Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target

A novel coronavirus [severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2)] outbreak has caused a global coronavirus disease 2019 (COVID-19) pandemic, resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase [(RdRp), also named nsp12] is the central component of coronaviral replication and transcription machinery, and it appears to be a primary target for the antiviral drug remdesivir. We report the cryo–electron microscopy structure of COVID-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-angstrom resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified β-hairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics that target viral RdRp.

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Virtual Screening of the Indonesian Medicinal Plant and Zinc Databases for Potential Inhibitors of the RNA-Dependent RNA Polymerase (RdRp) of 2019 Novel Coronavirus

Indonesian Journal of Chemistry ◽

10.22146/ijc.56120 ◽

2020 ◽

Vol 20 (6) ◽

pp. 1430

Author(s):

Muhammad Arba ◽

Andry Nur-Hidayat ◽

Ida Usman ◽

Arry Yanuar ◽

Setyanto Tri Wahyudi ◽

...

Keyword(s):

Binding Energy ◽

Rna Polymerase ◽

Antiviral Drug ◽

Dynamics Simulation ◽

Human Beings ◽

Rna Dependent Rna Polymerase ◽

Energy Prediction ◽

Binding Energy Prediction ◽

Solvation Energies ◽

Novel Coronavirus

The novel coronavirus disease 19 (Covid-19) which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a pandemic across the world, which necessitate the need for the antiviral drug discovery. One of the potential protein targets for coronavirus treatment is RNA-dependent RNA polymerase. It is the key enzyme in the viral replication machinery, and it does not exist in human beings, therefore its targeting has been considered as a strategic approach. Here we describe the identification of potential hits from Indonesian Herbal and ZINC databases. The pharmacophore modeling was employed followed by molecular docking and dynamics simulation for 40 ns. 151 and 14480 hit molecules were retrieved from Indonesian herbal and ZINC databases, respectively. Three hits that were selected based on the structural analysis were stable during 40 ns, while binding energy prediction further implied that ZINC1529045114, ZINC169730811, and 9-Ribosyl-trans-zeatin had tighter binding affinities compared to Remdesivir. The ZINC169730811 had the strongest affinity toward RdRp compared to the other two hits including Remdesivir and its binding was corroborated by electrostatic, van der Waals, and nonpolar contribution for solvation energies. The present study offers three hits showing tighter binding to RdRp based on MM-PBSA binding energy prediction for further experimental verification.

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Intermolecular Interaction Among Remdesivir, RNA and RNA-Dependent RNA Polymerase of SARS-CoV-2 Analyzed by Fragment Molecular Orbital Calculation

10.26434/chemrxiv.12362222 ◽

2020 ◽

Author(s):

Koichiro Kato ◽

Teruki Honma ◽

Kaori Fukuzawa

Keyword(s):

Rna Polymerase ◽

Molecular Orbital ◽

Antiviral Drug ◽

Molecular Orbital Calculation ◽

Data Bank ◽

Rna Dependent Rna Polymerase ◽

Fragment Molecular Orbital ◽

Global Pandemic ◽

The World ◽

Primer Rna

<p>COVID-19, a disease caused by a new strain of coronavirus (SARS-CoV-2) originating from Wuhan, China, has now spread around the world, triggering a global pandemic, leaving the public eagerly awaiting the development of a specific medicine and vaccine. In response, aggressive efforts are underway around the world to overcome COVID-19. In this study, referencing the data published on the Protein Data Bank (PDB ID: 7BV2) on April 22, we conducted a detailed analysis of the interaction between the complex structures of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and Remdesivir, an antiviral drug, from the quantum chemical perspective based on the fragment molecular orbital (FMO) method. In addition to the hydrogen bonding and intra-strand stacking between complementary strands as seen in normal base pairs, Remdesivir bound to the terminus of an primer-RNA strand was further stabilized by diagonal π-π stacking with the -1A base of the complementary strand and an additional hydrogen bond with an intra-strand base, due to the effect of chemically modified functional group. Moreover, stable OH/π interaction is also formed with Thr687 of the RdRp. We quantitatively revealed the exhaustive interaction within the complex among Remdesivir, template-primer-RNA, RdRp and co-factors, and published the results in the FMODB database.</p>

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Intermolecular Interaction Among Remdesivir, RNA and RNA-Dependent RNA Polymerase of SARS-CoV-2 Analyzed by Fragment Molecular Orbital Calculation

10.26434/chemrxiv.12362222.v1 ◽

2020 ◽

Author(s):

Koichiro Kato ◽

Teruki Honma ◽

Kaori Fukuzawa

Keyword(s):

Rna Polymerase ◽

Molecular Orbital ◽

Antiviral Drug ◽

Molecular Orbital Calculation ◽

Data Bank ◽

Rna Dependent Rna Polymerase ◽

Fragment Molecular Orbital ◽

Global Pandemic ◽

The World ◽

Primer Rna

<p>COVID-19, a disease caused by a new strain of coronavirus (SARS-CoV-2) originating from Wuhan, China, has now spread around the world, triggering a global pandemic, leaving the public eagerly awaiting the development of a specific medicine and vaccine. In response, aggressive efforts are underway around the world to overcome COVID-19. In this study, referencing the data published on the Protein Data Bank (PDB ID: 7BV2) on April 22, we conducted a detailed analysis of the interaction between the complex structures of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and Remdesivir, an antiviral drug, from the quantum chemical perspective based on the fragment molecular orbital (FMO) method. In addition to the hydrogen bonding and intra-strand stacking between complementary strands as seen in normal base pairs, Remdesivir bound to the terminus of an primer-RNA strand was further stabilized by diagonal π-π stacking with the -1A base of the complementary strand and an additional hydrogen bond with an intra-strand base, due to the effect of chemically modified functional group. Moreover, stable OH/π interaction is also formed with Thr687 of the RdRp. We quantitatively revealed the exhaustive interaction within the complex among Remdesivir, template-primer-RNA, RdRp and co-factors, and published the results in the FMODB database.</p>

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The RNA-Dependent-RNA Polymerase, an Emerging Antiviral Drug Target for the Hendra Virus

Current Drug Targets ◽

10.2174/1389450114888131204163210 ◽

2014 ◽

Vol 15 (1) ◽

pp. 103-113 ◽

Cited By ~ 12

Author(s):

Tony Velkov ◽

Vincenzo Carbone ◽

Jesmin Akter ◽

Sivashangarie Sivanesan ◽

Jian Li ◽

...

Keyword(s):

Rna Polymerase ◽

Drug Target ◽

Antiviral Drug ◽

Hendra Virus ◽

Rna Dependent Rna Polymerase

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Remdesivir MD Simulations Suggest a More Favourable Binding to SARS-CoV-2 RNA Dependent RNA Polymerase Mutant P323L Than Wild-Type

Biomolecules ◽

10.3390/biom11070919 ◽

2021 ◽

Vol 11 (7) ◽

pp. 919

Author(s):

Anwar Mohammad ◽

Fahd Al-Mulla ◽

Dong-Qing Wei ◽

Jehad Abubaker

Keyword(s):

Rna Polymerase ◽

Molecular Conformation ◽

Antiviral Drug ◽

Md Simulations ◽

Binding Energies ◽

Wild Type ◽

Rna Dependent Rna Polymerase ◽

Dynamic Motion ◽

Similar Dynamic ◽

Insight Into

SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) protein is the target for the antiviral drug Remdesivir (RDV). With RDV clinical trials on COVID-19 patients showing a reduced hospitalisation time. During the spread of the virus, the RdRp has developed several mutations, with the most frequent being A97V and P323L. The current study sought to investigate whether A97V and P323L mutations influence the binding of RDV to the RdRp of SARS-CoV-2 compared to wild-type (WT). The interaction of RDV with WT-, A97V-, and P323L-RdRp were measured using molecular dynamic (MD) simulations, and the free binding energies were extracted. Results showed that RDV that bound to WT- and A97V-RdRp had a similar dynamic motion and internal residue fluctuations, whereas RDV interaction with P323L-RdRp exhibited a tighter molecular conformation, with a high internal motion near the active site. This was further corroborated with RDV showing a higher binding affinity to P323L-RdRp (−24.1 kcal/mol) in comparison to WT-RdRp (−17.3 kcal/mol). This study provides insight into the potential significance of administering RDV to patients carrying the SARS-CoV-2 P323L-RdRp mutation, which may have a more favourable chance of alleviating the SARS-CoV-2 illness in comparison to WT-RdRp carriers, thereby suggesting further scientific consensus for the usage of Remdesivir as clinical candidate against COVID-19.

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Amoxicillin and Clavulanate as Potential Multiple Effect Inhibitors of 2019 Novel Coronavirus Main Protease and RNA-Dependent RNA Polymerase with Strong Receptor-Binding Domain (RBD), Molecular Docking and SAR Study

SSRN Electronic Journal ◽

10.2139/ssrn.3618303 ◽

2020 ◽

Author(s):

Khedidja benarous ◽

Talia Serseg ◽

Mohamed Yousfi

Keyword(s):

Molecular Docking ◽

Rna Polymerase ◽

Receptor Binding ◽

Binding Domain ◽

Receptor Binding Domain ◽

Rna Dependent Rna Polymerase ◽

Multiple Effect ◽

Main Protease ◽

Novel Coronavirus ◽

Sar Study

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Recent Advances towards Drug Design Targeting the Protease of 2019 novel coronavirus (2019-nCoV)

Current Medicinal Chemistry ◽

10.2174/0929867327666201027153617 ◽

2020 ◽

Vol 27 ◽

Author(s):

Sehrish Bano ◽

Abdul Hameed ◽

Mariya Al-Rashida ◽

Shafia Iftikhar ◽

Jamshed Iqbal

Keyword(s):

Drug Design ◽

Rna Polymerase ◽

Drug Targets ◽

Antiviral Agents ◽

Structural Features ◽

Antiviral Drugs ◽

Rna Dependent Rna Polymerase ◽

Mortality And Morbidity ◽

Functional Relationships ◽

Novel Coronavirus

Background: The 2019 novel coronavirus (2019-nCoV), also known as coronavirus 2 (SARS-CoV-2) acute respiratory syndrome has recently emerged and continued to spread rapidly with high level of mortality and morbidity rates. Currently, no efficacious therapy is available to relieve coronavirus infections. As new drug design and development takes much time, there is a possibility to find an effective treatment from existing antiviral agents. Objective: In this case, there is a need to find out the relationship between possible drug targets and mechanism of action of antiviral drugs. This review discusses about the efforts to develop drug from known or new molecules. Methods: Viruses usually have two structural integrities, proteins and nucleic acids, both of which can be possible drug targets. Herein, we systemically discuss the structural-functional relationships of the spike, 3-chymotrypsin-like protease (3CLpro), papain like protease (PLpro) and RNA-dependent RNA polymerase (RdRp), as these are prominent structural features of corona virus. Certain antiviral drugs such as Remdesivir are RNA dependent RNA polymerase inhibitor. It has the ability to terminate RNA replication by inhibiting ATP. Results: It is reported that ATP is involved in synthesis of coronavirus non-structural proteins from 3CLpro and PLpro. Similarly, mechanisms of action of many other antiviral agents has been discussed in this review. It will provide new insights into the mechanism of inhibition, and let us develop new therapeutic antiviral approaches against novel SARS-CoV-2 coronavirus. Conclusion: In conclusion, this review summarizes recent progress in developing protease inhibitors for SARS-CoV-2.

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Screening of Kabasura Kudineer Chooranam against COVID-19 through Targeting of Main Protease and RNA-Dependent RNA Polymerase of SARS-CoV-2 by Molecular Docking Studies

Asian Journal of Organic & Medicinal Chemistry ◽

10.14233/ajomc.2020.ajomc-p299 ◽

2020 ◽

Vol 5 (4) ◽

pp. 319-331

Author(s):

K. Gopalasatheeskumar ◽

Karthikeyen Lakshmanan ◽

Anguraj Moulishankar ◽

Jerad Suresh ◽

D. Kumuthaveni Babu ◽

...

Keyword(s):

Molecular Docking ◽

Rna Polymerase ◽

Docking Studies ◽

The Novel ◽

Rna Dependent Rna Polymerase ◽

Molecular Docking Studies ◽

Main Protease ◽

Short Span ◽

Novel Coronavirus

COVID-19 is the infectious pandemic disease caused by the novel coronavirus. The COVID-19 is spread globally in a short span of time. The Ministry of AYUSH, India which promotes Siddha and other Indian system of medicine recommends the use of formulation like Nilavembu Kudineer and Kaba Sura Kudineer Chooranam (KSKC). The present work seeks to provide the evidence for the action of 74 different constituents of the KSKC formulation acting on two critical targets. That is main protease and SARS-CoV-2 RNAdependent RNA polymerase target through molecular docking studies. The molecular docking was done by using AutoDock Tools 1.5.6 of the 74 compounds, about 50 compounds yielded docking results against COVID-19 main protease while 42 compounds yielded against SARSCoV- 2 RNA-dependent RNA polymerase. This research has concluded that the KSKC has the lead molecules that inhibits COVID-19’s target of main protease of COVID-19 and SARS-CoV-2 RNA-dependent RNA polymerase.

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Use of DNA, RNA, and Chimeric Templates by a Viral RNA-Dependent RNA Polymerase: Evolutionary Implications for the Transition from the RNA to the DNA World

Journal of Virology ◽

10.1128/jvi.73.8.6424-6429.1999 ◽

1999 ◽

Vol 73 (8) ◽

pp. 6424-6429 ◽

Cited By ~ 20

Author(s):

Robert W. Siegel ◽

Laurent Bellon ◽

Leonid Beigelman ◽

C. Cheng Kao

Keyword(s):

Rna Polymerase ◽

Mosaic Virus ◽

Rna Synthesis ◽

Brome Mosaic Virus ◽

Viral Rna ◽

Competition Assay ◽

Rna Dependent Rna Polymerase ◽

Dna Molecule ◽

Mechanism Of Catalysis ◽

Insight Into

ABSTRACT All polynucleotide polymerases have a similar structure and mechanism of catalysis, consistent with their evolution from one progenitor polymerase. Viral RNA-dependent RNA polymerases (RdRp) are expected to have properties comparable to those from this progenitor and therefore may offer insight into the commonalities of all classes of polymerases. We examined RNA synthesis by the brome mosaic virus RdRp on DNA, RNA, and hybrid templates and found that precise initiation of RNA synthesis can take place from all of these templates. Furthermore, initiation can take place from either internal or penultimate initiation sites. Using a template competition assay, we found that the BMV RdRp interacts with DNA only three- to fourfold less well than it interacts with RNA. Moreover, a DNA molecule with a ribonucleotide at position −11 relative to the initiation nucleotide was able to interact with RdRp at levels comparable to that observed with RNA. These results suggest that relatively few conditions were needed for an ancestral RdRp to replicate DNA genomes.

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