Predicted antiviral drugs Darunavir, Amprenavir, Rimantadine and Saquinavir can potentially bind to neutralize SARS-CoV-2 conserved proteins

Abstract Background: Novel Coronavirus disease 2019 or COVID-19 has become a threat to human society due to fast spreading and increasing mortality. It uses vertebrate hosts and presently deploying humans. Life cycle and pathogenicity of COVID-19 have already been deciphered and possible drug target tests are on the way.Results: The present study was aimed to analyze conserved Endoribonuclease, protease and replicase proteins of the virus as targets to all known drugs. A bioinformatics based web server Drug ReposeER predicted several drug binding motifs in these analyzed proteins. Results revealed that anti-viral Darunavir, Indinavir and Rimantadine were the most potent to have 3D-drug binding motifs on COVID-19 proteins.Conclusions: Repurposing of the antiviral drugs Darunavir, Indinavir and Rimantadine to treat COVID-19 infected persons could be useful that can potentially prevent thousands of human mortality.

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Drug Repurposing Studies Targeting SARS-nCoV2: An Ensemble Docking Approach on Drug Target 3C-like Protease (3CLpro)

10.26434/chemrxiv.12228831 ◽

2020 ◽

Author(s):

Shruti Koulgi ◽

Vinod Jani ◽

Mallikarjunachari Uppuladinne ◽

Uddhavesh Sonavane ◽

Asheet Kumar Nath ◽

...

Keyword(s):

Drug Repurposing ◽

Drug Binding ◽

Ensemble Docking ◽

Drug Molecules ◽

Drug Binding Site ◽

Main Protease ◽

Docking Approach ◽

Novel Coronavirus ◽

Markov State Modeling ◽

Viral Polyprotein

The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS-nCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of 3CLpro (main protease) of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration (FDA) approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for main protease helped in exploring the conformational variation in the drug binding site of the main protease leading to efficient binding of more relevant drug molecules. The drugs obtained as best hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove to be useful to treat symptoms exhibited in COVID-19. This in-silico ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.

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Phenylbenzopyrone of flavonoids as a potential scaffold to prevent SARS-CoV-2 replication by inhibiting its MPRO main protease

Current Pharmaceutical Biotechnology ◽

10.2174/1389201022666210127113027 ◽

2021 ◽

Vol 22 ◽

Author(s):

Angamba Meetei Potshangbam ◽

Potshangbam Nongdam ◽

A. Kiran Kumar ◽

R.S. Rathore

Keyword(s):

Antiviral Drugs ◽

Dynamics Simulation ◽

Compound Libraries ◽

Main Protease ◽

Enterovirus A71 ◽

Short Period ◽

Novel Coronavirus ◽

Effective Drugs ◽

Drug Leads ◽

Better Than

Background: In December 2019, an outbreak of a pneumonia-like illness, Coronavirusdisease-2019 (COVID-19), originating from Wuhan, China was linked to novel coronavirus, now termed SARS-CoV-2. Unfortunately, no effective drugs or vaccines have been reported yet. The main protease (MPRO) remains the most validated pharmacological target for the design and discovery of inhibitors. Objective: The purpose of the study was to find a prospective natural scaffold as an inhibitor for MPRO main protease in SARS-CoV-2 and compare it with repurposed antiviral drugs lopinavir and nelflinavir. Methods: Natural compound libraries were screened for potential scaffold against MPRO main protease. Molecular dynamics simulation, MM-GBSA and principle component analyses of enzyme-ligand complexes were carried out with the top-ranking hits and compared with the repurposed antiviral drugs lopinavir and nelfinavir. Results: The structure-based virtual screening indicated phenylbenzopyrone of flavonoids as one of the top-ranking scaffolds that have the potential to inhibit the main protease with O-glycosidic form performing better than corresponding aglyconic form. Simulation studies indicated that glycosidic form of flavonoid as more suitable inhibitor with compounds rutin, procyanidin B6, baicalin and galloylquercetin, demonstrating high affinity and stability, and rutin emerging as one of the best candidate compound. Interestingly, rutin was reported to have inhibitory activity against similar protease (3Cprotease of enterovirus A71) as well as implicated in lung fibrosis. Conclusion: The present study displaying flavonoids, possessing a potential scaffold for inhibiting main protease activity for all betacoronavirus is an attempt to provide new and safe drug leads within a reasonably short period.

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In silico Repositioning for Dual Inhibitor Discovery of SARS-CoV-2 (COVID-19) 3C-like Protease and Papain-like Peptidase

10.20944/preprints202004.0084.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Kowsar Bagherzadeh ◽

Kourosh Daneshvarnejad ◽

Mohammad Abbasinazari ◽

homa azizian

Keyword(s):

Active Sites ◽

Reproduction Number ◽

Antiviral Agents ◽

Binding Energies ◽

Dual Inhibitor ◽

Main Protease ◽

Inhibitor Discovery ◽

Dual Inhibitors ◽

Dual Inhibition ◽

Novel Coronavirus

Aims: In late December 2019, early reports predicted the onset of a potential Coronavirus outbreak in china, given the estimate of a reproduction number for the 2019 Novel Coronavirus (COVID-19). Because of high ability of transmission and widespread prevalence, the mortality of COVID-19 infection is growing fast worldwide. Absent of an anti-COVID-19 has put scientists on the urge to repurpose already approved therapeutics or to find new active compounds against coronavirus. Here in this study, a set of computational approaches were performed in order to repurpose antivirals for dual inhibition of the frontier proteases involved in virus replication, papain-like protease (PLpro; corresponding to nsp3) and a main protease (Mpro), 3C‑like protease (3CLpro; corresponding to nsp5). Materials and Methods: In this regard, a rational virtual screening procedure including exhaustive docking techniques was performed for a database of 160 antiviral agents over 3CLpro and PLpro active sites of SARS-CoV-2. The compounds binding energies and interaction modes over 3CLpro and PLpro active sites were analyzed and ranked with the aid of free Gibbs binding energy. The most potent compounds, based on our filtering process, are then proposed as dual inhibitors of SARSC-CoV-2 proteases. Key findings: Accordingly, seven antiviral agents including two FDA approved (Nelfinavir, Valaganciclovir) and five investigational compounds (Merimepodib, Inarigivir, Remdesivir, Taribavirine and TAS106-106) are proposed as potential dual inhibitors of the enzymes necessary for RNA replication in which Remdesivir as well as Inagrivir have the highest binding affinity for both of the active sites. Significance: The mentioned drug proposed to inhibit both PLpro and 3CLpro enzymes with the aim of finding dual inhibitors of SARSC-CoV-2 proteases.

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Computational Analysis of Dynamic Allostery and Control in the SARS-CoV-2 Main Protease

10.1101/2020.05.21.105965 ◽

2020 ◽

Cited By ~ 4

Author(s):

Igors Dubanevics ◽

Tom C.B. McLeish

Keyword(s):

Active Site ◽

Active Sites ◽

Competitive Inhibition ◽

Vital Role ◽

Dynamical Structure ◽

Elastic Network Model ◽

Correlated Motions ◽

Main Protease ◽

Candidate Regions ◽

Novel Coronavirus

AbstractThe COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has generated a global pandemic and no vaccine or antiviral drugs exist at the moment of writing. An attractive coronavirus drug target is the main protease (Mpro, also known as 3CLpro) because of its vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which bind and block the active site of the main protease, but little has been done to address potential non-competitive inhibition which targets regions beyond the active site, partly because the fundamental biophysics of such allosteric control is still poorly understood. In this work, we construct an Elastic Network Model (ENM) of the SARS-CoV-2 Mpro homodimer protein and analyse the dynamics and thermodynamics of the main protease’s ENM. We found a rich and heterogeneous dynamical structure in the correlated motions, including allosterically correlated motions between the homodimeric protease’s active sites. Exhaustive 1-point and 2-point mutation scans of the ENM and their effect on fluctuation free energies confirm previously experimentally identified bioactive residues, but also suggest several new candidate regions that are distant from the active site for control of the protease function. Our results suggest new dynamically-driven control regions as possible candidates for non-competitive inhibiting binding sites in the protease, which may assist the development of current fragmentbased binding screens. The results also provide new insight into the protein physics of fluctuation allostery and its underpinning dynamical structure.

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Insilico Identification of Potential Antivirals and Molecular Dynamics Against SARS-CoV2 Main Protease and RBD of Spike Protein

10.26434/chemrxiv.13181117.v1 ◽

2020 ◽

Author(s):

Vijayakumar Rajendran ◽

Saravanan Kandasamy ◽

Ankita Gupta ◽

Jagannathan Selvaraj ◽

Kukkaler Channappa Shivanandappa

Keyword(s):

Drug Target ◽

Antiviral Agent ◽

Antiviral Drugs ◽

World Health ◽

Definitive Treatment ◽

Potential Drug ◽

Dynamic Simulations ◽

Pubchem Database ◽

Novel Coronavirus ◽

Health Organization

A coronavirus identified as 2019 novel coronavirus (COVID-19) is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan has been declared as a pandemic by the World Health Organization. The virus is predominantly spread from person-to-person mainly through airborne, fomite, contact, and droplet from the infected patients. Also, the lack of definitive treatment is another concern that needs consideration. The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to angiotensin-converting enzyme 2 (ACE2). Mpro is a key coronavirus enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus. Considering the importance of these two proteins in the viral infection, these were preferred as a potential drug target against Covid19. In this study, we screened potential antiviral drugs from the Pubchem database and natural antiviral agent quercetin for induced fit docking against these two key proteins. The identified top hit was further evaluated through molecular dynamic simulations. Our results suggest that the antiviral drugs Indinavir and Famciclovir could be a potential drug against Covid19.

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Structure based drug discovery by virtual screening of 3699 compounds against the crystal structures of six key SARS-CoV-2 proteins

10.21203/rs.3.rs-28113/v1 ◽

2020 ◽

Cited By ~ 2

Author(s):

Shoab Saadat ◽

Salman Mansoor ◽

Naveen Naqvi ◽

Ammad Fahim ◽

Zaira Rehman ◽

...

Keyword(s):

Molecular Docking ◽

Crystal Structures ◽

Active Sites ◽

Data Bank ◽

Spike Protein ◽

Binding Affinities ◽

Methyl Transferase ◽

Main Protease ◽

Major Outbreak ◽

Novel Coronavirus

Abstract BackgroundThe current Novel Coronavirus (SARS-CoV-2) pandemic is the third major outbreak of the 21st century which emerged in December 2019 from Wuhan, China. At present there are no known treatments or vaccines to cure or prevent the illness.ObjectiveThe objective of this study was to explore a list of potential drugs (herbal and antivirals) for their role in inhibiting activity and or replication of SARS-CoV-2 by using molecular docking onto the crystal structures of key viral proteins.MethodologyIn this study, we used molecular docking to estimate the binding affinities of 3699 drugs on the potential active sites of the 6 main SARS-CoV-2 proteins (Papain like protease, Main protease, ADP Ribose phosphatase, Spike protein, NSP-9 and NSP-10 to 16 complex). While other studies have mostly been performed on the homology models, we obtained the most recently submitted crystal structures of all 6 proteins from the protein data bank for this analysis.ResultsOur results showed the top ligands as Theasinensin A, Epigallocatechin, Theaflavin, Theasinensin A, Epigallocatechin and Favipiravir showing the highest binding affinities against papain-like protease, ADP ribose phosphatase, main protease, spike protein, RNA replicase (NSP-9) and methyl-transferase (NSP-16) respectively.ConclusionWe show that the compounds from our list with the greatest inhibitory potential against SARS-CoV-2 activity or replication include Theasinensin A, Epigallocatechin-3-gallate, Theaflavin, Favipiravir, Curucumin, Quercetin, Mitoxantrone, Amentoflavone, Colistin, Cimicifugic acid, Theaflavin, Silymarin and Chebulagic. We recommend further wet-lab and clinical testing of these compounds to further explore their role against SARS-CoV-2.

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Drug Repurposing Studies Targeting SARS-nCoV2: An Ensemble Docking Approach on Drug Target 3C-like Protease (3CLpro)

10.26434/chemrxiv.12228831.v1 ◽

2020 ◽

Author(s):

Shruti Koulgi ◽

Vinod Jani ◽

Mallikarjunachari Uppuladinne ◽

Uddhavesh Sonavane ◽

Asheet Kumar Nath ◽

...

Keyword(s):

Drug Repurposing ◽

Drug Binding ◽

Ensemble Docking ◽

Drug Molecules ◽

Drug Binding Site ◽

Main Protease ◽

Docking Approach ◽

Novel Coronavirus ◽

Markov State Modeling ◽

Viral Polyprotein

The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS-nCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of 3CLpro (main protease) of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration (FDA) approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for main protease helped in exploring the conformational variation in the drug binding site of the main protease leading to efficient binding of more relevant drug molecules. The drugs obtained as best hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove to be useful to treat symptoms exhibited in COVID-19. This in-silico ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.

Download Full-text

Insilico Identification of Potential Antivirals and Molecular Dynamics Against SARS-CoV2 Main Protease and RBD of Spike Protein

10.26434/chemrxiv.13181117 ◽

2020 ◽

Author(s):

Vijayakumar Rajendran ◽

Saravanan Kandasamy ◽

Ankita Gupta ◽

Jagannathan Selvaraj ◽

Kukkaler Channappa Shivanandappa

Keyword(s):

Drug Target ◽

Antiviral Agent ◽

Antiviral Drugs ◽

World Health ◽

Definitive Treatment ◽

Potential Drug ◽

Dynamic Simulations ◽

Pubchem Database ◽

Novel Coronavirus ◽

Health Organization

A coronavirus identified as 2019 novel coronavirus (COVID-19) is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan has been declared as a pandemic by the World Health Organization. The virus is predominantly spread from person-to-person mainly through airborne, fomite, contact, and droplet from the infected patients. Also, the lack of definitive treatment is another concern that needs consideration. The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to angiotensin-converting enzyme 2 (ACE2). Mpro is a key coronavirus enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus. Considering the importance of these two proteins in the viral infection, these were preferred as a potential drug target against Covid19. In this study, we screened potential antiviral drugs from the Pubchem database and natural antiviral agent quercetin for induced fit docking against these two key proteins. The identified top hit was further evaluated through molecular dynamic simulations. Our results suggest that the antiviral drugs Indinavir and Famciclovir could be a potential drug against Covid19.

Download Full-text