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1.
Int J Mol Sci ; 23(4)2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1715403

ABSTRACT

As the etiological agent for the coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenges the ongoing efforts of vaccine development and drug design. Due to the accumulating cases of breakthrough infections, there are urgent needs for broad-spectrum antiviral medicines. Here, we designed and examined five new tetrapeptidomimetic anti-SARS-CoV-2 inhibitors targeting the 3C-Like protease (3CLPro), which is highly conserved among coronaviruses and essential for viral replications. We significantly improved the efficacy of a ketoamide lead compound based on high-resolution co-crystal structures, all-atom simulations, and binding energy calculations. The inhibitors successfully engaged the catalytic dyad histidine residue (H41) of 3CLPro as designed, and they exhibited nanomolar inhibitory capacity as well as mitigated the viral loads of SARS-CoV-2 in cellular assays. As a widely applicable design principle, our results revealed that the potencies of 3CLPro-specific drug candidates were determined by the interplay between 3CLPro H41 residue and the peptidomimetic inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Peptidomimetics/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , COVID-19/drug therapy , Catalytic Domain , Chlorocebus aethiops , Coronavirus 3C Proteases/chemistry , Drug Design , Fluorescence Resonance Energy Transfer , Histidine/chemistry , Ligands , Molecular Dynamics Simulation , Peptidomimetics/chemistry , Protease Inhibitors/chemistry , Structure-Activity Relationship , Vero Cells
2.
J Med Chem ; 65(4): 2880-2904, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1705973

ABSTRACT

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Glutamine/chemistry , Glutamine/pharmacology , Humans , Ketones/chemistry , Ketones/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptidomimetics/chemistry , SARS-CoV-2/enzymology , Vero Cells , Virus Replication/drug effects
3.
Chem Commun (Camb) ; 57(82): 10771-10774, 2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1442812

ABSTRACT

We have established a new protocol for detecting severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) using a peptidomimetic to covalently detect a viral marker protease.


Subject(s)
COVID-19 Testing , COVID-19/diagnosis , SARS-CoV-2 , Viral Proteases/isolation & purification , Biological Assay/economics , Biosensing Techniques/economics , COVID-19/blood , COVID-19/virology , COVID-19 Testing/economics , Cost Savings , Electrochemical Techniques/economics , Humans , Peptidomimetics/chemistry , Tyrosine/chemistry , Viral Proteases/chemistry
4.
Bioorg Med Chem Lett ; 50: 128333, 2021 10 15.
Article in English | MEDLINE | ID: covidwho-1363893

ABSTRACT

Specific anti-coronaviral drugs complementing available vaccines are urgently needed to fight the COVID-19 pandemic. Given its high conservation across the betacoronavirus genus and dissimilarity to human proteases, the SARS-CoV-2 main protease (Mpro) is an attractive drug target. SARS-CoV-2 Mpro inhibitors have been developed at unprecedented speed, most of them being substrate-derived peptidomimetics with cysteine-modifying warheads. In this study, Mpro has proven resistant towards the identification of high-affinity short substrate-derived peptides and peptidomimetics without warheads. 20 cyclic and linear substrate analogues bearing natural and unnatural residues, which were predicted by computational modelling to bind with high affinity and designed to establish structure-activity relationships, displayed no inhibitory activity at concentrations as high as 100 µM. Only a long linear peptide covering residues P6 to P5' displayed moderate inhibition (Ki = 57 µM). Our detailed findings will inform current and future drug discovery campaigns targeting Mpro.


Subject(s)
COVID-19/pathology , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Cysteine/chemistry , Cysteine/metabolism , Humans , Lactams/chemistry , Lactams/metabolism , Leucine/chemistry , Leucine/metabolism , Nitriles/chemistry , Nitriles/metabolism , Peptides/chemistry , Peptides/metabolism , Peptidomimetics/chemistry , Peptidomimetics/metabolism , Proline/chemistry , Proline/metabolism , Protease Inhibitors/metabolism , SARS-CoV-2/isolation & purification , Structure-Activity Relationship , Substrate Specificity
5.
J Med Chem ; 65(4): 2880-2904, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1340972

ABSTRACT

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Glutamine/chemistry , Glutamine/pharmacology , Humans , Ketones/chemistry , Ketones/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptidomimetics/chemistry , SARS-CoV-2/enzymology , Vero Cells , Virus Replication/drug effects
6.
J Med Chem ; 65(4): 2926-2939, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1327181

ABSTRACT

The novel coronavirus, SARS-CoV-2, has been identified as the causative agent for the current coronavirus disease (COVID-19) pandemic. 3CL protease (3CLpro) plays a pivotal role in the processing of viral polyproteins. We report peptidomimetic compounds with a unique benzothiazolyl ketone as a warhead group, which display potent activity against SARS-CoV-2 3CLpro. The most potent inhibitor YH-53 can strongly block the SARS-CoV-2 replication. X-ray structural analysis revealed that YH-53 establishes multiple hydrogen bond interactions with backbone amino acids and a covalent bond with the active site of 3CLpro. Further results from computational and experimental studies, including an in vitro absorption, distribution, metabolism, and excretion profile, in vivo pharmacokinetics, and metabolic analysis of YH-53 suggest that it has a high potential as a lead candidate to compete with COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Ketones/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Humans , Ketones/chemistry , Male , Microbial Sensitivity Tests , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Models, Molecular , Molecular Conformation , Peptidomimetics/chemical synthesis , Peptidomimetics/chemistry , Rats , Rats, Wistar , SARS-CoV-2/enzymology , Vero Cells
7.
Bioorg Med Chem Lett ; 48: 128263, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1309173

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has created an unprecedented global health emergency. As of July 2021, only three antiviral therapies have been approved by the FDA for treating infected patients, highlighting the urgent need for more antiviral drugs. The SARS-CoV-2 3CL protease (3CLpro) is deemed an attractive drug target due to its essential role in viral polyprotein processing and pathogenesis. Indeed, a number of peptidomimetic 3CLpro inhibitors armed with electrophilic warheads have been reported by various research groups that can potentially be developed for treating COVID-19. However, it is currently impossible to compare their relative potencies due to the different assays employed. To solve this, we conducted a head-to-head comparison of fifteen reported peptidomimetic inhibitors in a standard FRET-based SARS-CoV-2 3CLpro inhibition assay to compare and identify potent inhibitors for development. Inhibitor design and the suitability of various warheads are also discussed.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Peptidomimetics/chemistry , SARS-CoV-2/enzymology , Antiviral Agents/metabolism , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Enzyme Assays , Fluorescence Resonance Energy Transfer , Inhibitory Concentration 50 , Peptidomimetics/metabolism , Protein Binding
8.
J Med Chem ; 65(4): 2905-2925, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1303733

ABSTRACT

Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against a broad spectrum of coronaviruses. Described in this Article are novel α-acyloxymethylketone warhead peptidomimetic compounds with a six-membered lactam glutamine mimic in P1. Compounds with potent SARS-CoV-2 3CL protease and in vitro viral replication inhibition were identified with low cytotoxicity and good plasma and glutathione stability. Compounds 15e, 15h, and 15l displayed selectivity for SARS-CoV-2 3CL protease over CatB and CatS and superior in vitro SARS-CoV-2 antiviral replication inhibition compared with the reported peptidomimetic inhibitors with other warheads. The cocrystallization of 15l with SARS-CoV-2 3CL protease confirmed the formation of a covalent adduct. α-Acyloxymethylketone compounds also exhibited antiviral activity against an alphacoronavirus and non-SARS betacoronavirus strains with similar potency and a better selectivity index than remdesivir. These findings demonstrate the potential of the substituted heteroaromatic and aliphatic α-acyloxymethylketone warheads as coronavirus inhibitors, and the described results provide a basis for further optimization.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/metabolism , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Glutamine/chemistry , Glutamine/pharmacology , Humans , Ketones/chemistry , Ketones/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Peptidomimetics/chemistry , SARS-CoV-2/enzymology , Virus Replication/drug effects
9.
Biomolecules ; 11(4)2021 04 19.
Article in English | MEDLINE | ID: covidwho-1194605

ABSTRACT

The uncontrolled spread of the COVID-19 pandemic caused by the new coronavirus SARS-CoV-2 during 2020-2021 is one of the most devastating events in the history, with remarkable impacts on the health, economic systems, and habits of the entire world population. While some effective vaccines are nowadays approved and extensively administered, the long-term efficacy and safety of this line of intervention is constantly under debate as coronaviruses rapidly mutate and several SARS-CoV-2 variants have been already identified worldwide. Then, the WHO's main recommendations to prevent severe clinical complications by COVID-19 are still essentially based on social distancing and limitation of human interactions, therefore the identification of new target-based drugs became a priority. Several strategies have been proposed to counteract such viral infection, including the repurposing of FDA already approved for the treatment of HIV, HCV, and EBOLA, inter alia. Among the evaluated compounds, inhibitors of the main protease of the coronavirus (Mpro) are becoming more and more promising candidates. Mpro holds a pivotal role during the onset of the infection and its function is intimately related with the beginning of viral replication. The interruption of its catalytic activity could represent a relevant strategy for the development of anti-coronavirus drugs. SARS-CoV-2 Mpro is a peculiar cysteine protease of the coronavirus family, responsible for the replication and infectivity of the parasite. This review offers a detailed analysis of the repurposed drugs and the newly synthesized molecules developed to date for the treatment of COVID-19 which share the common feature of targeting SARS-CoV-2 Mpro, as well as a brief overview of the main enzymatic and cell-based assays to efficaciously screen such compounds.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Peptidomimetics/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Animals , Antiviral Agents/chemistry , COVID-19/virology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Drug Discovery , Drug Repositioning , Humans , Molecular Docking Simulation , Peptidomimetics/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Small Molecule Libraries/chemistry
10.
J Med Chem ; 65(4): 2794-2808, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1192017

ABSTRACT

A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3Cpro) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound 18p demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3Cpro in complex with 18p determined at a resolution of 1.2 Å revealed that 18p covalently linked to the catalytic Cys147 with an aldehyde group. In addition, these compounds also exhibited good inhibitory activity against the 3CLpro and the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially compound 18p (IC50 = 0.034 µM, EC50 = 0.29 µM). According to our previous work, these compounds have no reasons for concern regarding acute toxicity. Compared with AG7088, compound 18p also exhibited good pharmacokinetic properties and more potent anticoronavirus activity, making it an excellent lead for further development.


Subject(s)
Aldehydes/pharmacology , Antiviral Agents/pharmacology , Cysteine Proteinase Inhibitors/pharmacology , Enterovirus/drug effects , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Aldehydes/chemical synthesis , Aldehydes/chemistry , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line , Chlorocebus aethiops , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Design , Humans , Male , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptidomimetics/chemical synthesis , Peptidomimetics/chemistry , Structure-Activity Relationship
11.
Phys Chem Chem Phys ; 23(11): 6746-6757, 2021 Mar 21.
Article in English | MEDLINE | ID: covidwho-1132112

ABSTRACT

COVID-19, the disease caused by the newly discovered coronavirus-SARS-CoV-2, has created a global health, social, and economic crisis. As of mid-January 2021, there are over 90 million confirmed cases and more than 2 million reported deaths due to COVID-19. Currently, there are very limited therapeutics for the treatment or prevention of COVID-19. For this reason, it is important to find drug targets that will lead to the development of safe and effective therapeutics against the disease. The main protease (Mpro) of the virus is an attractive target for the development of effective antiviral therapeutics because it is required for proteolytic cleavage of viral polyproteins. Furthermore, the Mpro has no human homologues, so drugs designed to bind to this target directly have less risk for off-target effects. Recently, several high-resolution crystallographic structures of the Mpro in complex with inhibitors have been determined-to guide drug development and to spur efforts in structure-based drug design. One of the primary objectives of modern structure-based drug design is the accurate prediction of receptor-ligand binding affinities for rational drug design and discovery. Here, we perform rigorous alchemical absolute binding free energy calculations and QM/MM calculations to give insight into the total binding energy of two recently crystallized inhibitors of SARS-CoV-2 Mpro, namely, N3 and α-ketoamide 13b. The total binding energy consists of both covalent and non-covalent binding components since both compounds are covalent inhibitors of the Mpro. Our results indicate that the covalent and non-covalent binding free energy contributions of both inhibitors to the Mpro target differ significantly. The N3 inhibitor has more favourable non-covalent interactions, particularly hydrogen bonding, in the binding site of the Mpro than the α-ketoamide inhibitor. Also, the Gibbs energy of reaction for the Mpro-N3 covalent adduct is greater than the Gibbs reaction energy for the Mpro-α-ketoamide covalent adduct. These differences in the covalent and non-covalent binding free energy contributions for both inhibitors could be a plausible explanation for their in vitro differences in antiviral activity. Our findings are consistent with the reversible and irreversible character of both inhibitors as reported by experiment and highlight the importance of both covalent and non-covalent binding free energy contributions to the absolute binding affinity of a covalent inhibitor towards its target. This information could prove useful in the rational design, discovery, and evaluation of potent SARS-CoV-2 Mpro inhibitors for targeted antiviral therapy.


Subject(s)
Peptidomimetics/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Viral Matrix Proteins/antagonists & inhibitors , Amides/chemistry , Amides/metabolism , Binding Sites , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Drug Design , Humans , Hydrogen-Ion Concentration , Kinetics , Ligands , Molecular Dynamics Simulation , Peptidomimetics/metabolism , Protease Inhibitors/metabolism , Quantum Theory , SARS-CoV-2/isolation & purification , Thermodynamics , Viral Matrix Proteins/metabolism
12.
Comput Biol Med ; 128: 104124, 2021 01.
Article in English | MEDLINE | ID: covidwho-938855

ABSTRACT

The aim of the present study is to discuss the design of peptide vaccines and peptidomimetics against SARS-COV-2, to develop and apply a method of protein structure analysis that is particularly appropriate to applying and discussing such design, and also to use that method to summarize some important features of the SARS-COV-2 spike protein sequence. A tool for assessing sidechain exposure in the SARS-CoV-2 spike glycoprotein is described. It extends to assessing accessibility of sidechains by considering several different three-dimensional structure determinations of SARS-CoV-2 and SARS-CoV-1 spike protein. The method is designed to be insensitive to a distance limit for counting neighboring atoms and the results are in good agreement with the physical chemical properties and exposure trends of the 20 naturally occurring sidechains. The spike protein sequence is analyzed with comment regarding exposable character. It includes studies of complexes with antibody elements and ACE2. These indicate changes in exposure at sites remote to those at which the antibody binds. They are of interest concerning design of synthetic peptide vaccines, and for peptidomimetics as a basis of drug discovery. The method was also developed in order to provide linear (one-dimensional) information that can be used along with other bioinformatics data of this kind in data mining and machine learning, potentially as genomic data regarding protein polymorphisms to be combined with more traditional clinical data.


Subject(s)
COVID-19 Vaccines/chemistry , Models, Molecular , Peptidomimetics/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Computer Simulation , Humans , Vaccines, Subunit/chemistry
13.
Comput Biol Med ; 119: 103670, 2020 04.
Article in English | MEDLINE | ID: covidwho-1938

ABSTRACT

This paper concerns study of the genome of the Wuhan Seafood Market isolate believed to represent the causative agent of the disease COVID-19. This is to find a short section or sections of viral protein sequence suitable for preliminary design proposal for a peptide synthetic vaccine and a peptidomimetic therapeutic, and to explore some design possibilities. The project was originally directed towards a use case for the Q-UEL language and its implementation in a knowledge management and automated inference system for medicine called the BioIngine, but focus here remains mostly on the virus itself. However, using Q-UEL systems to access relevant and emerging literature, and to interact with standard publically available bioinformatics tools on the Internet, did help quickly identify sequences of amino acids that are well conserved across many coronaviruses including 2019-nCoV. KRSFIEDLLFNKV was found to be particularly well conserved in this study and corresponds to the region around one of the known cleavage sites of the SARS virus that are believed to be required for virus activation for cell entry. This sequence motif and surrounding variations formed the basis for proposing a specific synthetic vaccine epitope and peptidomimetic agent. The work can, nonetheless, be described in traditional bioinformatics terms, and readily reproduced by others, albeit with the caveat that new data and research into 2019-nCoV is emerging and evolving at an explosive pace. Preliminary studies using molecular modeling and docking, and in that context the potential value of certain known herbal extracts, are also described.


Subject(s)
Betacoronavirus/immunology , Betacoronavirus/physiology , Computational Biology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Peptidomimetics/chemistry , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Viral Vaccines , Amino Acid Sequence , Animals , Betacoronavirus/chemistry , Betacoronavirus/drug effects , COVID-19 , COVID-19 Vaccines , Computer Simulation , Coronavirus/chemistry , Coronavirus Infections/drug therapy , Drug Design , Epitopes , Genome, Viral , Humans , Models, Molecular , Peptidomimetics/metabolism , Peptidomimetics/pharmacology , Pneumonia, Viral/drug therapy , Programming Languages , Protein Conformation , Protein Structure, Secondary , SARS-CoV-2 , Sequence Homology, Amino Acid , Software , Spike Glycoprotein, Coronavirus/chemistry , Vaccines, Synthetic , Viral Vaccines/chemistry , Virus Internalization
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