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 Prediction of Off-Target Effects on Angiotensin-Converting Enzyme 2

2011 ◽  
Vol 16 (8) ◽  
pp. 878-885 ◽  
Author(s):  
Lidia V. Kulemina ◽  
David A. Ostrov
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Catalytic Efficiency ◽  
Converting Enzyme ◽  
Chemical Library ◽  
Angiotensin Converting Enzyme 2 ◽  
Specific Proteins ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Target Effects

The authors describe a structure-based strategy to identify therapeutically beneficial off-target effects by screening a chemical library of Food and Drug Administration (FDA)–approved small-molecule drugs matching pharmacophores defined for specific target proteins. They applied this strategy to angiotensin-converting enzyme 2 (ACE2), an enzyme that generates vasodilatory peptides and promotes protection from hypertension-associated cardiovascular disease. The conformation-based structural selection method by molecular docking using DOCK allowed them to identify a series of FDA-approved drugs that enhance catalytic efficiency of ACE2 in vitro. These data demonstrate that libraries of approved drugs can be rapidly screened to identify potential side effects due to interactions with specific proteins other than the intended targets.

scholarly journals Target-Centered Drug Repurposing Predictions of Human Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Protease Serine Subtype 2 (TMPRSS2) Interacting Approved Drugs for Coronavirus Disease 2019 (COVID-19) Treatment through a Drug-Target Interaction Deep Learning Model

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1325
Author(s):  
Yoonjung Choi ◽  
Bonggun Shin ◽  
Keunsoo Kang ◽  
Sungsoo Park ◽  
Bo Ram Beck
Keyword(s):  
Deep Learning ◽  
Angiotensin Converting Enzyme ◽  
Drug Target ◽  
Expression Profiles ◽  
Drug Repurposing ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Target Interaction ◽  
Approved Drugs ◽  
Fda Approved Drugs

Previously, our group predicted commercially available Food and Drug Administration (FDA) approved drugs that can inhibit each step of the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI). Unfortunately, additional clinically significant treatment options since the approval of remdesivir are scarce. To overcome the current coronavirus disease 2019 (COVID-19) more efficiently, a treatment strategy that controls not only SARS-CoV-2 replication but also the host entry step should be considered. In this study, we used MT-DTI to predict FDA approved drugs that may have strong affinities for the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease serine 2 (TMPRSS2) which are essential for viral entry to the host cell. Of the 460 drugs with Kd of less than 100 nM for the ACE2 receptor, 17 drugs overlapped with drugs that inhibit the interaction of ACE2 and SARS-CoV-2 spike reported in the NCATS OpenData portal. Among them, enalaprilat, an ACE inhibitor, showed a Kd value of 1.5 nM against the ACE2. Furthermore, three of the top 30 drugs with strong affinity prediction for the TMPRSS2 are anti-hepatitis C virus (HCV) drugs, including ombitasvir, daclatasvir, and paritaprevir. Notably, of the top 30 drugs, AT1R blocker eprosartan and neuropsychiatric drug lisuride showed similar gene expression profiles to potential TMPRSS2 inhibitors. Collectively, we suggest that drugs predicted to have strong inhibitory potencies to ACE2 and TMPRSS2 through the DTI model should be considered as potential drug repurposing candidates for COVID-19.

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 Stapled peptides based on Human Angiotensin-Converting Enzyme 2 (ACE2) potently inhibit SARS-CoV-2 infection in vitro

2020 ◽  
Author(s):  
Francesca Curreli ◽  
Sofia M B Victor ◽  
Shahad Ahmed ◽  
Aleksandra Drelich ◽  
Xiaohe Tong ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Angiotensin Converting Enzyme ◽  
Host Cells ◽  
Converting Enzyme ◽  
Stapled Peptides ◽  
Angiotensin Converting Enzyme 2 ◽  
Stapled Peptide ◽  
Human Lung Cells ◽  
Critical Binding

AbstractSARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as the primary receptor to enter host cells and initiate the infection. The critical binding region of ACE2 is a ∼30 aa long helix. Here we report the design of four stapled peptides based on the ACE2 helix, which is expected to bind to SARS-CoV-2 and prevent the binding of the virus to the ACE2 receptor and disrupt the infection. All stapled peptides showed high helical contents (50-94% helicity). On the contrary, the linear control peptide NYBSP-C showed no helicity (19%). We have evaluated the peptides in a pseudovirus based single-cycle assay in HT1080/ACE2 and human lung cells A549/ACE2, overexpressing ACE2. Three of the four stapled peptides showed potent antiviral activity in HT1080/ACE2 (IC50: 1.9 – 4.1 µM) and A549/ACE2 cells (IC50: 2.2 – 2.8 µM). The linear peptides NYBSP-C and the double-stapled peptide StRIP16, used as controls, showed no antiviral activity. Most significantly, none of the stapled peptides show any cytotoxicity at the highest dose tested. We also evaluated the antiviral activity of the peptides by infecting Vero E6 cells with the replication-competent authentic SARS-CoV-2 (US_WA-1/2020). NYBSP-1 was the most efficient preventing the complete formation of cytopathic effects (CPEs) at an IC100 17.2 µM. NYBSP-2 and NYBSP-4 also prevented the formation of the virus-induced CPE with an IC100 of about 33 µM. We determined the proteolytic stability of one of the most active stapled peptides, NYBSP-4, in human plasma, which showed a half-life (T1/2) of >289 min.

scholarly journals Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2

Science ◽  
2020 ◽  
Vol 369 (6508) ◽  
pp. 1261-1265 ◽  
Author(s):  
Kui K. Chan ◽  
Danielle Dorosky ◽  
Preeti Sharma ◽  
Shawn A. Abbasi ◽  
John M. Dye ◽  
...  
Keyword(s):  
Host Cells ◽  
Viral Escape ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity ◽  
Decoy Receptors ◽  
Catalytically Active ◽  
Interaction Surface

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds angiotensin-converting enzyme 2 (ACE2) on host cells to initiate entry, and soluble ACE2 is a therapeutic candidate that neutralizes infection by acting as a decoy. By using deep mutagenesis, mutations in ACE2 that increase S binding are found across the interaction surface, in the asparagine 90–glycosylation motif and at buried sites. The mutational landscape provides a blueprint for understanding the specificity of the interaction between ACE2 and S and for engineering high-affinity decoy receptors. Combining mutations gives ACE2 variants with affinities that rival those of monoclonal antibodies. A stable dimeric variant shows potent SARS-CoV-2 and -1 neutralization in vitro. The engineered receptor is catalytically active, and its close similarity with the native receptor may limit the potential for viral escape.

scholarly journals Natural Flavonoids as Potential Angiotensin-Converting Enzyme 2 Inhibitors for Anti-SARS-CoV-2

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3980 ◽  
Author(s):  
Muchtaridi Muchtaridi ◽  
M. Fauzi ◽  
Nur Kusaira Khairul Ikram ◽  
Amirah Mohd Gazzali ◽  
Habibah A. Wahab
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Host Cells ◽  
Angiotensin Converting Enzyme Inhibition ◽  
Converting Enzyme ◽  
Mortality And Morbidity ◽  
Angiotensin Converting Enzyme 2 ◽  
Arterial Blood ◽  
Potential Efficacy ◽  
Novel Coronavirus

Over the years, coronaviruses (CoV) have posed a severe public health threat, causing an increase in mortality and morbidity rates throughout the world. The recent outbreak of a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the current Coronavirus Disease 2019 (COVID-19) pandemic that affected more than 215 countries with over 23 million cases and 800,000 deaths as of today. The situation is critical, especially with the absence of specific medicines or vaccines; hence, efforts toward the development of anti-COVID-19 medicines are being intensively undertaken. One of the potential therapeutic targets of anti-COVID-19 drugs is the angiotensin-converting enzyme 2 (ACE2). ACE2 was identified as a key functional receptor for CoV associated with COVID-19. ACE2, which is located on the surface of the host cells, binds effectively to the spike protein of CoV, thus enabling the virus to infect the epithelial cells of the host. Previous studies showed that certain flavonoids exhibit angiotensin-converting enzyme inhibition activity, which plays a crucial role in the regulation of arterial blood pressure. Thus, it is being postulated that these flavonoids might also interact with ACE2. This postulation might be of interest because these compounds also show antiviral activity in vitro. This article summarizes the natural flavonoids with potential efficacy against COVID-19 through ACE2 receptor inhibition.

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 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 Ceftazidime Is a Potential Drug to Inhibit SARS-CoV-2 Infection In Vitro by Blocking Spike Protein-ACE2 Interaction

2020 ◽  
Author(s):  
ChangDong Lin ◽  
Yue Li ◽  
MengYa Yuan ◽  
MengWen Huang ◽  
Cui Liu ◽  
...  
Keyword(s):  
Small Molecules ◽  
High Throughput Screening ◽  
Inhibitory Concentration ◽  
Cell Entry ◽  
Host Cells ◽  
First Line ◽  
Angiotensin Converting Enzyme 2 ◽  
Approved Drugs ◽  
Fda Approved Drugs

SUMMARYCoronavirus Disease 2019 (COVID-19) spreads globally as a sever pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cell entry of SARS-CoV-2 mainly depends on binding of the viral spike (S) proteins to angiotensin converting enzyme 2 (ACE2) on host cells. Therefore, repurposing of known drugs to inhibit S protein-ACE2 interaction could be a quick way to develop effective therapy for COVID-19. Using a high-throughput screening system to investigate the interaction between spike receptor binding domain (S-RBD) and ACE2 extracellular domain, we screened 3581 FDA-approved drugs and natural small molecules and identified ceftazidime as a potent compound to inhibit S-RBD–ACE2 interaction by binding to S-RBD. In addition to significantly inhibit S-RBD binding to HPAEpiC cells, ceftazidime efficiently prevented SARS-CoV-2 pseudovirus to infect ACE2-expressing 293T cells. The inhibitory concentration (IC50) was 113.2 μM, which is far below the blood concentration (over 300 μM) of ceftazidime in patients when clinically treated with recommended dose. Notably, ceftazidime is a drug clinically used for the treatment of pneumonia with minimal side effects compared with other antiviral drugs. Thus, ceftazidime has both anti-bacterial and anti-SARS-CoV-2 effects, which should be the first-line antibiotics used for the clinical treatment of COVID-19.

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.

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