scholarly journals Identification of Pharmacophoric Features and Novel Compounds for Inhibition of SARS-Cov-2 Main Protease

2020 ◽  
Author(s):  
Priti Jain ◽  
Rupesh Dorik ◽  
Munendra Jain
Keyword(s):  
Crystal Structure ◽  
Phylogenetic Analysis ◽  
Nucleotide Sequence ◽  
Binding Affinity ◽  
High Mortality ◽  
Sequence Similarity ◽  
Mortality And Morbidity ◽  
Future Design ◽  
Main Protease ◽  
Approved Drugs

A big race for the search for novel lead has begun due to the emergence of COVID-19 across the globe. More than 6,00,000 cases of afflicted patients worldwide has been reported till date with high mortality and morbidity. At present no approved drugs are known for COVID-19. Phylogenetic analysis present strong nucleotide sequence similarity of around 80% with SARS-CoV. Therefore, the drugs used for treating SARS-CoV and MERS are being used for SARS-CoV-2 also. Recently, the crystal structure of COVID-19 is reported and hence, we have used this tom predict the binding affinity with SARS-CoV-2-main protease and prepared a pharmacophore that may be used for future design of novel inhibitors.

scholarly journals Vitamin C inhibits SARS coronavirus-2 main protease essential for viral replication

2021 ◽  
Author(s):  
Tek Narsingh Malla ◽  
Suraj Pandey ◽  
Ishwor Poudyal ◽  
Luis Aldama ◽  
Dennis Feliz ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Vitamin C ◽  
Antiviral Treatment ◽  
Cysteine Proteases ◽  
Vitamin Supplement ◽  
Sars Coronavirus ◽  
Over The Counter ◽  
Main Protease ◽  
Approved Drugs

There is an urgent need for anti-viral agents that treat and/or prevent Covid-19 caused by SARS-Coronavirus (CoV-2) infections. The replication of the SARS CoV-2 is dependent on the activity of two cysteine proteases, a papain-like protease, PL-pro, and the 3C-like protease known as main protease Mpro or 3CLpro. The shortest and the safest path to clinical use is the repurposing of drugs with binding affinity to PLpro or 3CLpro that have an established safety profile in humans. Several studies have reported crystal structures of SARS-CoV-2 main protease in complex with FDA approved drugs such as those used in treatment of hepatitis C. Here, we report the crystal structure of 3CLpro in complex Vitamin C (L-ascorbate) bound to the protein's active site at 2.5 Angstrom resolution. We also demonstrate that L-ascorbate inhibits the 3CLpro in vitro at mmol/L concentrations. The crystal structure of the Vitamin C 3CLpro complex may aid future studies on the effect of Vitamin C not only on the coronavirus main protease but on related proteases of other infectious viruses. Since ascorbate is readily available, as an over-the-counter vitamin supplement, our results have the potential for development of a global and inexpensive antiviral treatment.

scholarly journals Molecular Docking and Fragment-Based QSAR Modeling for In Silico Screening of Approved Drugs and Candidate Compounds Against COVID-19

2020 ◽  
Vol 8 (2) ◽  
pp. 83-88
Author(s):  
Saeid Afshar ◽  
Asrin Bahmani ◽  
Massoud Saidijam
Keyword(s):  
Molecular Docking ◽  
Autodock Vina ◽  
Qsar Modeling ◽  
Health Crisis ◽  
Mortality And Morbidity ◽  
Main Protease ◽  
Docking Calculations ◽  
Approved Drugs ◽  
Top 40 ◽  
Potential Inhibitors

Background: Coronavirus disease 2019 (COVID-19) as a serious global health crisis leads to high mortality and morbidity. However, currently, there are no effective vaccines and treatments for COVID-19. Main protease (Mpro) and angiotensin-converting enzyme 2 (ACE2) are the best therapeutic targets of COVID-19. Objectives: The main purpose of this study is to investigate the most appropriate drug and candidate compound for proper interaction with Mpro and ACE2 to inhibit the activity of COVID-19. Methods: In this study, repurposing of approved drugs and screening of candidate compounds using molecular docking and fragment-based QSAR method were performed to discover the potential inhibitors of Mpro and ACE2. QSAR and docking calculations were performed based on the prediction of the inhibitory activities of 5-hydroxy indanone derivatives. Based on the results, an optimal structure was proposed to inhibit the activity of COVID-19. Results: Among 2629 DrugBank approved drugs, 118 were selected considering the LibDock score and absolute energy for possible drug-Mpro interactions. Furthermore, the top 40 drugs were selected based on screening the results for possible drug- Mpro interactions with AutoDock Vina. Conclusion: Finally, evaluation of the top 40 selected drugs for possible drug-ACE2 interactions with AutoDock Vina indicated that deslanoside (DB01078) can interact effectively with both Mpro and ACE2. However, prior to conducting clinical trials, further experimental validation is needed.

scholarly journals A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients

2020 ◽  
Author(s):  
Dharmendra Kumar Maurya
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Binding Affinity ◽  
Viral Entry ◽  
Virus Disease ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Host Immune System ◽  
Main Protease ◽  
Approved Drugs

<p></p><p>The current outbreak of the corona virus disease 2019 (COVID-19), has affected almost entire world and become pandemic now. Currently, there is neither any FDA approved drugs nor any vaccines available to control it. Very recently in Bangladesh, a group of doctors reported astounding success in treating patients suffering from COVID-19 with two commonly used drugs, Ivermectin and Doxycycline. In the current study we have explored the possible mechanism by which these drugs might have worked for the positive response in the COVID-19 patients. To explore the mechanism we have used molecular docking and molecular dynamics simulation approach. Effectiveness of Ivermectin and doxycycline were evaluated against Main Protease (Mpro), Spike (S) protein, Nucleocapsid (N), RNA-dependent RNA polymerase (RdRp, NSP12), ADP Ribose Phosphatase (NSP3), Endoribonuclease (NSP15) and methyltransferase (NSP10-NSP16 complex) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor. Our study shows that both Ivermectin and doxycycline have significantly bind with SARS-CoV-2 proteins but Ivermectin was better binding than doxycycline. Ivermectin showed a perfect binding site to the Spike-RBD and ACE2 interacting region indicating that it might be interfering in the interaction of spike with ACE2 and preventing the viral entry in to the host cells. Ivermectin also exhibited significant binding affinity with different SARS-CoV-2 structural and non-structural proteins (NSPs) which have diverse functions in virus life cycle. Significant binding of Ivermectin with RdRp indicate its role in the inhibition of the viral replication and ultimately impeding the multiplication of the virus. Ivermectin also possess significant binding affinity with NSP3, NSP10, NSP15 and NSP16 which helps virus in escaping from host immune system. Molecular dynamics simulation study shows that binding of the Ivermectin with Mpro, Spike, NSP3, NSP16 and ACE2 was quiet stable. Thus, our docking and simulation studies reveal that combination of Ivermectin and doxycycline might be executing the effect by inhibition of viral entry and enhance viral load clearance by targeting various viral functional proteins.</p><p></p>

scholarly journals A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients

2020 ◽  
Author(s):  
Dharmendra Kumar Maurya
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Binding Affinity ◽  
Viral Entry ◽  
Virus Disease ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Host Immune System ◽  
Main Protease ◽  
Approved Drugs

<p></p><p>The current outbreak of the corona virus disease 2019 (COVID-19), has affected almost entire world and become pandemic now. Currently, there is neither any FDA approved drugs nor any vaccines available to control it. Very recently in Bangladesh, a group of doctors reported astounding success in treating patients suffering from COVID-19 with two commonly used drugs, Ivermectin and Doxycycline. In the current study we have explored the possible mechanism by which these drugs might have worked for the positive response in the COVID-19 patients. To explore the mechanism we have used molecular docking and molecular dynamics simulation approach. Effectiveness of Ivermectin and doxycycline were evaluated against Main Protease (Mpro), Spike (S) protein, Nucleocapsid (N), RNA-dependent RNA polymerase (RdRp, NSP12), ADP Ribose Phosphatase (NSP3), Endoribonuclease (NSP15) and methyltransferase (NSP10-NSP16 complex) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor. Our study shows that both Ivermectin and doxycycline have significantly bind with SARS-CoV-2 proteins but Ivermectin was better binding than doxycycline. Ivermectin showed a perfect binding site to the Spike-RBD and ACE2 interacting region indicating that it might be interfering in the interaction of spike with ACE2 and preventing the viral entry in to the host cells. Ivermectin also exhibited significant binding affinity with different SARS-CoV-2 structural and non-structural proteins (NSPs) which have diverse functions in virus life cycle. Significant binding of Ivermectin with RdRp indicate its role in the inhibition of the viral replication and ultimately impeding the multiplication of the virus. Ivermectin also possess significant binding affinity with NSP3, NSP10, NSP15 and NSP16 which helps virus in escaping from host immune system. Molecular dynamics simulation study shows that binding of the Ivermectin with Mpro, Spike, NSP3, NSP16 and ACE2 was quiet stable. Thus, our docking and simulation studies reveal that combination of Ivermectin and doxycycline might be executing the effect by inhibition of viral entry and enhance viral load clearance by targeting various viral functional proteins.</p><p></p>

scholarly journals IDENTIFYING PROPOLIS COMPOUNDS POTENTIAL TO BE COVID-19 THERAPIES BY TARGETING SARS-COV-2 MAIN PROTEASE

2021 ◽  
pp. 103-110
Author(s):  
LIA KUSUMA DEWI ◽  
MUHAMAD SAHLAN ◽  
DIAH KARTIKA PRATAMI ◽  
ALI AGUS ◽  
AGUSSALIM ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Bioactive Compounds ◽  
Protease Activity ◽  
Protein Target ◽  
Main Protease

Objective: The study aims to perform molecular docking to examine the interaction between propolis compound and SARS-CoV-2 main protease. Methods: The protein target of this research was the crystal structure of SARS-CoV-2 main protease in complex with an inhibitor N3 (PDB ID: 6LU7). The ligand of this research was the bioactive compounds from Propolis of Tetragonula aff. biroi. Results: The results showed that propolis compound which has the potential to inhibit SARS-CoV-2 protease activity was Sulabiroins A (binding affinity-8.1 kcal/mol), following by (2S)-5,7-dihydroxy-4'-methoxy-8-prenylflavanone acid and broussoflavonol F (binding affinity-7.9 kcal/mol) with binding similarity more than 50% compared to N3-main protease interaction. Conclusion: Molecular docking showed propolis compounds of Tetragonula aff. biroi potential to inhibit SARS-CoV-2 main protease activity. The highest binding affinity presented by Sulabiroins A, following by (2S)-5,7-dihydroxy-4'-methoxy-8-prenylflavanone acid and broussoflavonol F, with values of-8.1 kcal/mol,-7.9 kcal/mol, and-7.9 kcal/mol, respectively, with binding similarity more than 50% compared to N3 and SARS-CoV-2 main protease interaction.

Mechanism of Actions of Dexamethasone against COVID-19 predicted by Alpha Shape Analysis of Binding Sites

2021 ◽  
Vol 16 ◽  
Author(s):  
Mengxu Zhu ◽  
Avirup Ghosh ◽  
Hong Yan
Keyword(s):  
Binding Affinity ◽  
Shape Analysis ◽  
Binding Affinities ◽  
Mortality And Morbidity ◽  
Alpha Shape ◽  
Drug Molecules ◽  
Main Protease ◽  
Geometrical Features ◽  
Clinical Benefits ◽  
Geometrical Data

Background: COVID-19 emerged in late 2019 and became a pandemic disease with severe mortality and morbidity. No specific remedy exists at present, but some drugs, such as Dexamethasone, have shown clinical benefits against the causative agent, the SARS-CoV-2 virus. Objective: To analyze the binding affinity between drugs and an SARS-CoV-2 protein through geometrical methods and to study the theoretical effectiveness of Dexamethasone as a potential treatment for COVID-19. Method: The binding affinity of Dexamethasone to the target SARS-CoV-2 protein was compared with those of different inhibitors. Drug molecules were docked to the SARS-CoV-2 main protease, and the system was simulated by molecular dynamics, allowing alpha shape analysis to extract geometrical features, such as the matching rates of atoms, solid angles, and the distances between atoms at interfaces. Binding affinities between drugs and the main protease were assessed by these geometrical data and the free energy of binding. Results: The behaviour of Dexamethasone was similar to other inhibitors. The efficacy of Dexamethasone as a treatment may be due to it being a glucocorticoid and its properties as a potent inhibitor. Conclusion: This study revealed the mechanism of action of Dexamethasone and provided a geometrical method to distinguish among potential drugs for the treatment of COVID-19.

scholarly journals Computational Insights on the Potential of Some NSAIDs for Treating COVID-19: Priority Set and Lead Optimization

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3772
Author(s):  
Ayman Abo Elmaaty ◽  
Mohammed I. A. Hamed ◽  
Muhammad I. Ismail ◽  
Eslam B. Elkaeed ◽  
Hamada S. Abulkhair ◽  
...  
Keyword(s):  
Dynamic Properties ◽  
Good Description ◽  
Lung Damage ◽  
Human Beings ◽  
Hybrid Functional ◽  
Future Design ◽  
Main Protease ◽  
Anti Inflammatory ◽  
Approved Drugs ◽  
Dynamics Simulations

The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure–activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.

Discovery of Some Antiviral Natural products to fight against Novel Corona Virus (SARS-CoV-2) using Insilico approach

2020 ◽  
Vol 23 ◽  
Author(s):  
Ashish Shah ◽  
Vaishali Patel ◽  
Bhumika Parmar
Keyword(s):  
Binding Affinity ◽  
Protein S ◽  
Docking Studies ◽  
Spike Protein ◽  
Enveloped Viruses ◽  
Bioactivity Prediction ◽  
Corona Virus ◽  
Main Protease ◽  
Antiviral Activities ◽  
Deadly Disease

Background: Novel Corona virus is a type of enveloped viruses with a single stranded RNA enclosing helical nucleocapsid. The envelope consists of spikes on the surface which are made up of proteins through which virus enters into human cells. Until now there is no specific drug or vaccine available to treat COVID-19 infection. In this scenario, reposting of drug or active molecules may provide rapid solution to fight against this deadly disease. Objective: We had selected 30 phytoconstituents from the different plants which are reported for antiviral activities against corona virus (CoVs) and performed insilico screening to find out phytoconstituents which have potency to inhibit specific target of novel corona virus. Methods: We had perform molecular docking studies on three different proteins of novel corona virus namely COVID-19 main protease (3CL pro), papain-like protease (PL pro) and spike protein (S) attached to ACE2 binding domain. The screening of the phytoconstituents on the basis of binding affinity compared to standard drugs. The validations of screened compounds were done using ADMET and bioactivity prediction. Results: We had screened five compounds biscoclaurine, norreticuline, amentoflavone, licoricidin and myricetin using insilico approach. All compounds found safe in insilico toxicity studies. Bioactivity prediction reviles that these all compounds may act through protease or enzyme inhibition. Results of compound biscoclaurine norreticuline were more interesting as this biscoclaurine had higher binding affinity for the target 3CLpro and PLpro targets and norreticuline had higher binding affinity for the target PLpro and Spike protein. Conclusion: Our study concludes that these compounds could be further explored rapidly as it may have potential to fight against COVID-19.

Nucleotide sequence and phylogenetic analysis of the medium (M) genomic RNA segments of three hantaviruses isolated in China

1998 ◽  
Vol 56 (1) ◽  
pp. 69-76 ◽  
Author(s):  
Xiaohong Shi ◽  
Mifang Liang ◽  
Changshou Hang ◽  
Gan Song ◽  
Conall McCaughey ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Nucleotide Sequence ◽  
Genomic Rna

scholarly journals Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Vicky Mody ◽  
Joanna Ho ◽  
Savannah Wills ◽  
Ahmed Mawri ◽  
Latasha Lawson ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Inhibitory Effects ◽  
Major Threat ◽  
Main Protease ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Computational Molecular Modeling

AbstractEmerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.

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