scholarly journals Carnosine to Combat Novel Coronavirus (nCoV, COVID-19): Molecular Docking and Modeling to Co-Crystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein

2020 ◽  
Author(s):  
Loai M. Saadah ◽  
Ghina’a I Abu Deiab ◽  
Qosay Al-Balas ◽  
Iman A. Basheti
Keyword(s):  
Molecular Docking ◽  
Angiotensin Converting Enzyme ◽  
Active Site ◽  
Host Cells ◽  
Spike Protein ◽  
Drug Candidate ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Experimental Drugs ◽  
Starting Point

Aims: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. This paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 co-crystallized with COVID-19 spike protein. Methods: First, the starting point was ACE2 inhibitors and their structure-activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. In parallel, at all stages, authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 co-crystallized with COVID-19 spike protein. Results: Carnosine emerged as the best known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the co-crystallized protein structure, carnosine bind with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. Conclusion: Carnosine has promising inhibitory interactions with host ACE2 co-crystallized with COVID-19 spike protein and hence could offer potential mitigating effect against current COVID-19 pandemic.

scholarly journals Carnosine to Combat Novel Coronavirus (nCoV): Molecular Docking and Modeling to Cocrystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5605
Author(s):  
Loai M. Saadah ◽  
Ghina’a I. Abu Deiab ◽  
Qosay Al-Balas ◽  
Iman A. Basheti
Keyword(s):  
Molecular Docking ◽  
Angiotensin Converting Enzyme ◽  
Active Site ◽  
Host Cells ◽  
Spike Protein ◽  
Drug Candidate ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Experimental Drugs ◽  
Starting Point

Aims: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. The current paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 cocrystallized with nCoV spike protein. Methods: First, the starting point was ACE2 inhibitors and their structure–activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. Parallel, at all stages, the authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 with nCoV spike protein. Results: Carnosine emerged as the best-known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the protein–protein structure, carnosine bound with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. Conclusion: Carnosine has promising inhibitory interactions with host ACE2 and nCoV spike protein and hence could offer a potential mitigating effect against the current COVID-19 pandemic.

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 Structural Dissection of Viral Spike-Protein Binding of SARS-CoV-2 and SARS-CoV-1 to the Human Angiotensin-Converting Enzyme 2 (ACE2) as Cellular Receptor

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1038
Author(s):  
Deborah Giordano ◽  
Luigi De Masi ◽  
Maria Antonia Argenio ◽  
Angelo Facchiano
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico Analysis ◽  
Host Cells ◽  
Spike Protein ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
The World ◽  
Silico Analysis

An outbreak by a new severe acute respiratory syndrome betacoronavirus (SARS-CoV-2) has spread CoronaVirus Disease 2019 (COVID-19) all over the world. Immediately, following studies have confirmed the human Angiotensin-Converting Enzyme 2 (ACE2) as a cellular receptor of viral Spike-Protein (Sp) that mediates the CoV-2 invasion into the pulmonary host cells. Here, we compared the molecular interactions of the viral Sp from previous SARS-CoV-1 of 2002 and SARS-CoV-2 with the host ACE2 protein by in silico analysis of the available experimental structures of Sp-ACE2 complexes. The K417 amino acid residue, located in the region of Sp Receptor-Binding Domain (RBD) of the new coronavirus SARS-CoV-2, showed to have a key role for the binding to the ACE2 N-terminal region. The R426 residue of SARS-CoV-1 Sp-RBD also plays a key role, although by interacting with the central region of the ACE2 sequence. Therefore, our study evidenced peculiarities in the interactions of the two Sp-ACE2 complexes. Our outcomes were consistent with previously reported mutagenesis studies on SARS-CoV-1 and support the idea that a new and different RBD was acquired by SARS-CoV-2. These results have interesting implications and suggest further investigations.

scholarly journals Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy?

2020 ◽  
Vol 134 (5) ◽  
pp. 543-545 ◽  
Author(s):  
Daniel Batlle ◽  
Jan Wysocki ◽  
Karla Satchell
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Respiratory Disease ◽  
Host Cells ◽  
Spike Protein ◽  
Cellular Receptor ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Potential Approach ◽  
Recent Outbreak ◽  
Coronavirus Infection

Abstract A new coronavirus, referred to as SARS-CoV-2, is responsible for the recent outbreak of severe respiratory disease. This outbreak first detected in Wuhan, China in December 2019, has spread to other regions of China and to 25 other countries as of January, 2020. It has been known since the 2003 SARS epidemic that the receptor critical for SARS-CoV entry into host cells is the angiotensin-converting enzyme 2 (ACE2). The S1 domain of the spike protein of SARS-CoV attaches the virus to its cellular receptor ACE2 on the host cells. We thought that it is timely to explain the connection between the SARS-CoV, SARS-CoV-2, ACE2 and the rationale for soluble ACE2 as a potential therapy.

scholarly journals Identification of novel inhibitors of Angiotensin-converting enzyme 2 (ACE-2) receptor from Urtica dioica to combat coronavirus disease 2019 (COVID-19)

2020 ◽  
Author(s):  
Shobha Upreti ◽  
Jyoti Sankar Prusty ◽  
Satish Chandra Pandey ◽  
Awanish Kumar ◽  
Mukesh Samant
Keyword(s):  
Molecular Docking ◽  
Angiotensin Converting Enzyme ◽  
Binding Affinity ◽  
Active Site ◽  
Urtica Dioica ◽  
Receptor Protein ◽  
Amino Acid Residues ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Discovery Studio

Abstract The pandemic outbreak of coronavirus (SARS-CoV-2) is rapidly spreading across the globe, so the development of anti-SARS-CoV-2 agents is urgently needed. Angiotensin-converting enzyme 2 (ACE-2), a human receptor that facilitates entry of SARS-CoV-2, serves as a prominent target for drug discovery. In the present study, we have applied the bioinformatics approach for screening of a series of bioactive chemical compounds from Himalayan stinging nettle (Urtica dioica) as potent inhibitors of ACE-2 receptor (PDB ID: 1R4L). The molecular docking was applied to dock a set of representative compounds within the active site region of target receptor protein using 0.8 version of the PyRx virtual screen tool and analyzed by using discovery studio visualizer. Based on the highest binding affinity, 16 compounds were shortlisted as a lead molecule using molecular docking analysis. Among them, β-sitosterol was found with the highest binding affinity -12.2 Kcal/mol and stable interactions with the amino acid residues present on the active site of the ACE-2 receptor. Similarly, Luteoxanthin and Violaxanthin followed by rutin also displayed stronger binding efficiency. We propose these compounds as potential lead candidates for the development of target specific therapeutic drugs against COVID-19.

Cytoplasmic domain and enzymatic activity of ACE2 is not required for PI4KB dependent endocytosis entry of SARS-CoV-2 into host cells

2021 ◽  
Author(s):  
Hang Yang ◽  
Xiaohui Zhao ◽  
Meng Xun ◽  
Lingjie Xu ◽  
Bing Liu ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Angiotensin Converting Enzyme ◽  
Essential Role ◽  
Virus Entry ◽  
Host Cells ◽  
Spike Protein ◽  
Cellular Receptor ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Cellular Entry

AbstractThe recent COVID-19 pandemic poses a global health emergency. Cellular entry of the causative agent SARS-CoV-2 is mediated by its spike protein interacting with cellular receptor- human angiotensin converting enzyme 2 (ACE2). Here, we used lentivirus based pseudotypes bearing spike protein to demonstrate that entry of SARS-CoV-2 into host cells is dependent on clathrin-mediated endocytosis, and phosphoinositides play essential role during this process. In addition, we showed that the intracellular domain and the catalytic activity of ACE2 is not required for efficient virus entry. These results provide new insights into SARS-CoV-2 cellular entry and present potential targets for drug development.

scholarly journals Network proteins of angiotensin-converting enzyme 2 but not angiotensin-converting enzyme 2 itself are host cell receptors for SARS-Coronavirus-2 attachment

2020 ◽  
Author(s):  
Arun Kumar
Keyword(s):  
Molecular Docking ◽  
Angiotensin Converting Enzyme ◽  
Host Cell ◽  
Binding Affinity ◽  
Surface Proteins ◽  
Host Cells ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Cell Receptors ◽  
Dpp4 Inhibitors

Abstract Background: Coronaviruses causing severe acute respiratory syndrome (SARS-CoV) are known to enter the host cells by attaching to the membrane bound angiotensin-converting enzyme 2 (ACE2). Using molecular docking the efficiency of interaction between SARS-CoV-2 surface proteins and ACE2 network proteins was assessed. Materials and Methods: The ACE2 protein network was identified using the STRING database. The reported SARS-CoV-2 target proteins were searched in the protein data bank and uniport database. The protein-protein interactions were assessed by molecular docking using the Chimera software. The PubChem database was searched for known inhibitors of host cell receptors interacting with SARS-CoV-2 surface proteins. Molecular docking was performed to evaluate the binding efficacy of these compounds against the SARS-CoV-2 targets using AutoDock Vina and the docked protein-ligand complex were visualised using the Chimera and PyMOL software. Results: A low binding affinity was observed between SARS-CoV-2 spike proteins (protein S, M and 6YLA) and ACE2. Coronaviruses are also reported to bind to dipeptidyl peptidase 4 (DPP4), which is a network protein of ACE2. Network analysis showed five membrane proteins associated with ACE2. The ACE2 network proteins were assessed for their binding affinity with all known SARS-CoV-2 surface proteins. The SARS-CoV-2 surface proteins showed preferential binding to network proteins such as DPP4 and Meprin A alpha but not ACE2. The binding efficacy (affinity (-5.86 to -7.10 Kcal/mol), Ki (6.32 – 22.04 mM) and IC50 (12.63 – 113.71 mM) values) of DPP4 inhibitors (saxagliptin and sitagliptin) against SARS-CoV-2 surface proteins, was observed to be at a therapeutically feasible concentration to prevent SARS-CoV-2 attachment and entry into host cells. Conclusion: SARS-CoV-2 surface proteins has better interactions with DPP4 and Meprin A alpha host cells receptors rather than ACE2. DPP4 inhibitors (saxagliptin and sitagliptin) by binding with SARS-CoV-2 surface proteins may be helpful in preventing the virus entry into the host cells.

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>

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

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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