In silico characterization of the NiRAN domain of RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV2

Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of RdRp from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, we predict that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds nucleoside triphosphates at its proposed active site. Additionally, using molecular docking we have predicted the binding of three widely used kinase inhibitors and five well characterized anti-microbial compounds at the NiRAN domain active site along with their drug-likeliness. For the first time ever, using basic biochemical tools, this study shows the presence of a kinase like activity exhibited by the SARS-CoV-2 RdRp. Interestingly, a well-known kinase inhibitor- Sorafenib showed a significant inhibition and dampened viral load in SARS-CoV-2 infected cells. In line with the current global COVID-19 pandemic urgency and the emergence of newer strains with significantly higher infectivity, this study provides a new anti-SARS-CoV-2 drug target and potential lead compounds for drug repurposing against SARS-CoV-2.

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Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2

10.1101/2021.02.03.429510 ◽

2021 ◽

Author(s):

Abhisek Dwivedy ◽

Richard Mariadasse ◽

Mohammed Ahmad ◽

Sayan Chakraborty ◽

Deepsikha Kar ◽

...

Keyword(s):

Active Site ◽

Drug Target ◽

Kinase Inhibitors ◽

3D Structure ◽

Drug Repurposing ◽

Lead Compounds ◽

Nucleotidyl Transferase ◽

Domain Organisation ◽

First Time

AbstractApart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of RdRp from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, we predict that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds nucleoside triphosphates at its proposed active site. Additionally, using molecular docking we have predicted the binding of three widely used kinase inhibitors and five well characterized anti-microbial compounds at the NiRAN domain active site along with their drug-likeliness as well as DFT properties. For the first time ever, using basic biochemical tools, this study shows the presence of a kinase like activity exhibited by the SARS-CoV-2 RdRp. Interestingly, the proposed kinase inhibitors and a few of the predicted nucleotidyl transferase inhibitors significantly inhibited the aforementioned enzymatic activity. In line with the current global COVID-19 pandemic urgency and the emergence of newer strains with significantly higher infectivity, this study provides a new anti-SARS-CoV-2 drug target and potential lead compounds for drug repurposing against SARS-CoV-2.

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The Antiviral and Antimalarial Drug Repurposing in Quest of Chemotherapeutics to Combat COVID-19 Utilizing Structure-Based Molecular Docking

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323999200824115536 ◽

2020 ◽

Vol 23 ◽

Author(s):

Sisir Nandi ◽

Mohit Kumar ◽

Mridula Saxena ◽

Anil Kumar Saxena

Keyword(s):

Molecular Docking ◽

In Silico ◽

Drug Repurposing ◽

Clinical Settings ◽

The Novel ◽

In Silico Docking ◽

Biochemical Mechanisms ◽

Novel Coronavirus ◽

In Silico Molecular Docking

Background: The novel coronavirus disease (COVID-19) is caused by a new strain (SARS-CoV-2) erupted in 2019. Nowadays, it is a great threat that claims uncountable lives worldwide. There is no specific chemotherapeutics developed yet to combat COVID-19. Therefore, scientists have been devoted in the quest of the medicine that can cure COVID- 19. Objective: Existing antivirals such as ASC09/ritonavir, lopinavir/ritonavir with or without umifenovir in combination with antimalarial chloroquine or hydroxychloroquine have been repurposed to fight the current coronavirus epidemic. But exact biochemical mechanisms of these drugs towards COVID-19 have not been discovered to date. Method: In-silico molecular docking can predict the mode of binding to sort out the existing chemotherapeutics having a potential affinity towards inhibition of the COVID-19 target. An attempt has been made in the present work to carry out docking analyses of 34 drugs including antivirals and antimalarials to explain explicitly the mode of interactions of these ligands towards the COVID-19protease target. Results: 13 compounds having good binding affinity have been predicted towards protease binding inhibition of COVID-19. Conclusion: Our in silico docking results have been confirmed by current reports from clinical settings through the citation of suitable experimental in vitro data available in the published literature.

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Combined in silico docking and in vitro antiviral testing for drug repurposing identified lurasidone and elbasvir as SARS-CoV-2 and HCoV-OC43 inhibitors

10.1101/2020.11.12.379958 ◽

2020 ◽

Author(s):

Mario Milani ◽

Manuela Donalisio ◽

Rafaela Milan Bonotto ◽

Edoardo Schneider ◽

Irene Arduino ◽

...

Keyword(s):

In Silico ◽

Antiviral Drug ◽

Drug Repurposing ◽

Large Family ◽

The Novel ◽

In Silico Docking ◽

The Common ◽

Novel Coronavirus ◽

Micromolar Range

AbstractThe current emergency of the novel coronavirus SARS-CoV-2 urged the need for broad-spectrum antiviral drugs as the first line of treatment. Coronaviruses are a large family of viruses that already challenged humanity in at least two other previous outbreaks and are likely to be a constant threat for the future. In this work we developed a pipeline based on in silico docking of known drugs on SARS-CoV RNA-dependent RNA polymerase combined with in vitro antiviral assays on both SARS-CoV-2 and the common cold human coronavirus HCoV-OC43. Results showed that certain drugs displayed activity for both viruses at a similar inhibitory concentration, while others were specific. In particular, the antipsychotic drug lurasidone and the antiviral drug elbasvir showed promising activity in the low micromolar range against both viruses with good selective index.

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Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach

Molecules ◽

10.3390/molecules25235501 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5501

Author(s):

Teresa L. Augustin ◽

Roxanna Hajbabaie ◽

Matthew T. Harper ◽

Taufiq Rahman

Keyword(s):

In Silico ◽

3D Structure ◽

The Novel ◽

Health Crisis ◽

Protein Ligand Interactions ◽

Main Protease ◽

Ligand Interactions ◽

Spanish Flu ◽

Active Fragments ◽

Novel Coronavirus

The ongoing pandemic caused by the novel coronavirus has been the greatest global health crisis since the Spanish flu pandemic of 1918. Thus far, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 1 million deaths, and there is no cure or vaccine to date. The recently solved crystal structure of the SARS-CoV-2 main protease has been a major focus for drug-discovery efforts. Here, we present a fragment-guided approach using ZINCPharmer, where 17 active fragments known to bind to the catalytic centre of the SARS-CoV-2 main protease (SARS-CoV-2 Mpro) were used as pharmacophore queries to search the ZINC databases of natural compounds and natural derivatives. This search yielded 134 hits that were then subjected to multiple rounds of in silico analyses, including blind and focused docking against the 3D structure of the main protease. We scrutinised the poses, scores, and protein–ligand interactions of 15 hits and selected 7. The scaffolds of the seven hits were structurally distinct from known inhibitor scaffolds, thus indicating scaffold novelty. Our work presents several novel scaffolds as potential candidates for experimental validation against SARS-CoV-2 Mpro.

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In Silico Approaches for Novel Drug Discovery Against Coronavirus by Employing the Hybrid Molecular Technique: A Review

Journal of Computational Biophysics and Chemistry ◽

10.1142/s2737416521300017 ◽

2021 ◽

pp. 1-8

Author(s):

Noor ul Amin Mohsin ◽

Muhammad Irfan ◽

Muhammad Naeem Aamir

Keyword(s):

In Silico ◽

Antiviral Agent ◽

Molecular Technique ◽

The Novel ◽

Hybrid Molecules ◽

The World ◽

Being There ◽

Novel Coronavirus ◽

Novel Drug ◽

Day By Day

The coronavirus disease (COVID-19) is causing havoc all around the world. The number of active cases and deaths is increasing day by day. The novel coronavirus (CoV) is the causative agent of this disease. For the time being, there is no specific antiviral agent for the cure of COVID-19. A variety of drugs are being repurposed to counteract this disease. Scientists all over the world are striving to get some ideal molecules against this pandemic. Some hybrid molecules have been designed by coupling the privileged scaffolds of known antiviral and antimalarial drugs. This review deals with the hybrid molecules that have been designed and evaluated against the known targets of CoV by in silico techniques.

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Antiviral potential of phytoligands against chymotrypsin-like protease of COVID‐19 virus using molecular docking studies: An optimistic approach

10.21203/rs.3.rs-23956/v1 ◽

2020 ◽

Author(s):

Ratish Chandra Mishra ◽

Rosy Kumari ◽

Shivani Yadav ◽

Jaya Parkash Yadav

Keyword(s):

Molecular Docking ◽

Binding Energy ◽

Drug Repositioning ◽

Docking Studies ◽

The Novel ◽

Lead Compounds ◽

Recent Outbreak ◽

Novel Coronavirus ◽

The City ◽

Ucsf Chimera

Abstract A recent outbreak of the novel coronavirus, COVID‐19, in the city of Wuhan, Hubei province, China and its ensuing worldwide spread have resulted in lakhs of infections and thousands of deaths. As of now, there are no registered therapies for treating the contagious COVID‐19 infections, henceforth drug repositioning may provide a fast way out. In the present study, a total of thirty-five compounds including commonly used anti-viral drugs were screened against chymotrypsin-like protease (3CLpro) using SwissDock. Interaction between amino acid of targeted protein and ligands was visualized by UCSF Chimera. Docking studies revealed that the phytochemicals such as cordifolin, anisofolin A, apigenin 7-glucoside, luteolin, laballenic acid, quercetin, luteolin-4-glucoside exhibited significant binding energy with the enzyme viz. - 8.77, -8.72, -8.36, -8.35, -8.13, -8.04 and -7.87 Kcal/Mol respectively. Therefore, new lead compounds can be used for drug development against SARS‐CoV‐2 infections.

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In Silico Identification and Docking-Based Drug Repurposing Against the Main Protease of SARS-CoV-2, Causative Agent of COVID-19

10.26434/chemrxiv.12049590.v1 ◽

2020 ◽

Cited By ~ 3

Author(s):

Yogesh Kumar ◽

Harvijay Singh

Keyword(s):

Virtual Screening ◽

Active Site ◽

Viral Infections ◽

Drug Repurposing ◽

Docking Study ◽

Docking Studies ◽

Main Protease ◽

Novel Coronavirus ◽

Approved Drugs

<div>The rapidly enlarging COVID-19 pandemic caused by novel SARS-coronavirus 2 is a global</div><div>public health emergency of unprecedented level. Therefore the need of a drug or vaccine that</div><div>counter SARS-CoV-2 is an utmost requirement at this time. Upon infection the ssRNA genome</div><div>of SARS-CoV-2 is translated into large polyprotein which further processed into different</div><div>nonstructural proteins to form viral replication complex by virtue of virus specific proteases:</div><div>main protease (3-CL protease) and papain protease. This indispensable function of main protease</div><div>in virus replication makes this enzyme a promising target for the development of inhibitors and</div><div>potential treatment therapy for novel coronavirus infection. The recently concluded α-ketoamide</div><div>ligand bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al.</div><div>has revealed the potential inhibitor binding mechanism and the determinants responsible for</div><div>involved molecular interactions. Here, we have carried out a virtual screening and molecular</div><div>docking study of FDA approved drugs primarily targeted for other viral infections, to investigate</div><div>their binding affinity in Mpro active site. Virtual screening has identified a number of antiviral</div><div>drugs, top ten of which on the basis of their bending energy score are further examined through </div><div>molecular docking with Mpro. Docking studies revealed that drug Lopinavir-Ritonavir, Tipranavir</div><div>and Raltegravir among others binds in the active site of the protease with similar or higher</div><div>affinity than the crystal bound inhibitor α-ketoamide. However, the in-vitro efficacies of the drug</div><div>molecules tested in this study, further needs to be corroborated by carrying out biochemical and</div><div>structural investigation. Moreover, this study advances the potential use of existing drugs to be</div><div>investigated and used to contain the rapidly expanding SARS-CoV-2 infection.</div>

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Are we there yet? Analyzing scientific research related to COVID-19 drug repurposing

10.21203/rs.3.rs-80893/v1 ◽

2020 ◽

Author(s):

Namu Park ◽

Hyeyoung Ryu ◽

Ying Ding ◽

Qi Yu ◽

Yi Bu ◽

...

Keyword(s):

Scientific Research ◽

Drug Repurposing ◽

Drug Candidate ◽

The Novel ◽

Inverse Document Frequency ◽

Term Frequency ◽

Drug Candidates ◽

Document Frequency ◽

Explicit Consent ◽

Novel Coronavirus

Abstract Drug repurposing may be a pivotal means of fulfilling urgent needs for treatment of the novel coronavirus disease 2019 (COVID-19), but current studies on drug repurposing for COVID-19 seem to show a lack of consensus in their drug candidate focus. Using bibliometric methods in a non-expert perspective, in a review of 34 published articles on the COVID-19 and drug-repurposing, we investigated obvious and less obvious points of consensus on drug candidates. To establish these two types of consensus, we first implemented document clustering. Within a set of five clustered papers, we established an obvious consensus, relying solely on the occurrence of entities by using term frequency and inverse document frequency and a comparison of mentioned drugs, finding that remdesivir and chloroquine were discussed with a certain degree of agreement. For the less obvious consensus, we created a drug entity co-occurrence network to establish low-high centrality combinations to probe the crucial drugs found in article clustering that are not plainly apparent through the mere counting of the occurrence of drug entities occurrences. Lopinavir emerged as having possibly potent effects in spite of underuse, while the mainstream of studies focus more on drugs such as chloroquine that enjoy explicit consent. Using an entitymetrics perspective, we expect that our research will support investigations of drug repurposing, expediting the process of establishing treatment for COVID-19.

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Application of In-Silico Reverse Vaccinology for Designing Multi-Epitope Vaccine Against Coronavirus

10.26434/chemrxiv.12345653 ◽

2020 ◽

Author(s):

Kumar Sharp ◽

Dr. Shubhangi Dange

Keyword(s):

Immune Response ◽

In Silico ◽

Reverse Vaccinology ◽

Economic Losses ◽

The Novel ◽

Toll Like Receptor ◽

Ramachandran Plot ◽

Cell Mediated Immune Response ◽

Specific Medication ◽

Novel Coronavirus

In absence of any specific medication or vaccine till now, experimentation has reached new heights. With lockdown imposed in almost every country and huge economic losses the search for a suitable vaccine has still been unsuccessful. In this study we have approached through in-silico method or reverse vaccinology taking advantage of the genome sequence of the novel coronavirus. We created a multi-epitope model vaccine which can elicit both humoral as well as cell-mediated immune response. It is also docked with toll-like receptor 8 TLR-8. The sequence obtained is antigenic, non-allergenic and 86.3% residues are in favourable region of Ramachandran plot. This sequence might have good hope of emerging as the vaccine of the current pandemic if studied more in depth.

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