scholarly journals Targeting Novel Coronavirus 2019: A Systematic Drug Repurposing Approach to Identify Promising Inhibitors Against 3C-like Proteinase and 2'-O-Ribose Methyltransferase

2020 ◽  
Author(s):  
Rameez Jabeer Khan ◽  
Rajat Jha ◽  
Gizachew Muluneh Amera ◽  
Monika Jain ◽  
Ekampreet Singh ◽  
...  
Keyword(s):  
Drug Target ◽  
Structural Parameters ◽  
Physiological State ◽  
Drug Repurposing ◽  
Antiviral Drugs ◽  
Host Immune System ◽  
Infected People ◽  
Drug Molecules ◽  
Therapeutic Drugs ◽  
Novel Coronavirus

<div>The recent pandemic associated with 2019-nCoV, a virus of the Coronaviridae family, has resulted in an unprecedented number of infected people. The highly contagious nature of this virus makes it imperative for us to identify potential inhibitors from pre-existing antiviral drugs. Two druggable targets, namely 3C-like proteinase (3CLpro) and 2'-O-ribose methyltransferase (2'-O-MTase) were selected in this study due to their indispensable nature in the viral life cycle. 3CLpro is a cysteine protease responsible for the proteolysis of replicase polyproteins resulting in the formation of various functional proteins, whereas 2'-O-MTase methylates the ribose 2'-O position of the first and second nucleotide of viral mRNA, which sequesters it from the host immune system. The selected drug target proteins were screened against an in-house library of 123 antiviral drugs. Two promising drug molecules were identified for each protein based on their estimated free energy of binding (ΔG), the orientation of drug molecules in the active site and the interacting residues. The selected protein-drug complexes were then subjected to MD simulation, which consists of various structural parameters to equivalently reflect their physiological state. From the virtual screening results, two drug molecules were selected for each drug target protein [Paritaprevir (ΔG= -9.8 kcal/mol) & Raltegravir (ΔG= -7.8 kcal/mol) for 3CLpro and Dolutegravir (ΔG= -9.4 kcal/mol) and Bictegravir (ΔG= -8.4 kcal/mol) for 2'-OMTase]. After the extensive computational analysis, we proposed that Raltegravir, Paritaprevir, Bictegravir and Dolutegravir are excellent lead candidates for these crucial proteins and they could become potential therapeutic drugs against 2019-nCoV.</div>

scholarly journals Targeting Novel Coronavirus 2019: A Systematic Drug Repurposing Approach to Identify Promising Inhibitors Against 3C-like Proteinase and 2'-O-Ribose Methyltransferase

2020 ◽  
Author(s):  
Rameez Jabeer Khan ◽  
Rajat Jha ◽  
Gizachew Muluneh Amera ◽  
Monika Jain ◽  
Ekampreet Singh ◽  
...  
Keyword(s):  
Drug Target ◽  
Structural Parameters ◽  
Physiological State ◽  
Drug Repurposing ◽  
Antiviral Drugs ◽  
Host Immune System ◽  
Infected People ◽  
Drug Molecules ◽  
Therapeutic Drugs ◽  
Novel Coronavirus

<div>The recent pandemic associated with 2019-nCoV, a virus of the Coronaviridae family, has resulted in an unprecedented number of infected people. The highly contagious nature of this virus makes it imperative for us to identify potential inhibitors from pre-existing antiviral drugs. Two druggable targets, namely 3C-like proteinase (3CLpro) and 2'-O-ribose methyltransferase (2'-O-MTase) were selected in this study due to their indispensable nature in the viral life cycle. 3CLpro is a cysteine protease responsible for the proteolysis of replicase polyproteins resulting in the formation of various functional proteins, whereas 2'-O-MTase methylates the ribose 2'-O position of the first and second nucleotide of viral mRNA, which sequesters it from the host immune system. The selected drug target proteins were screened against an in-house library of 123 antiviral drugs. Two promising drug molecules were identified for each protein based on their estimated free energy of binding (ΔG), the orientation of drug molecules in the active site and the interacting residues. The selected protein-drug complexes were then subjected to MD simulation, which consists of various structural parameters to equivalently reflect their physiological state. From the virtual screening results, two drug molecules were selected for each drug target protein [Paritaprevir (ΔG= -9.8 kcal/mol) & Raltegravir (ΔG= -7.8 kcal/mol) for 3CLpro and Dolutegravir (ΔG= -9.4 kcal/mol) and Bictegravir (ΔG= -8.4 kcal/mol) for 2'-OMTase]. After the extensive computational analysis, we proposed that Raltegravir, Paritaprevir, Bictegravir and Dolutegravir are excellent lead candidates for these crucial proteins and they could become potential therapeutic drugs against 2019-nCoV.</div>

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

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

<p>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 3CL<sup>pro</sup> (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 <i>in-silico</i> ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.</p>

scholarly journals Indicator Regularized Non-Negative Matrix Factorization Method-Based Drug Repurposing for COVID-19

2021 ◽  
Vol 11 ◽  
Author(s):  
Xianfang Tang ◽  
Lijun Cai ◽  
Yajie Meng ◽  
JunLin Xu ◽  
Changcheng Lu ◽  
...  
Keyword(s):  
Matrix Factorization ◽  
De Novo ◽  
Characteristic Curve ◽  
Drug Repurposing ◽  
Factorization Method ◽  
Therapeutic Drugs ◽  
Indicator Matrix ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Non Negative Matrix Factorization

A novel coronavirus, named COVID-19, has become one of the most prevalent and severe infectious diseases in human history. Currently, there are only very few vaccines and therapeutic drugs against COVID-19, and their efficacies are yet to be tested. Drug repurposing aims to explore new applications of approved drugs, which can significantly reduce time and cost compared with de novo drug discovery. In this study, we built a virus-drug dataset, which included 34 viruses, 210 drugs, and 437 confirmed related virus-drug pairs from existing literature. Besides, we developed an Indicator Regularized non-negative Matrix Factorization (IRNMF) method, which introduced the indicator matrix and Karush-Kuhn-Tucker condition into the non-negative matrix factorization algorithm. According to the 5-fold cross-validation on the virus-drug dataset, the performance of IRNMF was better than other methods, and its Area Under receiver operating characteristic Curve (AUC) value was 0.8127. Additionally, we analyzed the case on COVID-19 infection, and our results suggested that the IRNMF algorithm could prioritize unknown virus-drug associations.

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

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

<p>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. <br></p>

scholarly journals Predicted antiviral drugs Darunavir, Indinavir and Rimantadine can potentially bind to neutralize COVID-19 conserved proteins

2020 ◽  
Author(s):  
Umesh Chandra Halder
Keyword(s):  
Life Cycle ◽  
Drug Target ◽  
Antiviral Drugs ◽  
Drug Binding ◽  
Human Society ◽  
Binding Motifs ◽  
Replicase Proteins ◽  
Fast Spreading ◽  
Vertebrate Hosts ◽  
Novel Coronavirus

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.

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

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

<p>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 3CL<sup>pro</sup> (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 <i>in-silico</i> ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.</p>

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

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

<p>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. <br></p>

scholarly journals Drug Repurposing for Candidate SARS-CoV-2 Papain-like protease (PLpro) Inhibitors by a combined in Silico Method

2021 ◽  
Author(s):  
Milan Sencanski ◽  
Vladimir Perovic ◽  
Jelena Milicevic ◽  
Tamara Todorovic ◽  
Radivoje Prodanovic ◽  
...  
Keyword(s):  
In Silico ◽  
Drug Target ◽  
Experimental Testing ◽  
Drug Repurposing ◽  
Innate Immune ◽  
Host Immune System ◽  
In Silico Screening ◽  
Safe Approach ◽  
Very High ◽  
Drugbank Database

The need for an effective drug against COVID-19, is, after almost 18 months since the global pandemics outburst, still very high. A very quick and safe approach to counteract COVID-19 is in silico drug repurposing. The SARS-CoV-2 PLpro promotes vi-ral replication and modulates the host immune system, resulting in inhibition of the host antiviral innate immune response, and there-fore is an attractive drug target. In this study, we used a combined in silico virtual screening candidates for SARS-CoV-2 PLpro protease inhibitors. We used the Informational spectrum method applied for Small Molecules for searching the Drugbank database and further followed by molecular docking. After in silico screening of drug space, we identified 44 drugs as potential SARS-CoV-2 PLpro inhibitors that we propose for further experimental testing.

scholarly journals Identification of SARS-CoV-2 Papain-like protease (PLpro) inhibitors using combined computational approach

2021 ◽  
Author(s):  
Milan Sencanski ◽  
Vladimir Perovic ◽  
Jelena Milicevic ◽  
Tamara Todorovic ◽  
Radivoje Prodanovic ◽  
...  
Keyword(s):  
Small Molecules ◽  
In Silico ◽  
Drug Target ◽  
Experimental Testing ◽  
Drug Repurposing ◽  
Innate Immune ◽  
Host Immune System ◽  
In Silico Screening ◽  
Safe Approach ◽  
Drugbank Database

In the current pandemic finding an effective drug to prevent or treat the infection is the highest priority. A rapid and safe approach to counteract COVID-19 is in silico drug repurposing. The SARS-CoV-2 PLpro promotes viral replication and modulates the host immune system, resulting in inhibition of the host antiviral innate immune response, and therefore is an attractive drug target. In this study, we used a combined in silico virtual screening for candidates for SARS-CoV-2 PLpro protease inhibitors. We used the Informational spectrum method applied for Small Molecules for searching the Drugbank database followed by molecular docking. After in silico screening of drug space, we identified 44 drugs as potential SARS-CoV-2 PLpro inhibitors that we propose for further experimental testing.

Sign in / Sign up

Export Citation Format

Share Document