Targeting SARS-CoV-2 Spike Protein of COVID-19 with Naturally Occurring Phytochemicals: An in Silco Study for Drug Development

2020 ◽  
Author(s):  
Jitendra Subhash Rane ◽  
Aroni Chatterjee ◽  
Abhijeet Kumar ◽  
Shashikant Ray
Keyword(s):  
Receptor Binding ◽  
Docking Study ◽  
Binding Energies ◽  
Host Cells ◽  
Spike Protein ◽  
Molecular Docking Study ◽  
Angiotensin Converting Enzyme 2 ◽  
Naturally Occurring

<p>Spike glycoprotein found on the surface of SARS-CoV-2 (SARS-CoV-2S) is a class I fusion protein which helps the virus in its initial attachment with human Angiotensin converting enzyme 2 (ACE2) receptor and its consecutive fusion with the host cells. The attachment is mediated by the S1 subunit of the protein via its receptor binding domain. Upon binding with the receptor the protein changes its conformation from a pre-fusion to a post-fusion form. The membrane fusion and internalization of the virus is brought about by the S2 domain of the spike protein. From ancient times people have relied on naturally occurring substances like phytochemicals to fight against diseases and infection. Among these phytochemicals, flavonoids and non-flavonoids have been found to be the active source of different anti-microbial agents. Recently, studies have shown that these phytochemicals have essential anti-viral activities. We performed a molecular docking study using 10 potential naturally occurring flavonoids/non-flavonoids against the SARS-CoV-2 spike protein and compared their affinity with the FDA approved drug hydroxychloroquine (HCQ). Interestingly, the docking analysis suggested that C-terminal of S1 domain and S2 domain of the spike protein are important for binding with these compounds. Kamferol, curcumin, pterostilbene, and HCQ interact with the C-terminal of S1 domain with binding energies of -7.4, -7.1, -6.7 and -5.6 Kcal/mol, respectively. Fisetin, quercetin, isorhamnetin, genistein, luteolin, resveratrol<b> </b>and apigenin on the other hand, interact with the S2 domain of spike protein with the binding energies of -8.5, -8.5, -8.3, -8.2, -8.2, -7.9, -7.7 Kcal/mol, respectively. Our study suggested that, these flavonoid and non-flavonoid moieties have significantly high binding affinity for the two main important domains of the spike protein which is responsible for the attachment and internalization of the virus in the host cell and their binding affinities are much higher compared to that of HCQ. In addition, ADME (absorption, distribution, metabolism and excretion) analysis also suggested that these compounds consist of drug likeness property which may help for further explore as anti-SARS-CoV-2 agents. Further, <i>in vitro</i> and <i>in vivo</i> study of these compounds will provide a clear path for the development of novel compounds that would most likely prevent the receptor binding or internalization of the SARS-CoV-2 spike protein and therefore could be used as drugs for COVID-19 therapy. </p>

Targeting SARS-CoV-2 Spike Protein of COVID-19 with Naturally Occurring Phytochemicals: An in Silco Study for Drug Development

2020 ◽  
Author(s):  
Jitendra Subhash Rane ◽  
Aroni Chatterjee ◽  
Abhijeet Kumar ◽  
Shashikant Ray
Keyword(s):  
Receptor Binding ◽  
Docking Study ◽  
Binding Energies ◽  
Host Cells ◽  
Spike Protein ◽  
Molecular Docking Study ◽  
Angiotensin Converting Enzyme 2 ◽  
Naturally Occurring

<p>Spike glycoprotein found on the surface of SARS-CoV-2 (SARS-CoV-2S) is a class I fusion protein which helps the virus in its initial attachment with human Angiotensin converting enzyme 2 (ACE2) receptor and its consecutive fusion with the host cells. The attachment is mediated by the S1 subunit of the protein via its receptor binding domain. Upon binding with the receptor the protein changes its conformation from a pre-fusion to a post-fusion form. The membrane fusion and internalization of the virus is brought about by the S2 domain of the spike protein. From ancient times people have relied on naturally occurring substances like phytochemicals to fight against diseases and infection. Among these phytochemicals, flavonoids and non-flavonoids have been found to be the active source of different anti-microbial agents. Recently, studies have shown that these phytochemicals have essential anti-viral activities. We performed a molecular docking study using 10 potential naturally occurring flavonoids/non-flavonoids against the SARS-CoV-2 spike protein and compared their affinity with the FDA approved drug hydroxychloroquine (HCQ). Interestingly, the docking analysis suggested that C-terminal of S1 domain and S2 domain of the spike protein are important for binding with these compounds. Kamferol, curcumin, pterostilbene, and HCQ interact with the C-terminal of S1 domain with binding energies of -7.4, -7.1, -6.7 and -5.6 Kcal/mol, respectively. Fisetin, quercetin, isorhamnetin, genistein, luteolin, resveratrol<b> </b>and apigenin on the other hand, interact with the S2 domain of spike protein with the binding energies of -8.5, -8.5, -8.3, -8.2, -8.2, -7.9, -7.7 Kcal/mol, respectively. Our study suggested that, these flavonoid and non-flavonoid moieties have significantly high binding affinity for the two main important domains of the spike protein which is responsible for the attachment and internalization of the virus in the host cell and their binding affinities are much higher compared to that of HCQ. In addition, ADME (absorption, distribution, metabolism and excretion) analysis also suggested that these compounds consist of drug likeness property which may help for further explore as anti-SARS-CoV-2 agents. Further, <i>in vitro</i> and <i>in vivo</i> study of these compounds will provide a clear path for the development of novel compounds that would most likely prevent the receptor binding or internalization of the SARS-CoV-2 spike protein and therefore could be used as drugs for COVID-19 therapy. </p>

scholarly journals Stereotypic neutralizing VH antibodies against SARS-CoV-2 spike protein receptor binding domain in COVID-19 patients and healthy individuals

2021 ◽  
pp. eabd6990
Author(s):  
Sang Il Kim ◽  
Jinsung Noh ◽  
Sujeong Kim ◽  
Younggeun Choi ◽  
Duck Kyun Yoo ◽  
...  
Keyword(s):  
B Cells ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Binding Domain ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Healthy Individuals

Stereotypic antibody clonotypes exist in healthy individuals and may provide protective immunity against viral infections by neutralization. We observed that 13 out of 17 patients with COVID-19 had stereotypic variable heavy chain (VH) antibody clonotypes directed against the receptor-binding domain (RBD) of SARS-CoV-2 spike protein. These antibody clonotypes were comprised of immunoglobulin heavy variable (IGHV)3-53 or IGHV3-66 and immunoglobulin heavy joining (IGHJ)6 genes. These clonotypes included IgM, IgG3, IgG1, IgA1, IgG2, and IgA2 subtypes and had minimal somatic mutations, which suggested swift class switching after SARS-CoV-2 infection. The different immunoglobulin heavy variable chains were paired with diverse light chains resulting in binding to the RBD of SARS-CoV-2 spike protein. Human antibodies specific for the RBD can neutralize SARS-CoV-2 by inhibiting entry into host cells. We observed that one of these stereotypic neutralizing antibodies could inhibit viral replication in vitro using a clinical isolate of SARS-CoV-2. We also found that these VH clonotypes existed in six out of 10 healthy individuals, with IgM isotypes predominating. These findings suggest that stereotypic clonotypes can develop de novo from naïve B cells and not from memory B cells established from prior exposure to similar viruses. The expeditious and stereotypic expansion of these clonotypes may have occurred in patients infected with SARS-CoV-2 because they were already present.

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.

DOCKING STUDY OF NOVEL N-SUBSTITUTED 2,5-BIS[(7-CHLOROQUINOLIN-4-YL)AMINO]PENTANOIC DERIVATIVES AS SELECTIVE HIGH-BINDER WITH ANGIOTENSIN CONVERTING ENZYME 2

INDIAN DRUGS ◽  
2020 ◽  
Vol 57 (08) ◽  
pp. 16-24
Author(s):  
Mohammed Oday Ezzat ◽  
Basma M. Abd Razik ◽  
Kutayba F. Dawood
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Active Site ◽  
Docking Study ◽  
World Health ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Pharmaceutical Properties ◽  
Novel Coronavirus

The prevalence of a novel coronavirus (2019-nCoV) in the last few months represents a serious threat as a world health emergency concern. Angiotensin-converting enzyme 2 (ACE2) is the host cellular receptor for the respiratory syndrome of coronavirus epidemic in 2019 (2019-nCoV). In this work, the active site of ACE2 is successfully located by Sitmap prediction tool and validated by different marketed drugs. To design and discover new medical countermeasure drugs, we evaluate a total of 184 molecules of 7-chloro-N-methylquinolin-4-amine derivatives for binding affinity inside the crystal structure of ACE2 located active site. A novel series of N-substituted 2,5-bis[(7-chloroquinolin-4-yl)amino]pentanoic acid derivatives is generated and evaluated for a prospect as a lead compound for (2019-nCoV) medication with a docking score range of (-10.60 to -8.99) kcal/mol for the highest twenty derivatives. Moreover, the ADME pharmaceutical properties were evaluated for further proposed experimental evaluation in vitro or in vivo

scholarly journals Identification of Common Deletions in the Spike Protein of Severe Acute Respiratory Syndrome Coronavirus 2

2020 ◽  
Vol 94 (17) ◽  
Author(s):  
Zhe Liu ◽  
Huanying Zheng ◽  
Huifang Lin ◽  
Mingyue Li ◽  
Runyu Yuan ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Virus Replication ◽  
Receptor Binding ◽  
Cleavage Site ◽  
Spike Protein ◽  
Clinical Samples ◽  
Receptor Binding Domain ◽  
Flanking Sequence

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus first identified in December 2019. Notable features that make SARS-CoV-2 distinct from most other previously identified betacoronaviruses include a receptor binding domain and a unique insertion of 12 nucleotides or 4 amino acids (PRRA) at the S1/S2 boundary. In this study, we identified two deletion variants of SARS-CoV-2 that either directly affect the polybasic cleavage site itself (NSPRRAR) or a flanking sequence (QTQTN). These deletions were verified by multiple sequencing methods. In vitro results showed that the deletion of NSPRRAR likely does not affect virus replication in Vero and Vero-E6 cells; however, the deletion of QTQTN may restrict late-phase viral replication. The deletion of QTQTN was detected in 3 of 68 clinical samples and 12 of 24 in vitro-isolated viruses, while the deletion of NSPRRAR was identified in 3 in vitro-isolated viruses. Our data indicate that (i) there may be distinct selection pressures on SARS-CoV-2 replication or infection in vitro and in vivo; (ii) an efficient mechanism for deleting this region from the viral genome may exist, given that the deletion variant is commonly detected after two rounds of cell passage; and (iii) the PRRA insertion, which is unique to SARS-CoV-2, is not fixed during virus replication in vitro. These findings provide information to aid further investigation of SARS-CoV-2 infection mechanisms and a better understanding of the NSPRRAR deletion variant observed here. IMPORTANCE The spike protein determines the infectivity and host range of coronaviruses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has two unique features in its spike protein, the receptor binding domain and an insertion of 12 nucleotides at the S1/S2 boundary resulting in a furin-like cleavage site. Here, we identified two deletion variants of SARS-CoV-2 that either directly affect the furin-like cleavage site itself (NSPRRAR) or a flanking sequence (QTQTN), and we investigated these deletions in cell isolates and clinical samples. The absence of the polybasic cleavage site in SARS-CoV-2 did not affect virus replication in Vero or Vero-E6 cells. Our data indicate the PRRAR sequence and the flanking QTQTN sequence are not fixed in vitro; thus, there appears to be distinct selection pressures on SARS-CoV-2 sequences in vitro and in vivo. Further investigation of the mechanism of generating these deletion variants and their infectivity in different animal models would improve our understanding of the origin and evolution of this virus.

scholarly journals Identification of Potent Inhibitors of COVID-19 Main Protease Enzyme by Molecular Docking Study

2020 ◽  
Author(s):  
pooja singh ◽  
Angkita Sharma ◽  
Shoma Paul Nandi
Keyword(s):  
Molecular Docking ◽  
Antiviral Drug ◽  
Cyclopiazonic Acid ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Docking Score ◽  
Protease Enzyme ◽  
Main Protease

<p>Within the span of a few months, the severe acute respiratory syndrome coronavirus, COVID-19 (SARS-CoV-2), has proven to be a pandemic, affecting the world at an exponential rate. It is extremely pathogenic and causes communicable infection in humans. Viral infection causes difficulties in breathing, sore throat, cough, high fever, muscle pain, diarrhea, dyspnea, and may lead to death. Finding a proper drug and vaccines against this virus is the need of the hour. The RNA genome of COVID19 codes for the main protease M<sup>pro</sup>, which is required for viral multiplication. To identify possible antiviral drug(s), we performed molecular docking studies. Our screen identified ten biomolecules naturally present in <i>Aspergillus flavus</i> and <i>Aspergillus oryzae</i> fungi. These molecules include Aspirochlorine, Aflatoxin B1, Alpha-Cyclopiazonic acid, Sporogen, Asperfuran, Aspergillomarasmine A, Maltoryzine, Kojic acid, Aflatrem and Ethyl 3-nitropropionic acid, arranged in the descending order of their docking score. Aspirochlorine exhibited the docking score of – 7.18 Kcal/mole, higher than presently used drug Chloroquine (-6.2930522 Kcal/mol) and out of ten ligands studied four has docking score higher than chloroquine. These natural bioactive compounds could be tested for their ability to inhibit viral growth <i>in- vitro</i> and <i>in-vivo</i>.<b> </b></p>

scholarly journals Molecular Docking Studies of Curcumin Analogues against SARS-CoV-2 Spike Protein

2021 ◽  
Author(s):  
Jéssica Nogueira ◽  
Flávia Verza ◽  
Felipe Nishimura ◽  
Umashankar Das ◽  
Ícaro Caruso ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Virus Disease ◽  
Etiologic Agent ◽  
Host Cells ◽  
Spike Protein ◽  
Therapeutic Effects ◽  
Host Cell Membrane ◽  
Curcumin Analogues

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the etiologic agent of the current pandemic of corona virus disease 2019 (COVID-19) that has inflicted the loss of thousands of lives worldwide. The coronavirus surface spike (S) glycoprotein is a class I fusion with a S1 domain which is attached to the human angiotensin converting enzyme 2 (ACE2) receptor, and a S2 domain which enables fusion with the host cell membrane and internalization of the virus. Curcumin has been suggested as a potential drug to control inflammation and as a potential inhibitor of S protein, but its therapeutic effects are hampered by poor bioavailability. We performed a molecular docking and dynamic study using 94 curcumin analogues designed to have improved metabolic stability against the SARS-CoV-2 spike protein and compared their affinity with curcumin and other potential inhibitors. The docking analysis suggested that the S2 domain is the main target of these compounds and compound 2606 displayed a higher binding affinity (-9.6 kcal mol-1) than curcumin (-6.8 kcal mol-1) and the Food and Drug Administration (FDA) approved drug hydroxychloroquine (-6.3 kcal mol-1). Further additional validation in vitro and in vivo of these compounds against SARS-CoV-2 may provide insights into the development of a drug that prevents virus entry into host cells.

scholarly journals In-vivo Protection from SARS-CoV-2 infection by ATN-161 in k18-hACE2 transgenic mice

2021 ◽  
Author(s):  
Amruta Narayanappa ◽  
Elizabeth B Engler-Chiurazzi ◽  
Isabel C Murray-Brown ◽  
Timothy E Gressett ◽  
Ifechukwude J Biose ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Viral Entry ◽  
Therapeutic Potential ◽  
Host Cells ◽  
Spike Protein ◽  
Cell Infection ◽  
Integrin Alpha5beta1 ◽  
Chemokine Ligand

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an infectious disease that has spread worldwide. Current treatments are limited in both availability and efficacy, such that improving our understanding of the factors that facilitate infection is urgently needed to more effectively treat infected individuals and to curb the pandemic. We and others have previously demonstrated the significance of interactions between the SARS-CoV-2 spike protein, integrin alpha5beta1 and human ACE2 to facilitate viral entry into host cells in vitro. We previously found that inhibition of integrin alpha5beta1 by the clinically validated small peptide ATN-161 inhibits these spike protein interactions and cell infection in vitro. In continuation with our previous findings, here we have further evaluated the therapeutic potential of ATN-161 on SARS-CoV-2 infection in k18-hACE2 transgenic (SARS-CoV-2 susceptible) mice in vivo. We discovered that treatment with single- or repeated intravenous doses of ATN-161 (1 mg/kg) within 48 hours after intranasal inoculation with SARS-CoV-2 lead to a reduction of lung viral load, viral immunofluorescence and improved lung histology in a majority of mice 72 hours post-infection. Furthermore, ATN-161 reduced SARS-CoV-2-induced increased expression of lung integrin alpha 5 and alpha v (an alpha 5-related integrin that has also been implicated in SARS-CoV-2 interactions) as well as the C-X-C motif chemokine ligand 10 (Cxcl10), further supporting the potential involvement of these integrins, and the anti-inflammatory potential of ATN-161, respectively, in SARS-CoV-2 infection. To the best of our knowledge, this is the first study demonstrating the potential therapeutic efficacy of targeting integrin alpha5beta1 in SARS-CoV-2 infection in vivo and supports the development of ATN-161 as a novel SARS-CoV-2 therapy.

scholarly journals Investigation of interaction between close and open types of SARS-Cov-2 spike glycoprotein with synthesized and natural Compounds as inhibitor; Molecular Docking Study

2020 ◽  
Author(s):  
Masume Jomhori ◽  
Hamid Mosaddeghi
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Antiviral Drug ◽  
Severe Infection ◽  
Docking Study ◽  
Spike Protein ◽  
Spike Glycoprotein ◽  
Molecular Docking Study ◽  
Antiviral Compound ◽  
Pubchem Database

Abstract Purpose Viral diseases are increasingly endangering universal public health because of a shortage of successful antiviral therapies. The novel pandemic 2019 n-Cov2 disease (COVID-19) is recently identified as viral disorder triggered by a new type of coronavirus. This type of coronavirus binds to the host human receptors through the Spike glycoprotein(S) Receptor Binding Domain (RBD). Two types of spike protein have been identified in open and closed states in which the open type causes severe infection. Thus, this receptor is a significant target for antiviral drug design.Methods Totally 111*2 natural and synthetic compounds were chosen from the PubChem database as ligands. To recognize the ability of direct contact between ligands and the binding site of 2019 n-Cov 2 -ACE2 protein, we have docked all compounds to the protein using AutoDock Vina. The FaF3-Drugs, Pan Assay Intrusion Compounds (PAINS), absorption, distribution, metabolism, excretion (ADME) and Lipinski's rules were used to evaluate the drug-like properties of the identified ligands. Antiviral compound prediction (AVC pred) also was used to assess antivirus properties.Results The results showed that seven ligands out of all had interactions with spike protein-angiotensin converting enzyme 2 binding site. We have found that six out of seven ligands show drug-like characteristics. We also found that the fluorophenyl and propane groups of ligands had the best interaction with the binding site of the protein.Conclusion Further, our results showed the ability of these ligands to prevent receptor binding of the spike protein SARS-CoV-2, so they would be considered as novel compounds of COVID-19 therapy drugs.

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