Determination of binding potential of HCV protease inhibitors against SARS-CoV-2 Papain-like protease with computational docking

2021 ◽  
Vol 18 ◽  
Author(s):  
Zihni Onur Çalışkaner
Keyword(s):  
Protease Inhibitors ◽  
Drug Repurposing ◽  
Docking Study ◽  
Binding Energies ◽  
Binding Potential ◽  
Computational Docking ◽  
In Silico Docking ◽  
Hcv Protease ◽  
Novel Coronavirus ◽  
Inhibitory Molecules

Background: SARS-CoV-2, a novel coronavirus that causes a pandemic respiratory disease, has recently emerged from China. Since it’s a life-threatening virus, investigation of curative medications along with protective vaccines still maintains its importance. Drug repurposing is a reasonable and immediate approach to combat SARS-CoV-2 infection by identifying inhibitory molecules from marketed drugs. PL protease (PLpro.) is one of the essential enzymes for the progression of SARS-CoV-2 replication and life cycle. Objective: We aimed to investigate the potential of 4 HCV protease inhibitors as probable repurposing drugs in Covid-19 treatment. Methods: In order to understand the possible binding affinity of HCV protease inhibitors, Boceprevir, Grazoprevir, Simeprevir, and Telaprevir, against to PLpro, we performed docking analysis in silico. Docking study was accomplished using AutoDock 4.2 software. Potential druggable pockets on PLpro were predicted by DoGSiteScorer tool in order to explore any overlapping with binding regions and these pockets. Results: This analysis demonstrated Boceprevir, Grazoprevir, Simeprevir and Telaprevir interacted by PLpro with binding energies (kcal/mol) of -4.97, -4.24, -6.98, -1.08, respectively. Asn109, one of the interacted residues with both Boceprevir and Simeprevir, is a neighbouring residue to catalytic Cys111. Additionally, Telaprevir notably interacted with catalytic His272 in the active site. Conclusion: Present study explains the binding efficiency and repurposing potential of certain HCV protease inhibitors against to SARS-CoV-2 PLpro enzyme. Docking sites and potential druggability of ligands were also crosschecked by the estimation of druggable pockets. Thereby our results can promote promising preliminary data for research on drug development in the fight of Covid-19.

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

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.

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

2020 ◽  
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>

scholarly journals Anti Hepatitis C virus drugs show potential drug repositioning for SARS CoV-2 main protease: an in silico study

2020 ◽  
Author(s):  
Arthikasree Anandamurthy ◽  
Roslin Elsa Varughese ◽  
Saranya Sivaraj ◽  
Gayathri Dasararaju
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
In Silico ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Docking Study ◽  
Binding Potential ◽  
Molecular Docking Study ◽  
Main Protease ◽  
Potent Drug

Abstract Developing effective and safe vaccines/drugs against SARS CoV-2 may take some time. The urgency of the outbreak has led to the usage of broad spectrum of existing anti-viral drugs, across the globe. Among the existing anti-viral drugs, there is still a challenge in identifying the potent drug or the combination of the drugs for the better treatment and faster recovery of the patients. In silico molecular docking study aids in the process of drug repurposing and we aimed to identify the binding potential of some of the existing anti-viral drugs and their interactions at the active site of SARS CoV-2 main protease. Results from our study revealed that the drugs Simeprevir, Elbasvir, Paritaprevir, Beclabuvir, Dasabuvir, Teleprevir, Velpatasvir, Ombitasvir, Ledipasvir, Boceprevir, Asunapervir, Declatasvir, Sofusbuvir which are used in the treatment of Hepatitis C virus infection may act as potent inhibitors for SARS CoV-2 main protease.

scholarly journals A Study of 3CLpros as Promising Targets against SARS-CoV and SARS-CoV-2

2021 ◽  
Vol 9 (4) ◽  
pp. 756
Author(s):  
Seri Jo ◽  
Suwon Kim ◽  
Jahyun Yoo ◽  
Mi-Sun Kim ◽  
Dong Hae Shin
Keyword(s):  
Protein Function ◽  
Antiviral Agents ◽  
Drug Repurposing ◽  
Docking Study ◽  
Inhibitory Effect ◽  
Active Site Residues ◽  
In Silico Docking ◽  
Inhibitory Function ◽  
Phosphodiesterase Type 5 Inhibitor ◽  
Phosphodiesterase Type

The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), results in serious chaos all over the world. In addition to the available vaccines, the development of treatments to cure COVID-19 should be done quickly. One of the fastest strategies is to use a drug-repurposing approach. To provide COVID-19 patients with useful information about medicines currently being used in clinical trials, twenty-four compounds, including antiviral agents, were selected and assayed. These compounds were applied to verify the inhibitory activity for the protein function of 3CLpros (main proteases) of SARS-CoV and SARS-CoV-2. Among them, viral reverse-transcriptase inhibitors abacavir and tenofovir revealed a good inhibitory effect on both 3CLpros. Intriguingly, sildenafil, a cGMP-specific phosphodiesterase type 5 inhibitor also showed significant inhibitory function against them. The in silico docking study suggests that the active-site residues located in the S1 and S2 sites play key roles in the interactions with the inhibitors. The result indicates that 3CLpros are promising targets to cope with SAR-CoV-2 and its variants. The information can be helpful to design treatments to cure patients with COVID-19.

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

2020 ◽  
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>

scholarly journals Computational prediction of Carica papaya extracts as potential drug agents against RNA polymerase and Spike proteins of SARS-nCoV2 

2020 ◽  
Author(s):  
Rashid Saif ◽  
Muhammad Osama Zafar ◽  
Muhammad Hassan Raza ◽  
Talha Rehman ◽  
Saeeda Zia ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Protein Interactions ◽  
Carica Papaya ◽  
Computational Prediction ◽  
Docking Study ◽  
Mass Scale ◽  
Binding Energies ◽  
Physiochemical Parameters ◽  
Novel Coronavirus ◽  
Major Drug

Abstract The emergence of COVID-19 outbreak caused by SARS-nCoV2 (Severe Acute Respiratory Syndrome novel coronavirus 2), lead to the mass-scale mortalities around the world within a short span of time. The hour of the need is to develop the strategies and designing drugs/vaccines to control the spread of this contagion. In this paper, we predict the promising drug agents from the Carica papaya compounds by docking them with two major drug target proteins of SARS-nCoV2, spike (7BZ5) and RNA-dependent RNA polymerase (7BW4). For this purpose, we used Molecular Operating Environment Software (MOE) for ligand-protein interactions and docking scores. Furthermore, we used PubChem, PDB and SwissADME web portals to retrieve ligands structures, proteins structures and to check Lipinski’s physiochemical parameters respectively. Cumulatively, this docking study has shown significant binding energies that (-4.2034 to -8.9013 Kcal/mol) indicates their potential against COVID-19 treatment. This study needs further evaluation on experimental basis.

COMPARATIVE DOCKING STUDY OF ‘DUKUNG ANAK’ PHYTONUTRIENT COMPOUNDS WITH ANTI-CHOLESTEROL PROPERTIES

2015 ◽  
Vol 77 (31) ◽  
Author(s):  
Lina Rozano ◽  
Muhammad Redha Abdullah Zawawi ◽  
Muhammad Aizuddin Ahmad ◽  
Indu Bala Jaganath
Keyword(s):  
Cardiovascular Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Docking Study ◽  
Docking Studies ◽  
Binding Energies ◽  
The Body ◽  
Molecular Docking Study ◽  
In Silico Docking ◽  
Coa Reductase

Inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) has been a useful strategy in the treatment of cardiovascular disease. Molecular docking study was carried out to study the effects of geraniin and its metabolites on 3-hydroxy-3-methyl-glutaryl-CoA reductase. 3-hydroxy-3-methyl-glutaryl-CoA reductase acts on melavonate pathway for cholesterol production in the liver but high level of cholesterol in the body may lead to cardiovascular disease where low density lipoprotein accumulates and forms atherosclerotic plaque. In clinical treatment, drug statin is used to block 3-hydroxy-3-methyl-glutaryl-CoA reductase function to reduce the risk of cardiovascular disease but there are unwanted effects where drug statin may cause muscle pain and liver damage. Naturally obtained phytonutrient compounds, geraniin and urolithin groups from dukung anak or scientifically known as Phyllanthus sp. were evaluated for 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitory activity using in silico docking studies. Most of these compounds were found to be potent inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase in comparison with known drugs of cardiovascular disease. The binding energies of urolithin A, urolithin B-glucoronide and urolithin D-glucoronide were compared with that of geraniin and it was found that these phytonutrient compounds may have more potent inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase comparable with the current drug for cardiovascular disease.

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

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.

scholarly journals Hepatitis C Virus NS3-NS4A Protease Inhibitors from the Endophytic Penicillium chrysogenum Isolated from the Red Alga Liagora viscida

2013 ◽  
Vol 68 (9-10) ◽  
pp. 355-366 ◽  
Author(s):  
Usama W. Hawas ◽  
Ali M. El-Halawany ◽  
Eman F. Ahmede
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Liquid Medium ◽  
Penicillium Chrysogenum ◽  
Docking Study ◽  
Biological Properties ◽  
Red Alga ◽  
Anticancer Activities ◽  
Computational Docking ◽  
Hcv Protease

Hepatitis C virus (HCV) NS3-NS4A protease is an attractive target for anti-HCV agents because of its important role in replication. In this work, we demonstrated that the ethyl acetate extract of the endophytic fungus Penicillium chrysogenum exhibited a potent activity against HCV NS3-NS4A protease with an IC50 value of 20 μg/ml. The fungus was isolated from the red alga Liagora viscida and identifi ed by its morphology and 18S rDNA. Largescale fermentation of the fungus in Czapek's peptone liquid medium followed by chromatographic purifi cation of the active extract from the liquid medium allowed the isolation of twelve known metabolites. The biological properties of the isolated compounds were explored for anti-HCV protease as well as antimicrobial and anticancer activities. A computational docking study of the active isolated compounds against HCV protease was used to formulate a hypothetical mechanism for the inhibitory activity of the active compounds on the tested enzymes

scholarly journals Potential Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 606 Million Compounds

2020 ◽  
Vol 21 (10) ◽  
pp. 3626 ◽  
Author(s):  
André Fischer ◽  
Manuel Sellner ◽  
Santhosh Neranjan ◽  
Martin Smieško ◽  
Markus A. Lill
Keyword(s):  
Viral Infections ◽  
Chemical Space ◽  
Drug Repurposing ◽  
Close Relation ◽  
Binding Energies ◽  
Proteolytic Processing ◽  
Binding Modes ◽  
Novel Coronavirus ◽  
Dynamics Simulations ◽  
Potential Inhibitors

The rapid outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China followed by its spread around the world poses a serious global concern for public health. To this date, no specific drugs or vaccines are available to treat SARS-CoV-2 despite its close relation to the SARS-CoV virus that caused a similar epidemic in 2003. Thus, there remains an urgent need for the identification and development of specific antiviral therapeutics against SARS-CoV-2. To conquer viral infections, the inhibition of proteases essential for proteolytic processing of viral polyproteins is a conventional therapeutic strategy. In order to find novel inhibitors, we computationally screened a compound library of over 606 million compounds for binding at the recently solved crystal structure of the main protease (Mpro) of SARS-CoV-2. A screening of such a vast chemical space for SARS-CoV-2 Mpro inhibitors has not been reported before. After shape screening, two docking protocols were applied followed by the determination of molecular descriptors relevant for pharmacokinetics to narrow down the number of initial hits. Next, molecular dynamics simulations were conducted to validate the stability of docked binding modes and comprehensively quantify ligand binding energies. After evaluation of potential off-target binding, we report a list of 12 purchasable compounds, with binding affinity to the target protease that is predicted to be more favorable than that of the cocrystallized peptidomimetic compound. In order to quickly advise ongoing therapeutic intervention for patients, we evaluated approved antiviral drugs and other protease inhibitors to provide a list of nine compounds for drug repurposing. Furthermore, we identified the natural compounds (−)-taxifolin and rhamnetin as potential inhibitors of Mpro. Rhamnetin is already commercially available in pharmacies.

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