scholarly journals Repurposing of Approved Drugs with Potential to Block SARS-CoV-2 Surface Glycoprotein Interaction with Host Receptor

2020 ◽  
Author(s):  
Abu Sajib
Keyword(s):  
In Silico ◽  
Potential Interaction ◽  
Surface Glycoprotein ◽  
Spike Protein ◽  
Striking Similarity ◽  
Spike Glycoprotein ◽  
Human Lung Epithelial Cell ◽  
Angiotensin I Converting Enzyme ◽  
Human Lungs ◽  
Approved Drugs

Background: Respiratory transmission is the primary route of SARS-CoV-2 infection. Angiotensin I converting enzyme 2 (ACE2) is the known receptor of SARS-CoV-2 spike glycoprotein for entry into human cells. A recent study reported absent to low ACE2 promoter activity in a variety of human lung epithelial cell samples. Three bioprojects (PRJEB4337, PRJNA270632 and PRJNA280600) invariably found abundant expression of ACE in human lungs compared to very low expression of ACE2. Methods: In silico tools were applied to assess potential interaction of SARS-CoV-2 surface spike protein with human ACE as well as predict the drugs that may block SARS-CoV-2 interaction with host receptor. Results: Although it is not obvious from the primary sequence alignment of ACE2 and its homolog ACE (also known as ACE1), comparison of X-ray crystallographic structures show striking similarity in the regions of these proteins which is known (for ACE2) to interact with the receptor binding domain (RBD) of SARS-CoV-2 spike protein. Critical amino acids that mediate interaction with the viral spike protein in ACE2 are organized in the same order in ACE. In silico analyses predicts comparable interaction of SARS-CoV-2 spike protein with ACE2 and ACE. In addition, this study predicts and selects already approved drugs from a list of 1263, which may interfere with the binding of SARS-CoV-2 spike glycoprotein to ACE2 and/or ACE.

scholarly journals Repurposing of Approved Drugs with Potential to Interact with SARS-CoV-2 Receptor

2020 ◽  
Author(s):  
Abu Sajib
Keyword(s):  
In Silico Analysis ◽  
Host Cells ◽  
Spike Protein ◽  
Human Lung Epithelial Cell ◽  
Angiotensin I Converting Enzyme ◽  
Human Lungs ◽  
Lung Epithelial ◽  
Approved Drugs ◽  
Primary Sequence Alignment ◽  
Low Expression

Respiratory transmission is the primary route of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Angiotensin I converting enzyme 2 (ACE2) is the known receptor of SARS-CoV-2 surface spike glycoprotein for entry into human cells. A recent study reported absent to low expression of ACE2 in a variety of human lung epithelial cell samples. Three bioprojects (PRJEB4337, PRJNA270632 and PRJNA280600) invariably found abundant expression of ACE1 (a homolog of ACE2 and also known as ACE) in human lungs compared to very low expression of ACE2. In fact, ACE1 has a wider and more abundant tissue distribution compared to ACE2. Although it is not obvious from the primary sequence alignment of ACE1 and ACE2, comparison of X-ray crystallographic structures show striking similarities in the regions of the peptidase domains (PD) of these proteins, which is known (for ACE2) to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Critical amino acids in ACE2 that mediate interaction with the viral spike protein are present and organized in the same order in the PD of ACE1. In silico analysis predicts comparable interaction of SARS-CoV-2 spike protein with ACE1 and ACE2. In addition, this study predicts from a list of 1263 already approved drugs that may interact with ACE2 and/or ACE1, potentially interfere with the entry of SARS-CoV-2 inside the host cells and alleviate the symptoms of Coronavirus disease (COVID-19).

scholarly journals Optimized Pseudotyping Conditions for the SARS-COV-2 Spike Glycoprotein

2020 ◽  
Vol 94 (21) ◽  
Author(s):  
Marc C. Johnson ◽  
Terri D. Lyddon ◽  
Reinier Suarez ◽  
Braxton Salcedo ◽  
Mary LePique ◽  
...  
Keyword(s):  
Signal Peptide ◽  
Neutralizing Antibodies ◽  
Particle Production ◽  
Surface Glycoprotein ◽  
Spike Protein ◽  
Target Cells ◽  
Spike Glycoprotein ◽  
Infectious Particle ◽  
Pathogenic Virus ◽  
Hiv 1

ABSTRACT The severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) Spike glycoprotein is solely responsible for binding to the host cell receptor and facilitating fusion between the viral and host membranes. The ability to generate viral particles pseudotyped with SARS-COV-2 Spike is useful for many types of studies, such as characterization of neutralizing antibodies or development of fusion-inhibiting small molecules. Here, we characterized the use of a codon-optimized SARS-COV-2 Spike glycoprotein for the generation of pseudotyped HIV-1, murine leukemia virus (MLV), and vesicular stomatitis virus (VSV) particles. The full-length Spike protein functioned inefficiently with all three systems but was enhanced over 10-fold by deleting the last 19 amino acids of the cytoplasmic tail. Infection of 293FT target cells was possible only if the cells were engineered to stably express the human angiotensin-converting enzyme 2 (ACE2) receptor, but stably introducing an additional copy of this receptor did not further enhance susceptibility. Stable introduction of the Spike-activating protease TMPRSS2 further enhanced susceptibility to infection by 5- to 10-fold. Replacement of the signal peptide of the Spike protein with an optimal signal peptide did not enhance or reduce infectious particle production. However, modifications D614G and R682Q further enhanced infectious particle production. With all enhancing elements combined, the titer of pseudotyped HIV-1 particles reached almost 106 infectious particles/ml. Finally, HIV-1 particles pseudotyped with SARS-COV-2 Spike were successfully used to detect neutralizing antibodies in plasma from coronavirus disease 2019 (COVID-19) patients, but not in plasma from uninfected individuals. IMPORTANCE In work with pathogenic viruses, it is useful to have rapid quantitative tests for viral infectivity that can be performed without strict biocontainment restrictions. A common way of accomplishing this is to generate viral pseudoparticles that contain the surface glycoprotein from the pathogenic virus incorporated into a replication-defective viral particle that contains a sensitive reporter system. These pseudoparticles enter cells using the glycoprotein from the pathogenic virus, leading to a readout for infection. Conditions that block entry of the pathogenic virus, such as neutralizing antibodies, will also block entry of the viral pseudoparticles. However, viral glycoproteins often are not readily suited for generating pseudoparticles. Here, we describe a series of modifications that result in the production of relatively high-titer SARS-COV-2 pseudoparticles that are suitable for the detection of neutralizing antibodies from COVID-19 patients.

scholarly journals An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

2020 ◽  
Author(s):  
Alfonso Trezza ◽  
Daniele Iovinelli ◽  
Filippo Prischi ◽  
Annalisa Santucci ◽  
Ottavia Spiga
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Spike Protein ◽  
Effective Vaccine ◽  
Docking Simulations ◽  
Approved Drugs

Abstract The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein – ACE2 interaction inhibitor. Our data showed that Nilotinib and Imatinib bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.

scholarly journals SARS-COV-2 Spike Glycoprotein as Inhibitory Target for In silico Screening of Natural Compounds

2021 ◽  
Vol 11 (6) ◽  
pp. 14974-14985
Keyword(s):  
In Silico ◽  
Md Simulation ◽  
Simulation Analysis ◽  
Binding Pocket ◽  
Natural Compounds ◽  
Spike Glycoprotein ◽  
Life Threatening ◽  
Inhibitory Potential ◽  
The Stability ◽  
Approved Drugs

Coronavirus disease (Covid-19) caused by SARS-Cov-2 has raised global health concerns without approved drugs to manage this life-threatening disease. This study aimed to predict the inhibitory potential of quercetin-3-o-rutinoside against SARS-Cov-2 spike glycoprotein. Targeting the SARS-Cov-2 Nucleocapsid spike glycoprotein (pdb id: 6m3m) is gaining importance. In this present study, the relationship between plant-derived natural drug and spike glycoprotein was predicted using in silico computational approach. The results were evaluated according to the glide (Schrodinger) dock score. Among the five (5) screened natural compounds, quercetin-3-o-rutinoside has the best docking score (-9.296) with the target. Molecular dynamic (MD) simulation analysis was performed for 1000ps to confirm the spike protein's stability behavior and quercetin-3-o-rutinoside complex. The MD simulation analysis validated the stability of quercetin-3-o-rutinoside in the spike protein binding pocket as a potent inhibitor. The pharmacokinetics screening of the natural compounds showed that quercetin-3-o-rutinoside possesses good oral bioavailability with no side effects.

scholarly journals Spike protein modeling and single amino acid variant analysis might suggest reduced transmitability of SARS-CoV-2 in Jordan, Middle East

2020 ◽  
Author(s):  
Walid Al-Zyoud ◽  
Hazem Haddad
Keyword(s):  
Crystal Structure ◽  
Amino Acid ◽  
Middle East ◽  
Active Sites ◽  
Trna Synthetase ◽  
Surface Glycoprotein ◽  
Spike Protein ◽  
Single Amino Acid ◽  
Spike Glycoprotein ◽  
Amino Acid Variants

Abstract Spike protein (approx. 180 kDa) is the surface glycoprotein of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) necessary for the interaction of the virus with human endothelial cell receptors on the cell membrane to be engulfed causing COVID-19 disease after binding with the angiotensin-converting enzyme 2 (ACE2) with an evident activation by type II transmembrane protease TMPRSS2 . Therefore, mutations and amino acid variants analysis are essential in characterizing the mechanism of binding of spike protein with its receptor, which totally gives insights on possibilities to design a peptide or nucleotide-based vaccine for COVID-19. Here, we employed Iterative Threading Assembly Refinement (I-TASSER) and Multiple Alignment using Fast Fourier Transform (MAFFT) to predict the three-dimensional structure and to analyze the amino acid variants for spike protein sequences of SARS-CoV-2 from GISAID database of samples collected from Jordan to try to find a justification for low number of confirmed COVID-19 in Jordan, Middle East. Our findings showed the molecules structurally close to the spike glycoprotein from the Enzyme Commission (EC) numbers and active sites included Isoleucyl-tRNA synthetase, Crystal structure of the tricorn protease (hydrolase); Crystal structure of the T. Thermophilus RNA polymerase holoenzyme (transferase); Crystal structure of the complex between pyruvate-ferredoxin oxidoreductase from Desulfovibrio africanus and pyruvate (oxidoreductase); and Reovirus core (virus). Our MAFFT findings showed that Four Amino Acid Variants (SAV) founded in 20 samples of SARS-CoV-2 were not conserved residues in spike glycoprotein. What is equal to 5% of samples showed tyrosine (polar) deletion at Y144 , 62% of samples showed aspartate (polar, acidic) substitution to glycine (nonpolar) at D614G, 5% of samples showed aspartate (polar, acidic) substitution to tyrosine (polar) at D1139Y and 5% of samples showed glycine (nonpolar) substitution to serine (polar) at G1167S respectively. By using Phyre2, our findings have shown lower sensitive mutational that cannot affect the pocket region or alpha and beta-sheet in all mutations except for D614G, which has the highest mutational sensitivity score (5 out of 9) indicating a bigger effect on the function of spike protein. This might suggest, in general, a reduced transmitability of SARS-CoV-2 in Jordan, Middle East. As the crystal structure of spike protein is not revealed yet, it was not possible to compare the predicted modes versus each other.

scholarly journals An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

2020 ◽  
Author(s):  
Alfonso Trezza ◽  
Daniele Iovinelli ◽  
Filippo Prischi ◽  
Annalisa Santucci ◽  
Ottavia Spiga
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Spike Protein ◽  
Effective Vaccine ◽  
Docking Simulations ◽  
Approved Drugs

Abstract The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein – ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.Authors Alfonso Trezza and Daniele Iovinelli contributed equally to this work.

Silybin B and Cianidanol Inhibit M pro and Spike Protein of SARS-CoV-2: Evidence from in Silico Molecular Docking Studies

2020 ◽  
Vol 26 ◽  
Author(s):  
Rashi Srivastava ◽  
Shubham Tripathi ◽  
Sreepoorna Unni ◽  
Arif Hussain ◽  
Shafiul Haque ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Drug Repositioning ◽  
Docking Studies ◽  
Host Cells ◽  
Spike Protein ◽  
Ligand Interactions ◽  
Adme Properties ◽  
Approved Drugs ◽  
In Silico Molecular Docking

Background: The main proteases (Mpro) and Spike Proteins (SP) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2) play a major role in viral infection development by producing several non-structural proteins (nsPs) and penetrating the host cells respectively. In this study, the potential of in silico molecular docking-based drug repositioning approach was exploited for identifying the inhibitors of Mpro and SP of SARS-CoV-2. Methods: A total of 196 compounds including various US-FDA-approved drugs, vitamins and their analogs were docked with Mpro (PDB IDs: 6YB7 and 6Y84), and the top six ligands were further tested for ADME properties followed by docking with SP (PDB IDs: 6LXT and 6W41). Results: Out of 196 compounds, binding energy (DE) of Silybin B (6YB7: DE: -11.20 kcal/mol; 6Y84: DE: -10.18 kcal/mol; 6LXT:DE: -10.47 kcal/mol; 6W41:DE: -10.96 kcal/mol) and Cianidanol (6YB7:DE: -8.85 kcal/mol; 6Y84:DE:-10.02 kcal/mol; 6LXT:DE:-9.36 kcal/mol; 6W41:DE: -9.52 kcal/mol) demonstrated better binding and ADME properties compared with the currently endeavored drugs like Hydroxychloroquine and Lopinavir. Additionally, Elliptinone, Diospyirin, SCHEMBL94263 and Fiboflavin have shown encouraging results. Fiboflavin, an immunity booster, was found to inhibit both the Mpro and spike protein of SARS-CoV-2. It was observed that amino acid residues MET6, ALA7, PHE8, PRO9, ASP295, GLY302, VAL303 and THR304 play significant roles in protein-ligand interactions through hydrogen bonds and Vander Waals forces. Conclusion: Silybin B and Cianidanol showed excellent binding and ADME properties compared with the currently endeavored drugs and can be exploited as therapeutic options against SARS-CoV-2 infection after experimental validation and clinical trials.

scholarly journals in silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy

2020 ◽  
Author(s):  
Tianzi Wei ◽  
Hao Wang ◽  
Xueqing Wu ◽  
Yi Lu ◽  
Shenghui Guan ◽  
...  
Keyword(s):  
Drug Development ◽  
Binding Capacity ◽  
Drug Repurposing ◽  
Integrase Inhibitor ◽  
Spike Protein ◽  
Hiv Integrase ◽  
Spike Glycoprotein ◽  
High Binding ◽  
Potential Spike ◽  
Approved Drugs

Abstract COVID-19 has globally spread and has become a new pandemic, but there is still no effective drugs or vaccines to treat or prevent this disease. SARS-Cov-2 invades human cells through its spike proteins interacting with human ACE2 receptors. One strategy to prevent the virus from entering cells is the interruption of the viral spike protein interacting with ACE2. In such an emergent situation, drug repurposing is a promising method for rapid drug development. Here, we selected around 15000 molecular candidates including FDA-approved drugs from DrugBank and natural compounds from TCMSP to perform virtual screening for potential molecules that can target viral spike protein based on its crystal structure. In this article, we present the top 20 molecules with high binding affinity with spike protein, of which, digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP, extracted from indigo naturalis and polygoni tinctorii foliu, have the highest docking scores. In addition, we also found that raltegravir, an HIV integrase inhibitor, has a relatively high binding score. Those molecules with high binding capacity to spike glycoprotein might be used by other researchers for further anti-COVID-19 drug development.

scholarly journals In-silico identification of natural antiviral drug against SARS-CoV-2 and comparison with potential FDA approved drug targets

2020 ◽  
Vol 3 (4) ◽  
pp. 1-11
Author(s):  
SARRA AKERMI ◽  
Neha Lohar ◽  
Subrata Sinha ◽  
Surabhi Johari ◽  
Sunil Jayant ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Antiviral Drug ◽  
Spike Protein ◽  
Plant Metabolites ◽  
Secondary Plant Metabolites ◽  
Approved Drugs ◽  
Fda Approved Drugs

Antimalarial drugs Chloroquine and Hydroxychloroquine have garnered most attention recently as a successful remedy for COVID19. However, the use of these drugs is still questionable due to its undetermined efficacy and side effects. The present study utilizes in-silico high throughput screening of FDA approved antiviral compounds and secondary plant metabolites against spike protein of novel coronavirus (SARS-CoV-2). This target was chosen because it is instrumental in entry of virus into human cells. It is observed that the plant compound Tocopheryl-curcumin has more affinity for spike protein of SARS-CoV-2 in comparison to the majority of FDA approved drugs. Tocopheryl-curcumin binds with the binding site of RBD domain of spike protein (6VSB, chain A) with free energy (∆G) of binding of -11.20 kcal/mol and makes strong hydrogen bonds with amino acid residues of S366, V367, L368, S373, and K529. Among the FDA approved drugs, Pibrentasvir obtains top rank with free energy (∆G) of binding of -9.69 kcal/mol. whereas; surprisingly Chloroquine (-6.87 kcal/mol) and Hydroxychloroquine (-7.24 kcal/mol) ranked lower in our docking study. The toxicity prediction by VEGA predicts that tocopheryl-curcumin shows no toxicity as compared to FDA approved drugs. Therefore, we infer that the plant-based tocopheryl-curcumin could be considered as potential and safer drug against COVID 19 disease as compared to chemical based drugs.

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