
Recent Emergence ◽  
Novel Coronavirus

Recent emergence of novel coronavirus (SARS-CoV-2) in Wuhan, China has resulted more than 14,510 global deaths. To date well-established therapeutics modules for infected patients are unknown. In this present initiative, molecular interactions between well-known antiviral drugs against the Hepatitis-C virus (HCV) have been investigated theoretically against the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. HCV and SARS-CoV-2 are both +ssRNA viruses. At 25o C beclabuvir, a non-nucleoside inhibitor of the RdRp of the HCV can efficiently bind to RdRp of the SARS-CoV-2 (ΔGAutoDock = -9.95 kcal mol-1) with an inhibition constant of only 51.03 nM. Both the ΔGLondon and ΔGGBVI / WSA values were - 9.06 and - 6.67 kcal mol-1, respectively for SARS-CoV-2. In addition, beclabuvir also shows better binding free energy (ΔGvina = 9.7 kcal mol-1) than that of the Thumb 1 domain of RdRp of HCV (ΔGvina = 7.7 kcal mol-1). InterProScan has suggested the RNA-directed 5'-3' polymerase activity existed within 549 to 776 amino acid residues of RdRp. Moreover, major interacting amino acid residues were I591, Y621, C624, D625, A690, N693, L760, D762, D763 and E813-N817. Molecular interaction suggests occupancy of beclabuvir inside the active site environment of the RdRp which is essential for viral RNA synthesis. In conclusion, results suggest beclabuvir has high therapeutic potential as an anti-SARS-CoV-2 drug.

In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA Dependent RNA polymerase (RdRp) and Essential Proteases

2020 ◽  
Vol 20 ◽  
Author(s):  
Trinath Chowdhury ◽  
Gourisankar Roymahapatra ◽  
Santi M. Mandal
Keyword(s):  
Rna Polymerase ◽  
Viral Entry ◽  
In Silico ◽  
Rna Dependent Rna Polymerase ◽  
Replication Complex ◽  
In Silico Study ◽  
Life Threatening ◽  
In Vivo Analysis ◽  
3Cl Protease

Background: COVID-19 is a life threatening novel corona viral infection to our civilization and spreading rapidly. Terrific efforts are generous by the researchers to search for a drug to control SARS-CoV-2. Methods: Here, a series of arsenical derivatives were optimized and analyzed with in silico study to search the inhibitor of RNA dependent RNA polymerase (RdRp), the major replication factor of SARS-CoV-2. All the optimized derivatives were blindly docked with RdRp of SARS-CoV-2 using iGEMDOCK v2.1. Results: Based on the lower idock score in the catalytic pocket of RdRp, darinaparsin (-82.52 kcal/mol) revealed most effective among them. Darinaparsin strongly binds with both Nsp9 replicase protein (-8.77 kcal/mol) and Nsp15 endoribonuclease (-8.3 kcal/mol) of SARS-CoV-2 as confirmed from the AutoDock analysis. During infection, the ssRNA of SARS-CoV2 is translated into large polyproteins forming viral replication complex by specific proteases like 3CL protease and papain protease. This is also another target to control the virus infection where darinaparsin also perform the inhibitory role to proteases of 3CL protease (-7.69 kcal/mol) and papain protease (-8.43 kcal/mol). Conclusion: In host cell, the furin protease serves as a gateway to the viral entry and darinaparsin docked with furin protease which revealed a strong binding affinity. Thus, screening of potential arsenic drugs would help in providing the fast invitro to in-vivo analysis towards development of therapeutics against SARS-CoV-2.

scholarly journals In silico study indicates antimalarials as direct inhibitors of SARS-CoV-2-RNA dependent RNA polymerase

2021 ◽  
pp. 1-18
Author(s):  
Pawan Kumar Doharey ◽  
Vishal Singh ◽  
Mallikarjuna Rao Gedda ◽  
Amaresh Kumar Sahoo ◽  
Pritish Kumar Varadwaj ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
In Silico ◽  
Rna Dependent Rna Polymerase ◽  
In Silico Study ◽  
Direct Inhibitors

scholarly journals Identification and in silico characterization of hemocyanin γ-type subunit protein in Vibrio harveyi infected freshwater prawn, Macrobrachium rosenbergii

2021 ◽  
Vol 42 (1) ◽  
pp. 14-23
Author(s):  
B.B. Patnaik ◽  
◽  
S. Baliarsingh ◽  
S. Sahoo ◽  
J.M. Chung ◽  
...  
Keyword(s):  
Amino Acid ◽  
In Silico ◽  
Vibrio Harveyi ◽  
Macrobrachium Rosenbergii ◽  
Full Length ◽  
Freshwater Prawn ◽  
Amino Acid Residues ◽  
Subunit Protein ◽  
In Silico Tools

Aim: Identification of full-length ORF of hemocyanin subunit-1 (Mr_HC_1) from the hepatopancreas transcriptome of freshwater prawn, Macrobrachium rosenbergii infected with Vibrio harveyi and characterization of its sequence and structure by in silico tools and softwares. Methodology: Illumina HiSeq and de novo assembled unigenes were scanned against PANM-DB to screen Mr_HC_1. FGENESH gene prediction and SMART programs were used to predict the ORF region. Subsequently, Clustal X2 and MEGA in-silico tools were used to understand the sequence relatedness and evolutionary status of Mr_HC_1. Structural prediction was performed by SWISS-MODEL and Ramachandran plot modeling programs Results: The full-length ORF was 1983 bp in length encoding a polypeptide of 661 amino acid residues. Mr_HC_1 showed a putative signal peptide of 21 amino acid residues at the N-terminus and three hemocyanin domains. Homology analysis of Mr_HC_1 amino acid sequence confirms maximum identity to M. nipponense hemocyanin subunit-1 (Mn_HC_1). Phylogenetic analysis showed that Mr_HC_1 is more closely related to the hemocyanin γ-type subunit of freshwater shrimps. Homology modeling of Mr_HC_1 showed homo-hexameric protein containing 12 copper ions. With a QMEAN score of -3.33 and model-template sequence identity of 59.15%, the predicted model of Mr_HC_1 is convincing Interpretation: This study characterizes the hemocyanin γ-type subunit protein of freshwater prawn, M. rosenbergii for future studies on host defense mechanisms.

scholarly journals RPC53 encodes a subunit of Saccharomyces cerevisiae RNA polymerase C (III) whose inactivation leads to a predominantly G1 arrest.

1992 ◽  
Vol 12 (10) ◽  
pp. 4314-4326 ◽  
Author(s):  
C Mann ◽  
J Y Micouin ◽  
N Chiannilkulchai ◽  
I Treich ◽  
J M Buhler ◽  
...  
Keyword(s):  
Cell Division ◽  
Amino Acid ◽  
Rna Polymerase ◽  
Essential Gene ◽  
Temperature Sensitive ◽  
G1 Arrest ◽  
Restrictive Temperature ◽  
Amino Acid Residues ◽  
Gene Encoding ◽  
Carboxy Terminal

RPC53 is shown to be an essential gene encoding the C53 subunit specifically associated with yeast RNA polymerase C (III). Temperature-sensitive rpc53 mutants were generated and showed a rapid inhibition of tRNA synthesis after transfer to the restrictive temperature. Unexpectedly, the rpc53 mutants preferentially arrested their cell division in the G1 phase as large, round, unbudded cells. The RPC53 DNA sequence is predicted to code for a hydrophilic M(r)-46,916 protein enriched in charged amino acid residues. The carboxy-terminal 136 amino acids of C53 are significantly similar (25% identical amino acid residues) to the same region of the human BN51 protein. The BN51 cDNA was originally isolated by its ability to complement a temperature-sensitive hamster cell mutant that undergoes a G1 cell division arrest, as is true for the rpc53 mutants.

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