scholarly journals Potential inhibitors against papain-like protease of novel coronavirus (SARS-CoV-2) from FDA approved drugs

2020 ◽  
Author(s):  
Rimanshee Arya ◽  
Amit Das ◽  
Vishal Prashar ◽  
Mukesh Kumar
Keyword(s):  
Life Cycle ◽  
Active Site ◽  
Homology Model ◽  
Docking Studies ◽  
Rational Selection ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs ◽  
Selection Of

<p></p><p>The cases of 2019 novel coronavirus (SARS-CoV-2) infection have been continuously increasing ever since its outbreak in China last December. Currently, there are no approved drugs to treat the infection. In this scenario, there is a need to utilize the existing repertoire of FDA approved drugs to treat the disease. The rational selection of these drugs could be made by testing their ability to inhibit any SARS-CoV-2 proteins essential for viral life-cycle. We chose one such crucial viral protein, the papain-like protease (PLpro), to screen the FDA approved drugs <i>in silico</i>. The homology model of the protease was built based on the SARS-coronavirus PLpro structure, and the drugs were docked in S3/S4 pockets of the active site of the enzyme. In our docking studies, sixteen FDA approved drugs, including chloroquine and formoterol, was found to bind the target enzyme with significant affinity and good geometry, suggesting their potential to be utilized against the virus.</p><br><p></p>

scholarly journals Potential Inhibitors Against Papain-like Protease of Novel Coronavirus (COVID-19) from FDA Approved Drugs

2020 ◽  
Author(s):  
Rimanshee Arya ◽  
Amit Das ◽  
Vishal Prashar ◽  
Mukesh Kumar
Keyword(s):  
Life Cycle ◽  
Active Site ◽  
Homology Model ◽  
Docking Studies ◽  
Rational Selection ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs ◽  
Selection Of

<p>The cases of 2019 novel coronavirus (COVID-19) infection have been continuously increasing ever since its outbreak in China last December. Currently, there are no approved drugs to treat the infection. In this scenario, there is a need to utilize the existing repertoire of FDA approved drugs to treat the disease. The rational selection of these drugs could be made by testing their ability to inhibit any COVID-19 proteins essential for viral life-cycle. We chose one such crucial viral protein, the papain-like protease (PLpro), to screen the FDA approved drugs <i>in silico</i>. The homology model of the protease was built based on the SARS-coronavirus PLpro structure, and the drugs were docked in S3/S4 pockets of the active site of the enzyme. In our docking studies, fifteen FDA approved drugs, including chloroquine and formoterol, bind the target enzyme with significant affinity and good geometry, suggesting their potential to be utilized against the virus.</p>

scholarly journals Potential inhibitors against papain-like protease of novel coronavirus (SARS-CoV-2) from FDA approved drugs

2020 ◽  
Author(s):  
Rimanshee Arya ◽  
Amit Das ◽  
Vishal Prashar ◽  
Mukesh Kumar
Keyword(s):  
Life Cycle ◽  
Active Site ◽  
Homology Model ◽  
Docking Studies ◽  
Rational Selection ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs ◽  
Selection Of

<p></p><p>The cases of 2019 novel coronavirus (SARS-CoV-2) infection have been continuously increasing ever since its outbreak in China last December. Currently, there are no approved drugs to treat the infection. In this scenario, there is a need to utilize the existing repertoire of FDA approved drugs to treat the disease. The rational selection of these drugs could be made by testing their ability to inhibit any SARS-CoV-2 proteins essential for viral life-cycle. We chose one such crucial viral protein, the papain-like protease (PLpro), to screen the FDA approved drugs <i>in silico</i>. The homology model of the protease was built based on the SARS-coronavirus PLpro structure, and the drugs were docked in S3/S4 pockets of the active site of the enzyme. In our docking studies, sixteen FDA approved drugs, including chloroquine and formoterol, was found to bind the target enzyme with significant affinity and good geometry, suggesting their potential to be utilized against the virus.</p><br><p></p>

scholarly journals Repurposing of FDA Approved Drugs for the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Abhik Kumar Ray ◽  
Parth Sarthi Sen Gupta ◽  
Saroj Kumar Panda ◽  
Satyaranjan Biswal ◽  
Malay Kumar Rana
Keyword(s):  
Virtual Screening ◽  
Binding Energies ◽  
Great Promise ◽  
Main Protease ◽  
Promising Target ◽  
Inhibitory Potential ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs

<p>COVID-19, responsible for several deaths, demands a cumulative effort of scientists worldwide to curb the pandemic. The main protease, responsible for the cleavage of the polyprotein and formation of replication complex in virus, is considered as a promising target for the development of potential inhibitors to treat the novel coronavirus. The effectiveness of FDA approved drugs targeting the main protease in previous SARS-COV (s) reported earlier indicates the chances of success for the repurposing of FDA drugs against SARS-COV-2. Therefore, in this study, molecular docking and virtual screening of FDA approved drugs, primarily of three categories: antiviral, antimalarial, and peptide, are carried out to investigate their inhibitory potential against the main protease. Virtual screening has identified 53 FDA drugs on the basis of their binding energies (< -7.0 kcal/mol), out of which the top two drugs Velpatasvir (-9.1 kcal/mol) and Glecaprevir (-9.0 kcal/mol) seem to have great promise. These drugs have a stronger affinity to the SARS-CoV-2 main protease than the crystal bound inhibitor α-ketoamide 13B (-6.7 kcal/mol) or Indinavir (-7.5 kcal/mol) that has been proposed in a recent study as one of the best drugs for SARS-CoV-2. The <i>in-silico</i> efficacies of the screened drugs could be instructive for further biochemical and structural investigation for repurposing. The molecular dynamics studies on the shortlisted drugs are underway. </p>

scholarly journals Evaluation of Yashtimadhu (Glycyrrhiza glabra) active Phytochemicals Against Novel Coronavirus (SARS-CoV-2)

2020 ◽  
Author(s):  
Dharmendra Kumar Maurya
Keyword(s):  
Viral Entry ◽  
Virus Disease ◽  
Scientific Basis ◽  
Docking Studies ◽  
Angiotensin Converting Enzyme 2 ◽  
Main Protease ◽  
Docking Approach ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Corona Virus Disease 2019 (COVID-19) caused by a novel coronavirus emerged from Wuhan, China in December 2019. It has spread to more than 205 countries and become pandemic now. Currently, there are no FDA approved drugs or vaccines available and hence several studies are going on in search of suitable drug that can target viral proteins or host receptor for the prevention and management of COVID-19. The search for plant-based anti-viral agents against the SARS-CoV-2 is promising because several of plants have been shown to possess anti-viral activities against different viruses. Here, we used molecular docking approach to explore the use of Indian Ayurvedic herbs, Yashtimadhu in prevention and management of COVID-19. In the present study we have evaluated the effectiveness of phytochemicals found in Yashtimadhu against Main Protease (Mpro), Spike (S) protein and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor and furin protease. Apart from this, we have also performed in-silico drug-likeness and predicted pharmacokinetics of the selected phytochemicals found in the Yashtimadhu. Our study shows that several phytochemicals found in this plant have potential to bind with important proteins of SARS-CoV-2 which are essential for viral infection and replication. Overall our study provides scientific basis in terms of binding of active ingredients present in Yashtimadhu with SARS-CoV-2 target proteins. Our docking studies reveal that Yashtimadhu may inhibit the viral severity by interfering with viral entry as well as its multiplication in the infected persons. Thus Yashtimadhu may be helpful in the prevention and management of the 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 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 Ritonavir May Inhibit Exoribonuclease Activity of Nsp14 from the SARS-CoV-2 Virus and Potentiate the Activity of Chain Terminating Drugs

2020 ◽  
Author(s):  
naveen narayanan ◽  
deepak t nair
Keyword(s):  
Active Site ◽  
Genome Duplication ◽  
Protein A ◽  
Homology Model ◽  
Inhibitory Effect ◽  
Computational Studies ◽  
In Silico Screening ◽  
Therapeutic Properties ◽  
Approved Drugs ◽  
Fda Approved Drugs

<div>SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3’ to 5’ exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SCV2-nsp10-nsp14 complex</div><div>bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3’ nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavir</div><div>may serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome</div><div>replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.</div>

scholarly journals Ritonavir may inhibit exoribonuclease activity of nsp14 from the SARS-CoV-2 virus and potentiate the activity of chain terminating drugs

2020 ◽  
Author(s):  
naveen narayanan ◽  
deepak t nair
Keyword(s):  
Active Site ◽  
Protein A ◽  
Homology Model ◽  
Inhibitory Effect ◽  
Genome Replication ◽  
In Silico Screening ◽  
Viral Genome Replication ◽  
Therapeutic Properties ◽  
Approved Drugs ◽  
Fda Approved Drugs

SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3’ to 5’exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SCV2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3’nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavirmay serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.

scholarly journals Compilation of Potential Protein Targets for SARS-CoV-2: Preparation of Homology Model and Active Site Determination for Future Rational Antiviral Design

2020 ◽  
Author(s):  
Sourav Pal ◽  
Dr. Arindam Talukdar
Keyword(s):  
Active Site ◽  
Drug Targets ◽  
Active Sites ◽  
Structural Alignment ◽  
Homology Model ◽  
Active Site Residues ◽  
Protein Targets ◽  
Rational Development ◽  
Novel Coronavirus ◽  
Approved Drugs

<p>The recent pandemic due to the novel coronavirus SARS-CoV-2 (COVID-19) is causing significant mortality worldwide. However, there is a lack of specific drugs which can either prevent or treat the patient suffering from COVID-19. To understand the SARS-CoV-2 receptor recognition causing infectivity and pathogenesis, we have compiled a list of 20 probable drug targets on host and virus based on viral life cycle along with their PDB IDs for the rational development of future antivirals. We have prepared nine homology model for vital proteins for which no crystal structure is reported, which includes protein from host, viral membrane proteins and essential non-structural proteins (NSPs) of virus. The generated models were validated followed by Ramachandran plot along with their sequence and structural alignment. The active site residues of all the protein models are calculated by utilizing COACH meta-server and also cross verified with the CASTp webservers. All the active sites of the homology build proteins were evaluated after superimposition of the closely related X-ray crystallized structure bound with the co-crystal ligands. These information present in the manuscript can be used for the discovery effort towards new antivirals as well as repurposing FDA approved drugs against SARS-CoV-2.</p><br>

scholarly journals Prediction of potential inhibitors of the dimeric SARS-CoV-2 main proteinase through the MM/GBSA approach

2020 ◽  
Author(s):  
Martiniano Bello
Keyword(s):  
3D Structure ◽  
Antiviral Drug ◽  
Md Simulations ◽  
X Ray Crystallography ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs ◽  
Insight Into ◽  
Hiv 1 ◽  
Selection Of

Abstract Since the emergence of SARS-CoV-2, to date, no effective antiviral drug has been approved to treat the disease, and no vaccine against SARS-CoV-2 is available. Under this scenario, the combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has attracted attention since they have been previously employed against the SARS-CoV main proteinase (Mpro) and exhibited some signs of effectiveness. Recently, the 3D structure of SARS-CoV-2 Mpro was constructed based on the monomeric SARS-CoV Mpro and employed to identify potential FDA-approved small inhibitors against SARS-CoV-2 Mpro, allowing the selection of 15 drugs among 1903 approved drugs to be employed. In this study, we performed docking of these 15 approved drugs against the recently solved X-ray crystallography structure of SARS-CoV-2 Mpro (PDB ID: 6LU7) in the monomeric and dimeric states; the latter is the functional state that was determined in a biological context, and these were submitted for MD simulations coupled with the MM/GBSA approach to obtain insight into the inhibitory activity of these compounds. Similar studies were performed with lopinavir and ritonavir coupled to monomeric and dimeric SARS-CoV Mpro and SARS-CoV-2 Mpro to compare the inhibitory differences. Our study provides the structural and energetic basis of the inhibitory properties of lopinavir and ritonavir on SARS-CoV Mpro and SARS-CoV-2 Mpro, allowing us to identify two FDA-approved drugs that can be used against SARS-CoV-2 Mpro. This study also demonstrated that drug discovery requires the dimeric state to obtain good results.

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