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1.
Molecules ; 25(20)2020 Oct 12.
Article in English | MEDLINE | ID: covidwho-1389460

ABSTRACT

Docking of over 160 aminothiourea derivatives at the SARS-CoV-2 S-protein-human ACE2 receptor interface, whose structure became available recently, has been evaluated for its complex stabilizing potency and subsequently subjected to quantitative structure-activity relationship (QSAR) analysis. The structural variety of the studied compounds, that include 3 different forms of the N-N-C(S)-N skeleton and combinations of 13 different substituents alongside the extensive length of the interface, resulted in the failure of the QSAR analysis, since different molecules were binding to different parts of the interface. Subsequently, absorption, distribution, metabolism, and excretion (ADME) analysis on all studied compounds, followed by a toxicity analysis using statistical models for selected compounds, was carried out to evaluate their potential use as lead compounds for drug design. Combined, these studies highlighted two molecules among the studied compounds, i.e., 5-(pyrrol-2-yl)-2-(2-methoxyphenylamino)-1,3,4-thiadiazole and 1-(cyclopentanoyl)-4-(3-iodophenyl)-thiosemicarbazide, as the best candidates for the development of future drugs.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/isolation & purification , Coronavirus Infections/drug therapy , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/drug therapy , Protein Interaction Domains and Motifs/drug effects , Semicarbazides/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2 , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/virology , Humans , Models, Statistical , Molecular Structure , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Protein Conformation , Quantitative Structure-Activity Relationship , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
2.
Mini Rev Med Chem ; 21(6): 689-703, 2021.
Article in English | MEDLINE | ID: covidwho-1150627

ABSTRACT

BACKGROUND: COVID-19 has become a pandemic with higher morbidity and mortality rates after its start from Wuhan city of China. The infection by RNA virus, also known as SARS-CoV-2 or 2019-nCoV, from the beta class of coronaviruses, has been found to be responsible for COVID-19. Structural analysis and evidences have been indicated that interaction between a segment of receptor binding domain (RBD) from S protein of the virus and human angiotensin-converting enzyme 2 (hACE2) is essential for cellular entry of the virus. OBJECTIVE: The current review sheds light on structural aspects for the inhibition of RBD-hACE2 interaction mediated cellular entry of SARS-CoV-2. METHODS: The present study provides a critical review of recently published information on RBDhACE2 interaction and its inhibitors to control SARS-CoV-2 infection. The review highlighted the structural aspects of the interaction between RBD-hACE2 and involved amino acid residues. RESULTS: Recently, several studies are being conducted for the inhibition of the SARS-CoV-2 attachment and entry to the human cellular system. One of the important targets for viral invasion is its binding with cell surface receptor, hACE2, through RBD on S-protein. Mimicking of three residues on ACE2 (Lys31, Glu35 and Lys353 on B chain) provided a hot target directed strategy for the inhibition of early attachment of the virus to the cell. Early screening of peptidic or non-peptidic molecules for the inhibition of RBD-hACE2 interaction has raised the hope for potential therapeutics against COVID-19. The higher affinity of molecules toward RBD than ACE2 is an important factor for selectivity and minimization of ACE2 related adverse events on the cardiovascular system, brain, kidney, and foetus development during pregnancy. CONCLUSION: Inhibition of RBD-hACE2 interaction by different molecular scaffolds can be used as a preferred strategy for control of SARS-CoV-2 infection. Recently, published reports pointed out Lys31, Glu35 and Lys353 on the B chain of ACE2 as crucial residues for mimicking and design of novel molecules as inhibitors SARS-CoV-2 attachment to human cells. Moreover, some recently identified RBD-hACE2 interaction inhibitors have also been described with their protein binding pattern and potencies (IC50 values), which will help for further improvement in the selectivity.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , Protein Binding/drug effects , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemistry , COVID-19/metabolism , Drug Design , Drug Discovery/methods , Humans , Molecular Docking Simulation , Protein Conformation/drug effects , Protein Interaction Domains and Motifs/drug effects , Protein Interaction Maps/drug effects , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Virus Internalization/drug effects
3.
Angew Chem Int Ed Engl ; 60(18): 10279-10285, 2021 04 26.
Article in English | MEDLINE | ID: covidwho-1122115

ABSTRACT

The receptor binding domain (RBD) of the spike glycoprotein of the coronavirus SARS-CoV-2 (CoV2-S) binds to the human angiotensin-converting enzyme 2 (ACE2) representing the initial contact point for leveraging the infection cascade. We used an automated selection process and identified an aptamer that specifically interacts with CoV2-S. The aptamer does not bind to the RBD of CoV2-S and does not block the interaction of CoV2-S with ACE2. Nevertheless, infection studies revealed potent and specific inhibition of pseudoviral infection by the aptamer. The present study opens up new vistas in developing SARS-CoV2 infection inhibitors, independent of blocking the ACE2 interaction of the virus, and harnesses aptamers as potential drug candidates and tools to disentangle hitherto inaccessible infection modalities, which is of particular interest in light of the increasing number of escape mutants that are currently being reported.


Subject(s)
Antiviral Agents/pharmacology , Aptamers, Nucleotide/pharmacology , COVID-19/drug therapy , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Aptamers, Nucleotide/chemistry , Binding Sites/drug effects , COVID-19/metabolism , Drug Discovery , HEK293 Cells , Humans , Protein Binding/drug effects , Protein Interaction Domains and Motifs/drug effects , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , SELEX Aptamer Technique , Spike Glycoprotein, Coronavirus/chemistry
4.
Angew Chem Int Ed Engl ; 60(18): 10266-10272, 2021 04 26.
Article in English | MEDLINE | ID: covidwho-1074294

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 is threating global health. Inhibiting interaction of the receptor-binding domain of SARS-CoV-2 S protein (SRBD ) and human ACE2 receptor is a promising treatment strategy. However, SARS-CoV-2 neutralizing antibodies are compromised by their risk of antibody-dependent enhancement (ADE) and unfavorably large size for intranasal delivery. To avoid these limitations, we demonstrated an aptamer blocking strategy by engineering aptamers' binding to the region on SRBD that directly mediates ACE2 receptor engagement, leading to block SARS-CoV-2 infection. With aptamer selection against SRBD and molecular docking, aptamer CoV2-6 was identified and applied to prevent, compete with, and substitute ACE2 from binding to SRBD . CoV2-6 was further shortened and engineered as a circular bivalent aptamer CoV2-6C3 (cb-CoV2-6C3) to improve the stability, affinity, and inhibition efficacy. cb-CoV2-6C3 is stable in serum for more than 12 h and can be stored at room temperature for more than 14 days. Furthermore, cb-CoV2-6C3 binds to SRBD with high affinity (Kd =0.13 nM) and blocks authentic SARS-CoV-2 virus with an IC50 of 0.42 nM.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Aptamers, Nucleotide/pharmacology , COVID-19/drug therapy , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Antiviral Agents/chemistry , Aptamers, Nucleotide/chemistry , COVID-19/metabolism , Drug Discovery , HEK293 Cells , Humans , Molecular Docking Simulation , Protein Binding/drug effects , Protein Interaction Domains and Motifs/drug effects , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry
5.
Molecules ; 26(1)2020 Dec 24.
Article in English | MEDLINE | ID: covidwho-1044927

ABSTRACT

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.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Protein Interaction Domains and Motifs/drug effects , SARS-CoV-2/metabolism , Surface Plasmon Resonance/methods , Triterpenes/pharmacology , Viral Proteins/metabolism , HEK293 Cells , Humans , Protein Binding
6.
Molecules ; 25(23)2020 Nov 28.
Article in English | MEDLINE | ID: covidwho-948909

ABSTRACT

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.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/chemistry , Antiviral Agents/pharmacology , Biological Availability , Carnosine/chemistry , Carnosine/metabolism , Carnosine/pharmacology , Catalytic Domain , Crystallization , Humans , Molecular Docking Simulation , Protein Interaction Domains and Motifs/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship
7.
Curr Top Med Chem ; 20(26): 2362-2378, 2020.
Article in English | MEDLINE | ID: covidwho-789061

ABSTRACT

The article highlights an up-to-date progress in studies on structural and the remedial aspects of novel coronavirus 2019-nCoV, renamed as SARS-CoV-2, leading to the disease COVID-19, a pandemic. In general, all CoVs including SARS-CoV-2 are spherical positive single-stranded RNA viruses containing spike (S) protein, envelope (E) protein, nucleocapsid (N) protein, and membrane (M) protein, where S protein has a Receptor-binding Domain (RBD) that mediates the binding to host cell receptor, Angiotensin Converting Enzyme 2 (ACE2). The article details the repurposing of some drugs to be tried for COVID-19 and presents the status of vaccine development so far. Besides drugs and vaccines, the role of Convalescent Plasma (CP) therapy to treat COVID-19 is also discussed.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Pandemics , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Spike Glycoprotein, Coronavirus/genetics , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Angiotensin-Converting Enzyme 2 , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Betacoronavirus/ultrastructure , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Gene Expression , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Hydroxychloroquine/therapeutic use , Immunization, Passive/methods , Ivermectin/therapeutic use , Models, Molecular , Niclosamide/therapeutic use , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Protein Interaction Domains and Motifs/drug effects , Protein Structure, Secondary , /immunology , /ultrastructure , SARS-CoV-2 , Severe Acute Respiratory Syndrome , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/biosynthesis
8.
J Mol Med (Berl) ; 98(12): 1659-1673, 2020 12.
Article in English | MEDLINE | ID: covidwho-784429

ABSTRACT

The outbreak of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus continually led to infect a large population worldwide. SARS-CoV-2 utilizes its NSP6 and Orf9c proteins to interact with sigma receptors that are implicated in lipid remodeling and ER stress response, to infect cells. The drugs targeting the sigma receptors, sigma-1 and sigma-2, have emerged as effective candidates to reduce viral infectivity, and some of them are in clinical trials against COVID-19. The antipsychotic drug, haloperidol, exerts remarkable antiviral activity, but, at the same time, the sigma-1 benzomorphan agonist, dextromethorphan, showed pro-viral activity. To explore the potential mechanisms of biased binding and activity of the two drugs, haloperidol and dextromethorphan towards NSP6, we herein utilized molecular docking-based molecular dynamics simulation studies. Our extensive analysis of the protein-drug interactions, structural and conformational dynamics, residual frustrations, and molecular switches of NSP6-drug complexes indicates that dextromethorphan binding leads to structural destabilization and increase in conformational dynamics and energetic frustrations. On the other hand, the strong binding of haloperidol leads to minimal structural and dynamical perturbations to NSP6. Thus, the structural insights of stronger binding affinity and favorable molecular interactions of haloperidol towards viral NSP6 suggests that haloperidol can be potentially explored as a candidate drug against COVID-19. KEY MESSAGES: •Inhibitors of sigma receptors are considered as potent drugs against COVID-19. •Antipsychotic drug, haloperidol, binds strongly to NSP6 and induces the minimal changes in structure and dynamics of NSP6. •Dextromethorphan, agonist of sigma receptors, binding leads to overall destabilization of NSP6. •These two drugs bind with NSP6 differently and also induce differences in the structural and conformational changes that explain their different mechanisms of action. •Haloperidol can be explored as a candidate drug against COVID-19.


Subject(s)
Coronavirus Nucleocapsid Proteins/chemistry , Dextromethorphan/chemistry , Haloperidol/chemistry , SARS-CoV-2/drug effects , Binding Sites/drug effects , COVID-19/virology , Computer Simulation , Coronavirus Nucleocapsid Proteins/genetics , Dextromethorphan/therapeutic use , Haloperidol/therapeutic use , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Protein Binding/drug effects , Protein Interaction Domains and Motifs/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity
9.
Proc Natl Acad Sci U S A ; 117(29): 17195-17203, 2020 07 21.
Article in English | MEDLINE | ID: covidwho-624792

ABSTRACT

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.


Subject(s)
Actinobacteria/genetics , Antiviral Agents/pharmacology , Genome, Bacterial , Macrolides/pharmacology , Protein Interaction Domains and Motifs/drug effects , Small Molecule Libraries/pharmacology , Tacrolimus Binding Protein 1A/chemistry , Tacrolimus Binding Protein 1A/metabolism , Actinobacteria/metabolism , Amino Acid Sequence , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Autoantigens/genetics , Autoantigens/metabolism , Calcineurin/genetics , Calcineurin/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Evolution, Molecular , HEK293 Cells , Humans , Macrolides/chemistry , Macrolides/metabolism , Models, Molecular , Protein Conformation , Sequence Homology , Sirolimus/chemistry , Sirolimus/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism
10.
J Mol Graph Model ; 101: 107716, 2020 12.
Article in English | MEDLINE | ID: covidwho-726645

ABSTRACT

BACKGROUND: The receptor binding domain (RBD) of spike protein S1 domain SARS-CoV-2 plays a key role in the interaction with ACE2, which leads to subsequent S2 domain mediated membrane fusion and incorporation of viral RNA into host cells. In this study we tend to repurpose already approved drugs as inhibitors of the interaction between S1-RBD and the ACE2 receptor. METHODS: 2456 approved drugs were screened against the RBD of S1 protein of SARS-CoV-2 (target PDB ID: 6M17). As the interacting surface between S1-RBD and ACE2 comprises of bigger region, the interacting surface was divided into 3 sites on the basis of interactions (site 1, 2 and 3) and a total of 5 grids were generated (site 1, site 2, site 3, site 1+site 2 and site 2+site 3). A virtual screening was performed using GLIDE implementing HTVS, SP and XP screening. The top hits (on the basis of docking score) were further screened for MM-GBSA. All the top hits were further evaluated in molecular dynamics studies. Performance of the virtual screening protocol was evaluated using enrichment studies. RESULT: and discussion: We performed 5 virtual screening against 5 grids generated. A total of 42 compounds were identified after virtual screening. These drugs were further assessed for their interaction dynamics in molecular dynamics simulation. On the basis of molecular dynamics studies, we come up with 10 molecules with favourable interaction profile, which also interacted with physiologically important residues (residues taking part in the interaction between S1-RBD and ACE2. These are antidiabetic (acarbose), vitamins (riboflavin and levomefolic acid), anti-platelet agents (cangrelor), aminoglycoside antibiotics (Kanamycin, amikacin) bronchodilator (fenoterol), immunomodulator (lamivudine), and anti-neoplastic agents (mitoxantrone and vidarabine). However, while considering the relative side chain fluctuations when compared to the S1-RBD: ACE2 complex riboflavin, fenoterol, cangrelor and vidarabine emerged out as molecules with prolonged relative stability. CONCLUSION: We identified 4 already approved drugs (riboflavin, fenoterol, cangrelor and vidarabine) as possible agents for repurposing as inhibitors of S1:ACE2 interaction. In-vitro validation of these findings are necessary for identification of a safe and effective inhibitor of S1: ACE2 mediated entry of SARS-CoV-2 into the host cell.


Subject(s)
Antiviral Agents/pharmacology , Drug Evaluation, Preclinical/methods , Peptidyl-Dipeptidase A/metabolism , Protein Interaction Domains and Motifs/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2 , Antiviral Agents/chemistry , Computer Simulation , Databases, Pharmaceutical , Host-Pathogen Interactions/drug effects , Models, Molecular , Molecular Dynamics Simulation , Peptidyl-Dipeptidase A/chemistry , Reproducibility of Results , Spike Glycoprotein, Coronavirus/chemistry
11.
Int J Biol Macromol ; 164: 66-76, 2020 Dec 01.
Article in English | MEDLINE | ID: covidwho-653164

ABSTRACT

The global outbreak of COVID-19 (Coronavirus Disease 2019) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome caused by Coronavirus 2) began in December 2019. Its closest relative, SARS-CoV-1, has a slightly mutated Spike (S) protein, which interacts with ACE2 receptor in human cells to start the infection. So far, there are no vaccines or drugs to treat COVID-19. So, research groups worldwide are seeking new molecules targeting the S protein to prevent infection by SARS-CoV-2 and COVID-19 establishment. We performed molecular docking analysis of eight synthetic peptides against SARS-CoV-2 S protein. All interacted with the protein, but Mo-CBP3-PepII and PepKAA had the highest affinity with it. By binding to the S protein, both peptides led to conformational alterations in the protein, resulting in incorrect interaction with ACE2. Therefore, given the importance of the S protein-ACE2 interaction for SARS-CoV-2 infection, synthetic peptides could block SARS-CoV-2 infection. Moreover, unlike other antiviral drugs, peptides have no toxicity to human cells. Thus, these peptides are potential molecules to be tested against SARS-CoV-2 and to develop new drugs to treat COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Coronavirus Infections/drug therapy , Peptides/pharmacology , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2 , Antiviral Agents/chemistry , Betacoronavirus/drug effects , Betacoronavirus/metabolism , Binding Sites/drug effects , COVID-19 , Computational Biology , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Humans , Molecular Docking Simulation , Pandemics , Peptides/chemistry , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Protein Binding/drug effects , Protein Conformation/drug effects , Protein Interaction Domains and Motifs/drug effects , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
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