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)

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.

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

10.26434/chemrxiv.12198369 ◽

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

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

10.26434/chemrxiv.12198369.v1 ◽

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

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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)

10.26434/chemrxiv.12857678.v1 ◽

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.

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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

10.26434/chemrxiv.12186624.v3 ◽

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>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.</div>

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Intermolecular Interaction Analyses on SARS-CoV-2 Spike Protein Receptor Binding Domain and Human Angiotensin-Converting Enzyme 2 Receptor-Blocking Antibody/Peptide Using Fragment Molecular Orbital Calculation

The Journal of Physical Chemistry Letters ◽

10.1021/acs.jpclett.1c00663 ◽

2021 ◽

Vol 12 (16) ◽

pp. 4059-4066

Author(s):

Kazuki Watanabe ◽

Chiduru Watanabe ◽

Teruki Honma ◽

Yu-Shi Tian ◽

Yusuke Kawashima ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Receptor Binding ◽

Molecular Orbital Calculation ◽

Spike Protein ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Blocking Antibody ◽

Angiotensin Converting Enzyme 2 ◽

Receptor Blocking ◽

Protein Receptor

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The Effects of Aβ1-42 Binding to the SARS-CoV-2 Spike Protein S1 Subunit and Angiotensin-Converting Enzyme 2

International Journal of Molecular Sciences ◽

10.3390/ijms22158226 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8226

Author(s):

John Tsu-An Hsu ◽

Chih-Feng Tien ◽

Guann-Yi Yu ◽

Santai Shen ◽

Yi-Hsuan Lee ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Viral Entry ◽

Negative Impact ◽

Spike Protein ◽

Infection Model ◽

Converting Enzyme ◽

Viral Receptor ◽

Angiotensin Converting Enzyme 2 ◽

People With Dementia ◽

The Impact

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer’s disease (AD), the major form of dementia, β-amyloid (Aβ) levels in the blood are increased; however, the impact of elevated Aβ levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aβ1-42, but not Aβ1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aβ1-42. Furthermore, Aβ1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aβ1-42 show that the clearance of Aβ1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aβ antibody. In conclusion, these findings suggest that the binding of Aβ1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aβ1-42 in the blood is beneficial to the fight against COVID-19 and AD.

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SARS-CoV-2 Spike Protein Induces Degradation of Junctional Proteins That Maintain Endothelial Barrier Integrity

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.687783 ◽

2021 ◽

Vol 8 ◽

Author(s):

Somasundaram Raghavan ◽

Divya Borsandra Kenchappa ◽

M. Dennis Leo

Keyword(s):

Endothelial Cells ◽

Angiotensin Converting Enzyme ◽

Spike Protein ◽

Endothelial Barrier ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Barrier Integrity ◽

Junctional Proteins ◽

Junction Protein ◽

Junctional Protein

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the Angiotensin converting enzyme 2 (ACE2) receptor present on the cell surface to enter cells. Angiotensin converting enzyme 2 is present in many cell types including endothelial cells, where it functions to protect against oxidative damage. There is growing evidence to suggest that coronavirus disease (COVID-19) patients exhibit a wide range of post-recovery symptoms and shows signs related to cardiovascular and specifically, endothelial damage. We hypothesized that these vascular symptoms might be associated with disrupted endothelial barrier integrity. This was investigated in vitro using endothelial cell culture and recombinant SARS-CoV-2 spike protein S1 Receptor-Binding Domain (Spike). Mouse brain microvascular endothelial cells from normal (C57BL/6 mice) and diabetic (db/db) mice were used. An endothelial transwell permeability assay revealed increased permeability in diabetic cells as well as after Spike treatment. The expression of VE-Cadherin, an endothelial adherens junction protein, JAM-A, a tight junctional protein, Connexin-43, a gap junctional protein, and PECAM-1, were all decreased significantly after Spike treatment in control and to a greater extent, in diabetic cells. In control cells, Spike treatment increased association of endothelial junctional proteins with Rab5a, a mediator of the endocytic trafficking compartment. In cerebral arteries isolated from control and diabetic animals, Spike protein had a greater effect in downregulating expression of endothelial junctional proteins in arteries from diabetic animals than from control animals. In conclusion, these experiments reveal that Spike-induced degradation of endothelial junctional proteins affects endothelial barrier function and is the likely cause of vascular damage observed in COVID-19 affected individuals.

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