scholarly journals Targeting Virus-Host Interaction: An in Silico Approach to Develop Promising Inhibitors Against COVID-19

2020 ◽  
Author(s):  
Jitendra Subhash Rane ◽  
Aroni Chatterjee ◽  
Rajni Khan ◽  
Abhijeet Kumar ◽  
Shashikant Ray
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico ◽  
Virus Disease ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Host Cell Membrane ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Interaction

The entire human population all over the globe is currently facing appalling conditions due to<br>the spread of infection from COVID-19 (corona virus disease-2019). In the last few months<br>enormous amount of studies have been continuously trying to target several potential drug<br>sites to identify a novel therapeutic target. Spike protein of severe acute respiratory syndrome<br>coronavirus 2 (SARS-CoV-2) is also being targeted by several scientific groups as a novel<br>drug target. The spike glycoprotein protein is present on the surface of the virion and binds to<br>the human angiotensin-converting enzyme-2 (hACE2) membrane receptor thereby promoting<br>its fusion to the host cell membrane. The binding and internalization of the virus is a crucial<br>step in the process of infection and hence any molecule that can inhibit this, certainly holds a<br>significant therapeutic value. We have identified AP-NP (2-(2-amino-5-(naphthalen-2-<br>yl)pyrimidin-4-yl)phenol) and AP-4-Me-Ph (2-(2-amino-5-(p-tolyl)pyrimidin-4-yl)phenol)<br>from a group of diaryl pyrimidine derivatives which appear to bind at the interface of<br>hACE2-SARS-CoV-2S complex (human angiotensin converting enzyme 2 and spike<br>glycoprotein complex) with a low binding energy (<-8 Kcal/mol). In this in-silico study we<br>also found that AP-NP interacts with S1 domain of C-terminal part of SARS-CoV-2S<br>however AP-4-Me-Ph was found to interact with S2 domain of SARS-CoV-2S. The result<br>suggested that AP-NP and AP-4-Me-Ph have potential to inhibit the interaction between<br>spike protein and hACE2 receptor also AP-4-Me-Ph might be prevent internalization of the<br>virion within the host. Further in vitro and in vivo study will strengthen these drug candidates<br>against the COVID-19. <br>

scholarly journals Targeting Virus-Host Interaction: An in Silico Approach to Develop Promising Inhibitors Against COVID-19

2020 ◽  
Author(s):  
Jitendra Subhash Rane ◽  
Aroni Chatterjee ◽  
Rajni Khan ◽  
Abhijeet Kumar ◽  
Shashikant Ray
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico ◽  
Virus Disease ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Host Cell Membrane ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Interaction

The entire human population all over the globe is currently facing appalling conditions due to<br>the spread of infection from COVID-19 (corona virus disease-2019). In the last few months<br>enormous amount of studies have been continuously trying to target several potential drug<br>sites to identify a novel therapeutic target. Spike protein of severe acute respiratory syndrome<br>coronavirus 2 (SARS-CoV-2) is also being targeted by several scientific groups as a novel<br>drug target. The spike glycoprotein protein is present on the surface of the virion and binds to<br>the human angiotensin-converting enzyme-2 (hACE2) membrane receptor thereby promoting<br>its fusion to the host cell membrane. The binding and internalization of the virus is a crucial<br>step in the process of infection and hence any molecule that can inhibit this, certainly holds a<br>significant therapeutic value. We have identified AP-NP (2-(2-amino-5-(naphthalen-2-<br>yl)pyrimidin-4-yl)phenol) and AP-4-Me-Ph (2-(2-amino-5-(p-tolyl)pyrimidin-4-yl)phenol)<br>from a group of diaryl pyrimidine derivatives which appear to bind at the interface of<br>hACE2-SARS-CoV-2S complex (human angiotensin converting enzyme 2 and spike<br>glycoprotein complex) with a low binding energy (<-8 Kcal/mol). In this in-silico study we<br>also found that AP-NP interacts with S1 domain of C-terminal part of SARS-CoV-2S<br>however AP-4-Me-Ph was found to interact with S2 domain of SARS-CoV-2S. The result<br>suggested that AP-NP and AP-4-Me-Ph have potential to inhibit the interaction between<br>spike protein and hACE2 receptor also AP-4-Me-Ph might be prevent internalization of the<br>virion within the host. Further in vitro and in vivo study will strengthen these drug candidates<br>against the COVID-19. <br>

scholarly journals Virtual screening as therapeutic strategy of COVID-19 targeting angiotensin-converting enzyme 2

2021 ◽  
Vol 2 (1) ◽  
pp. 16-27
Author(s):  
Zahra Sharifinia ◽  
◽  
Samira Asadi ◽  
Mahyar Irani ◽  
Abdollah Allahverdi ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Angiotensin Converting Enzyme ◽  
Host Cells ◽  
Spike Protein ◽  
Potential Drug ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Approved Drugs ◽  
Fda Approved Drugs

Objective: The receptor-binding domain (RBD) of the S1 domain of the SARS-CoV- 2 Spike protein performs a key role in the interaction with Angiotensin-converting enzyme 2 (ACE2), leading to both subsequent S2 domain-mediated membrane fusion and incorporation of viral RNA in host cells. Methods: In this study, we investigated the inhibitor’s targeted compounds through existing human ACE2 drugs to use as a future viral invasion. 54 FDA approved drugs were selected to assess their binding affinity to the ACE2 receptor. The structurebased methods via computational ones have been used for virtual screening of the best drugs from the drug database. Key Findings: The ligands “Cinacalcet” and “Levomefolic acid” highaffinity scores can be a potential drug preventing Spike protein of SARS-CoV-2 and human ACE2 interaction. Levomefolic acid from vitamin B family was proved to be a potential drug as a spike protein inhibitor in previous clinical and computational studies. Besides that, in this study, the capability of Levomefolic acid to avoid ACE2 and Spike protein of SARS-CoV-2 interaction is indicated. Therefore, it is worth to consider this drug for more in vitro investigations as ACE2 and Spike protein inhibition candidate. Conclusion: The two Cinacalcet and Levomefolic acid are the two ligands that have highest energy binding for human ACE2 blocking among 54 FDA approved drugs.

DOCKING STUDY OF NOVEL N-SUBSTITUTED 2,5-BIS[(7-CHLOROQUINOLIN-4-YL)AMINO]PENTANOIC DERIVATIVES AS SELECTIVE HIGH-BINDER WITH ANGIOTENSIN CONVERTING ENZYME 2

INDIAN DRUGS ◽  
2020 ◽  
Vol 57 (08) ◽  
pp. 16-24
Author(s):  
Mohammed Oday Ezzat ◽  
Basma M. Abd Razik ◽  
Kutayba F. Dawood
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Active Site ◽  
Docking Study ◽  
World Health ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Pharmaceutical Properties ◽  
Novel Coronavirus

The prevalence of a novel coronavirus (2019-nCoV) in the last few months represents a serious threat as a world health emergency concern. Angiotensin-converting enzyme 2 (ACE2) is the host cellular receptor for the respiratory syndrome of coronavirus epidemic in 2019 (2019-nCoV). In this work, the active site of ACE2 is successfully located by Sitmap prediction tool and validated by different marketed drugs. To design and discover new medical countermeasure drugs, we evaluate a total of 184 molecules of 7-chloro-N-methylquinolin-4-amine derivatives for binding affinity inside the crystal structure of ACE2 located active site. A novel series of N-substituted 2,5-bis[(7-chloroquinolin-4-yl)amino]pentanoic acid derivatives is generated and evaluated for a prospect as a lead compound for (2019-nCoV) medication with a docking score range of (-10.60 to -8.99) kcal/mol for the highest twenty derivatives. Moreover, the ADME pharmaceutical properties were evaluated for further proposed experimental evaluation in vitro or in vivo

scholarly journals Molecular Docking Studies of Curcumin Analogues against SARS-CoV-2 Spike Protein

2021 ◽  
Author(s):  
Jéssica Nogueira ◽  
Flávia Verza ◽  
Felipe Nishimura ◽  
Umashankar Das ◽  
Ícaro Caruso ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Virus Disease ◽  
Etiologic Agent ◽  
Host Cells ◽  
Spike Protein ◽  
Therapeutic Effects ◽  
Host Cell Membrane ◽  
Curcumin Analogues

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the etiologic agent of the current pandemic of corona virus disease 2019 (COVID-19) that has inflicted the loss of thousands of lives worldwide. The coronavirus surface spike (S) glycoprotein is a class I fusion with a S1 domain which is attached to the human angiotensin converting enzyme 2 (ACE2) receptor, and a S2 domain which enables fusion with the host cell membrane and internalization of the virus. Curcumin has been suggested as a potential drug to control inflammation and as a potential inhibitor of S protein, but its therapeutic effects are hampered by poor bioavailability. We performed a molecular docking and dynamic study using 94 curcumin analogues designed to have improved metabolic stability against the SARS-CoV-2 spike protein and compared their affinity with curcumin and other potential inhibitors. The docking analysis suggested that the S2 domain is the main target of these compounds and compound 2606 displayed a higher binding affinity (-9.6 kcal mol-1) than curcumin (-6.8 kcal mol-1) and the Food and Drug Administration (FDA) approved drug hydroxychloroquine (-6.3 kcal mol-1). Further additional validation in vitro and in vivo of these compounds against SARS-CoV-2 may provide insights into the development of a drug that prevents virus entry into host cells.

scholarly journals Conformational Perturbation of SARS-CoV-2 Spike Protein Using N-Acetyl Cysteine, a Molecular Scissor: A Probable Strategy to Combat COVID-19

2020 ◽  
Author(s):  
Utsab Debnath ◽  
Varun Dewaker ◽  
Yenamandra S. Prabhakar ◽  
Parthasarathi Bhattacharyya ◽  
Amit Mandal
Keyword(s):  
Disulfide Bond ◽  
In Silico ◽  
Ex Vivo ◽  
Virus Disease ◽  
Spike Protein ◽  
Early 21St Century ◽  
Acetyl Cysteine ◽  
Structural Architecture

The infection caused by Severe Acute Respiratory Syndrome–CoronaVirus-2 (SARS-CoV-2) resulted in a pandemic across the globe with a huge death toll. The symptoms from SARS-CoV2 appear somewhat similar to the SARS-CoV-1 infection that appeared in early 21st century but the infectivity is far higher for the SARS-CoV-2. The virus attaches itself to exposed human epithelial cells through the spike protein. Recently discovered crystal structure of the complex of spike protein of SARS-CoV-2 with human angiotensin-converting enzyme 2 (ACE2) receptor indicated that the virus binds with the host cell very strongly. We hypothesized that the perturbation of the functionally active conformation of spike protein through the reduction of a solvent accessible disulfide bond (Cys391-Cys525) that provides its structural architecture, may 2 be a feasible strategy to disintegrate the spike protein from ACE2 receptor and thereby prevent the infection. Using in silico platform we showed that N-acetyl cysteine (NAC), a drug used as antioxidant and mucolytic agent, binds in the close proximity of above disulfide bond. The reduction of the disulfide bond via thiol/disulfide exchange, followed by covalent conjugation of NAC perturbed the stereo specific orientations of interacting key residues of spike protein. This resulted in threefold weakening in the binding affinity of spike protein with ACE2 receptor. This opens avenues for exploring the effect of NAC in vitro, ex vivo and in vivo and on successful observation of the similar effect as in silico, the intervention of NAC may be translated in the pharmacoprevention and treatment of Corona virus disease 2019.

scholarly journals Dalbavancin binds ACE2 to block its interaction with SARS-CoV-2 spike protein and is effective in inhibiting SARS-CoV-2 infection in animal models

Cell Research ◽  
2020 ◽  
Vol 31 (1) ◽  
pp. 17-24 ◽  
Author(s):  
Gan Wang ◽  
Meng-Li Yang ◽  
Zi-Lei Duan ◽  
Feng-Liang Liu ◽  
Lin Jin ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spike Protein ◽  
Drug Candidate ◽  
Peptide Drug ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity ◽  
Plasma Half Life

AbstractInfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8–10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.

scholarly journals Computational drug repurposing strategy predicted peptide-based drugs that can potentially inhibit the interaction of SARS-CoV-2 spike protein with its target (humanACE2)

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245258
Author(s):  
Samuel Egieyeh ◽  
Elizabeth Egieyeh ◽  
Sarel Malan ◽  
Alan Christofells ◽  
Burtram Fielding
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Protein Interaction ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Peptide Drugs ◽  
Angiotensin Converting Enzyme 2 ◽  
Protein Protein Interaction ◽  
Potential Inhibitors

Drug repurposing for COVID-19 has several potential benefits including shorter development time, reduced costs and regulatory support for faster time to market for treatment that can alleviate the current pandemic. The current study used molecular docking, molecular dynamics and protein-protein interaction simulations to predict drugs from the Drug Bank that can bind to the SARS-CoV-2 spike protein interacting surface on the human angiotensin-converting enzyme 2 (hACE2) receptor. The study predicted a number of peptide-based drugs, including Sar9 Met (O2)11-Substance P and BV2, that might bind sufficiently to the hACE2 receptor to modulate the protein-protein interaction required for infection by the SARS-CoV-2 virus. Such drugs could be validated in vitro or in vivo as potential inhibitors of the interaction of SARS-CoV-2 spike protein with the human angiotensin-converting enzyme 2 (hACE2) in the airway. Exploration of the proposed and current pharmacological indications of the peptide drugs predicted as potential inhibitors of the interaction between the spike protein and hACE2 receptor revealed that some of the predicted peptide drugs have been investigated for the treatment of acute respiratory distress syndrome (ARDS), viral infection, inflammation and angioedema, and to stimulate the immune system, and potentiate antiviral agents against influenza virus. Furthermore, these predicted drug hits may be used as a basis to design new peptide or peptidomimetic drugs with better affinity and specificity for the hACE2 receptor that may prevent interaction between SARS-CoV-2 spike protein and hACE2 that is prerequisite to the infection by the SARS-CoV-2 virus.

scholarly journals Rapid Assessment of Binding Affinity of SARS-COV-2 Spike Protein to the Human Angiotensin-Converting Enzyme 2 Receptor and to Neutralizing Biomolecules Based on Computer Simulations

2021 ◽  
Vol 12 ◽  
Author(s):  
Damiano Buratto ◽  
Abhishek Saxena ◽  
Qun Ji ◽  
Guang Yang ◽  
Sergio Pantano ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Binding Affinity ◽  
Rapid Assessment ◽  
Cost Effective ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Spike Glycoprotein ◽  
Host Cell Membrane ◽  
Angiotensin Converting Enzyme 2 ◽  
Dynamics Simulations

SARS-CoV-2 infects humans and causes Coronavirus disease 2019 (COVID-19). The S1 domain of the spike glycoprotein of SARS-CoV-2 binds to human angiotensin-converting enzyme 2 (hACE2) via its receptor-binding domain, while the S2 domain facilitates fusion between the virus and the host cell membrane for entry. The spike glycoprotein of circulating SARS-CoV-2 genomes is a mutation hotspot. Some mutations may affect the binding affinity for hACE2, while others may modulate S-glycoprotein expression, or they could result in a virus that can escape from antibodies generated by infection with the original variant or by vaccination. Since a large number of variants are emerging, it is of vital importance to be able to rapidly assess their characteristics: while changes of binding affinity alone do not always cause direct advantages for the virus, they still can provide important insights on where the evolutionary pressure is directed. Here, we propose a simple and cost-effective computational protocol based on Molecular Dynamics simulations to rapidly screen the ability of mutated spike protein to bind to the hACE2 receptor and selected neutralizing biomolecules. Our results show that it is possible to achieve rapid and reliable predictions of binding affinities. A similar approach can be used to perform preliminary screenings of the potential effects of S-RBD mutations, helping to prioritize the more time-consuming and expensive experimental work.

scholarly journals A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2)

2021 ◽  
Vol 14 (10) ◽  
pp. 954
Author(s):  
Paolo Coghi ◽  
Li Jun Yang ◽  
Jerome P. L. Ng ◽  
Richard K. Haynes ◽  
Maurizio Memo ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Cell Invasion ◽  
Binding Domain ◽  
Spike Protein ◽  
Interaction Patterns ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2

Host cell invasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, computational and experimental techniques were combined to screen antimalarial compounds from different chemical classes, with the aim of identifying small molecules interfering with the RBD-ACE2 interaction and, consequently, with cell invasion. Docking studies showed that the compounds interfere with the same region of the RBD, but different interaction patterns were noted for ACE2. Virtual screening indicated pyronaridine as the most promising RBD and ACE2 ligand, and molecular dynamics simulations confirmed the stability of the predicted complex with the RBD. Bio-layer interferometry showed that artemisone and methylene blue have a strong binding affinity for RBD (KD = 0.363 and 0.226 μM). Pyronaridine also binds RBD and ACE2 in vitro (KD = 56.8 and 51.3 μM). Overall, these three compounds inhibit the binding of RBD to ACE2 in the μM range, supporting the in silico data.

scholarly journals In silico study of potential anti-SARS cell entry phytoligands from Phlomis aurea: a promising avenue for prophylaxis

2021 ◽  
Author(s):  
Amira R Khattab ◽  
Mohamed Teleb ◽  
Mohamed S Kamel
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico ◽  
Protective Role ◽  
Cell Entry ◽  
Health Concern ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
In Silico Study ◽  
Promising Avenue

Aim: The severity of COVID-19 has raised a great public health concern evoking an urgency for developing multitargeted therapeutics. Phlomis species was ethno-pharmacologically practiced for respiratory ailments. Materials & methods: An array of 15 phytoligands previously isolated from Phlomis aurea were subjected to molecular docking to explore their potential SARS-CoV-Spike-angiotensin-converting enzyme 2 complex inhibition, that is essential for virus entry to host cell. Results: Acteoside (11) showed the most potent in silico inhibition with an additional merit, over hesperidin (16), of not binding to angiotensin-converting enzyme 2 with well proven in vivo pulmonary protective role in acute lung injury, followed by chrysoeriol-7- O-β-glucopyranoside (12) and luteolin-7- O-β-glucopyranoside (14). Conclusion: Phytoligands (11, 12 and 14) were posed as promising candidates with potential prophylactic action against COVID-19. These phytoligands were prioritized for further biological experimentation because of their acceptable predicted ADME and drug-likeness parameters. Moreover, they could aid in developing multitargeted strategy for better management of COVID-19 using phytomedicines.

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