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 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.

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 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 Drug Repurposing for Coronavirus (COVID-19): In Silico Screening of Known Drugs Against the SARS-CoV-2 Spike Protein Bound to Angiotensin Converting Enzyme 2 (ACE2) (6M0J)

2020 ◽  
Author(s):  
Konstantinos Kalamatianos
Keyword(s):  
Clinical Trials ◽  
Angiotensin Converting Enzyme ◽  
Antiviral Agents ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Frontier Molecular Orbital ◽  
Converting Enzyme ◽  
Orbital Theory ◽  
Angiotensin Converting Enzyme 2 ◽  
Reactivity Descriptors

In this study FDA approved antiviral drugs and lopinavir analogues in clinical trials were tested for their inhibitory properties towards the SARS-CoV-2 Spike protein bound to angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. The most stable structures and the corresponding binding affinities of seventeen such antiretroviral compounds were obtained. Frontier molecular orbital theory, global reactivity descriptors, molecular docking calculations and electrostatic potential (ESP) analysis were used to hypothesize the bioactivity of these drugs against 6M0J. It is found that increased affinity for the protein is shown by inhibitors with large compound volume, small charge separation, low electrophilicity, aromatic rings and heteroatoms that participate in hydrogen bonding. Amongst the drugs tested, four compounds, PubChem CID 492005, CID 486507, CID 3010249 and lopinavir showed excellent results – binding interactions -9.0 to -9.3 kcal.mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2.<br>

Thermodynamics of the interaction between the spike protein of severe acute respiratory syndrome- coronavirus-2 and the receptor of human angiotensin converting enzyme 2. Effects of possible ligands

2020 ◽  
Author(s):  
Cristina Garcia-Iriepa ◽  
Cecilia Hognon ◽  
Antonio Francés-Monerris ◽  
Isabel Iriepa ◽  
Tom Miclot ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Molecular Mechanisms ◽  
Molecular Design ◽  
Binding Free Energy ◽  
Transmembrane Protein ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Rational Molecular Design ◽  
Rational Evaluation

<div><p>Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.</p></div>

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