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)

Experimental Validation ◽

Antiviral Agents ◽

Spike Protein ◽

Binding Affinities ◽

Converting Enzyme ◽

Lead Compounds ◽

Virtual Screening Approach

E2/21-12-2020<br><br>In this study FDA approved HCV antiviral drugs and their structural analogues – several of them 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 correspond-ing binding affinities of thirteen such antiretroviral com-pounds 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, relatively higher electrophilicity index, aromatic rings and heteroatoms that participate in hydrogen bonding. Amongst the drugs tested, four compounds 10-13 showed excellent results – binding affinities -11.2 to -11.5 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><br><div><br></div><div>E1/24-08-2020</div><br>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<br>angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. Amongst the drugs tested, four compounds, PubChem CID 492005, CID 486507, CID 3010249 and<br><div>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> </div><div><br></div>

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 ◽

2020 ◽

Author(s):

Konstantinos Kalamatianos

Keyword(s):

Clinical Trials ◽

Experimental Validation ◽

Antiviral Agents ◽

Spike Protein ◽

Binding Affinities ◽

Converting Enzyme ◽

Lead Compounds ◽

Virtual Screening Approach

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.v3 ◽

2021 ◽

Author(s):

Konstantinos Kalamatianos

Keyword(s):

Clinical Trials ◽

Experimental Validation ◽

Antiviral Agents ◽

Spike Protein ◽

Binding Affinities ◽

Converting Enzyme ◽

Lead Compounds ◽

Virtual Screening Approach

<div>E3/03-03-2021<br></div><div>Molecular Dynamics Simulation has been added to E2/21-12-2020<br></div><div><br></div><div><br></div><div><br></div><div><br></div><div>E2/21-12-2020</div><br>In this study FDA approved HCV antiviral drugs and their structural analogues – several of them 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 correspond-ing binding affinities of thirteen such antiretroviral com-pounds 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, relatively higher electrophilicity index, aromatic rings and heteroatoms that participate in hydrogen bonding. Amongst the drugs tested, four compounds 10-13 showed excellent results – binding affinities -11.2 to -11.5 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><br><div><br></div><div>E1/24-08-2020</div><br>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<br>angiotensin converting enzyme 2 (ACE2) (6M0J) using a virtual screening approach and computational chemistry methods. Amongst the drugs tested, four compounds, PubChem CID 492005, CID 486507, CID 3010249 and<br><div>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> </div><div><br></div>

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 ◽

Antiviral Agents ◽

Drug Repurposing ◽

Spike Protein ◽

Frontier Molecular Orbital ◽

Converting Enzyme ◽

Orbital Theory ◽

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>

Testing of natural products in clinical trials targeting the SARS-CoV-2 (Covid-19) viral spike protein-angiotensin converting enzyme-2 (ACE2) interaction

Biochemical Pharmacology ◽

10.1016/j.bcp.2020.114123 ◽

2020 ◽

Vol 178 ◽

pp. 114123 ◽

Cited By ~ 5

Author(s):

Gary Williamson ◽

Asimina Kerimi

Keyword(s):

Clinical Trials ◽

Natural Products ◽

Spike Protein ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2

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):

Molecular Mechanisms ◽

Molecular Design ◽

Binding Free Energy ◽

Transmembrane Protein ◽

Spike Protein ◽

Converting Enzyme ◽

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>

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):

Receptor Binding ◽

Molecular Orbital Calculation ◽

Spike Protein ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Blocking Antibody ◽

Receptor Blocking ◽

Protein Receptor

Blocking Effect of Demethylzeylasteral on the Interaction between Human ACE2 Protein and SARS-CoV-2 RBD Protein Discovered Using SPR Technology

Molecules ◽

10.3390/molecules26010057 ◽

2020 ◽

Vol 26 (1) ◽

pp. 57

Author(s):

Zhi-Ling Zhu ◽

Xiao-Dan Qiu ◽

Shuo Wu ◽

Yi-Tong Liu ◽

Ting Zhao ◽

...

Keyword(s):

Therapeutic Strategy ◽

Blocking Effect ◽

Spike Protein ◽

Binding Affinities ◽

The Novel ◽

Converting Enzyme ◽

Primary Method ◽

Novel Coronavirus ◽

Effective Drugs

The novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019, and there is no sign that the epidemic is abating. Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. In this study, surface plasmon resonance (SPR) was used as the primary method to screen a library of 960 compounds. A compound 02B05 (demethylzeylasteral, CAS number: 107316-88-1) that had high affinities for S-RBD and ACE2 was discovered, and binding affinities (KD, μM) of 02B05-ACE2 and 02B05-S-RBD were 1.736 and 1.039 μM, respectively. The results of a competition experiment showed that 02B05 could effectively block the binding of S-RBD to ACE2 protein. Furthermore, pseudovirus infection assay revealed that 02B05 could inhibit entry of SARS-CoV-2 pseudovirus into 293T cells to a certain extent at nontoxic concentration. The compoundobtained in this study serve as references for the design of drugs which have potential in the treatment of COVID-19 and can thus accelerate the process of developing effective drugs to treat SARS-CoV-2 infections.

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):

Viral Entry ◽

Negative Impact ◽

Spike Protein ◽

Infection Model ◽

Converting Enzyme ◽

Viral Receptor ◽

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.

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 ◽

Spike Protein ◽

Endothelial Barrier ◽

Converting Enzyme ◽

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.

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

Frontiers in Molecular Immunology ◽

10.25082/fmi.2021.01.002 ◽

2021 ◽

Vol 2 (1) ◽

pp. 16-27

Author(s):

Zahra Sharifinia ◽

◽

Samira Asadi ◽

Mahyar Irani ◽

Abdollah Allahverdi ◽

...

Keyword(s):

Virtual Screening ◽

Host Cells ◽

Spike Protein ◽

Potential Drug ◽

Converting Enzyme ◽

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.