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1.
Front Cell Infect Microbiol ; 12: 933824, 2022.
Article in English | MEDLINE | ID: covidwho-2022656

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic has killed huge populations throughout the world and acts as a high-risk factor for elderly and young immune-suppressed patients. There is a critical need to build up secure, reliable, and efficient drugs against to the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Bioactive compounds of Ashwagandha [Withania somnifera (L.) Dunal] may implicate as herbal medicine for the management and treatment of patients infected by SARS-CoV-2 infection. The aim of the current work is to update the knowledge of SARS-CoV-2 infection and information about the implication of various compounds of medicinal plant Withania somnifera with minimum side effects on the patients' organs. The herbal medicine Withania somnifera has an excellent antiviral activity that could be implicated in the management and treatment of flu and flu-like diseases connected with SARS-CoV-2. The analysis was performed by systematically re-evaluating the published articles related to the infection of SARS-CoV-2 and the herbal medicine Withania somnifera. In the current review, we have provided the important information and data of various bioactive compounds of Withania somnifera such as Withanoside V, Withanone, Somniferine, and some other compounds, which can possibly help in the management and treatment of SARS-CoV-2 infection. Withania somnifera has proved its potential for maintaining immune homeostasis of the body, inflammation regulation, pro-inflammatory cytokines suppression, protection of multiple organs, anti-viral, anti-stress, and anti-hypertensive properties. Withanoside V has the potential to inhibit the main proteases (Mpro) of SARS-CoV-2. At present, synthetic adjuvant vaccines are used against COVID-19. Available information showed the antiviral activity in Withanoside V of Withania somnifera, which may explore as herbal medicine against to SARS-CoV-2 infection after standardization of parameters of drug development and formulation in near future.


Subject(s)
COVID-19 , Withania , Aged , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Discovery , Humans , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , SARS-CoV-2
2.
J Biomol Struct Dyn ; : 1-23, 2022 Sep 12.
Article in English | MEDLINE | ID: covidwho-2017224

ABSTRACT

Honokiol (HNK) is a natural polyphenolic compound extracted from the bark and leaves of Magnolia grandiflora. It has been traditionally used as a medicinal compound to treat inflammatory diseases. HNK possesses numerous health benefits with a minimal level of toxicity. It can cross the blood-brain barrier and blood-cerebrospinal fluid, thus having significant bioavailability in the neurological tissues. HNK is a promising bioactive compound possesses neuroprotective, antimicrobial, anti-tumorigenic, anti-spasmodic, antidepressant, analgesic, and antithrombotic features . HNK can prevent the growth of several cancer types and haematological malignancies. Recent studies suggested its role in COVID-19 therapy. It binds effectively with several molecular targets, including apoptotic factors, chemokines, transcription factors, cell surface adhesion molecules, and kinases. HNK has excellent pharmacological features and a wide range of chemotherapeutic effects, and thus, researchers have increased interest in improving the therapeutic implications of HNK to the clinic as a novel agent. This review focused on the therapeutic implications of HNK, highlighting clinical and pharmacological features and the underlying mechanism of action.Communicated by Ramaswamy H. Sarma.

3.
Mol Cell Biochem ; 477(5): 1607-1619, 2022 May.
Article in English | MEDLINE | ID: covidwho-1777759

ABSTRACT

The outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in December 2019 and caused coronavirus disease 2019 (COVID-19), which causes pneumonia and severe acute respiratory distress syndrome. It is a highly infectious pathogen that promptly spread. Like other beta coronaviruses, SARS-CoV-2 encodes some non-structural proteins (NSPs), playing crucial roles in viral transcription and replication. NSPs likely have essential roles in viral pathogenesis by manipulating many cellular processes. We performed a sequence-based analysis of NSPs to get insights into their intrinsic disorders, and their functions in viral replication were annotated and discussed in detail. Here, we provide newer insights into the structurally disordered regions of SARS-CoV-2 NSPs. Our analysis reveals that the SARS-CoV-2 proteome has a chunk of the disordered region that might be responsible for increasing its virulence. In addition, mutations in these regions are presumably responsible for drug and vaccine resistance. These findings suggested that the structurally disordered regions of SARS-CoV-2 NSPs might be invulnerable in COVID-19.


Subject(s)
COVID-19 , Vaccines , Humans , SARS-CoV-2
4.
RSC Adv ; 12(13): 7872-7882, 2022 Mar 08.
Article in English | MEDLINE | ID: covidwho-1751769

ABSTRACT

Casein kinase 2 (CK2) is a conserved serine/threonine-protein kinase involved in hematopoietic cell survival, cell cycle control, DNA repair, and other cellular processes. It plays a significant role in cancer progression and viral infection. CK2 is considered a potential drug target in cancers and COVID-19 therapy. In this study, we have performed a virtual screening of phytoconstituents from the IMPPAT database to identify some potential inhibitors of CK2. The initial filter was the physicochemical properties of the molecules following the Lipinski rule of five. Then binding affinity calculation, PAINS filter, ADMET, and PASS analyses followed by interaction analysis were carried out to discover nontoxic and better hits. Finally, two compounds, stylopine and dehydroevodiamines with appreciable affinity and specific interaction towards CK2, were identified. Their time-evolution analyses were carried out using all-atom molecular dynamics simulation, principal component analysis and free energy landscape. Altogether, we propose that stylopine and dehydroevodiamines can be further explored in in vitro and in vivo settings to develop anticancer and antiviral therapeutics.

5.
Front Cell Infect Microbiol ; 11: 806265, 2021.
Article in English | MEDLINE | ID: covidwho-1714991

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is spreading across the world, and vaccinations are running parallel. Coronavirus has mutated into a triple-mutated virus, rendering it deadlier than before. It spreads quickly from person to person by contact and nasal or pharyngeal droplets. The COVID-19 database 'Our World in Data' was analyzed from February 24, 2020, to September 26, 2021, and predictions on the COVID positives and their mortality rate were made. Factors such as Vaccine data for the First and Second Dose vaccinated individuals and COVID positives that influence the fluctuations in the COVID-19 death ratio were investigated and linear regression analysis was performed. Based on vaccination doses (partial or complete vaccinated), models are created to estimate the number of patients who die from COVID infection. The estimation of variance in the datasets was investigated using Karl Pearson's coefficient. For COVID-19 cases and vaccination doses, a quartic polynomial regression model was also created. This predictor model helps to predict the number of deaths due to COVID-19 and determine the susceptibility to COVID-19 infection based on the number of vaccine doses received. SVM was used to analyze the efficacy of models generated.


Subject(s)
COVID-19 , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Machine Learning , SARS-CoV-2 , Vaccination
6.
Biomed Pharmacother ; 147: 112658, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1641135

ABSTRACT

The unexpected emergence of the new Coronavirus disease (COVID-19) has affected more than three hundred million individuals and resulted in more than five million deaths worldwide. The ongoing pandemic has underscored the urgent need for effective preventive and therapeutic measures to develop anti-viral therapy. The natural compounds possess various pharmaceutical properties and are reported as effective anti-virals. The interest to develop an anti-viral drug against the novel severe acute respiratory syndrome Coronavirus (SARS-CoV-2) from natural compounds has increased globally. Here, we investigated the anti-viral potential of selected promising natural products. Sources of data for this paper are current literature published in the context of therapeutic uses of phytoconstituents and their mechanism of action published in various reputed peer-reviewed journals. An extensive literature survey was done and data were critically analyzed to get deeper insights into the mechanism of action of a few important phytoconstituents. The consumption of natural products such as thymoquinone, quercetin, caffeic acid, ursolic acid, ellagic acid, vanillin, thymol, and rosmarinic acid could improve our immune response and thus possesses excellent therapeutic potential. This review focuses on the anti-viral functions of various phytoconstituent and alkaloids and their potential therapeutic implications against SARS-CoV-2. Our comprehensive analysis provides mechanistic insights into phytoconstituents to restrain viral infection and provide a better solution through natural, therapeutically active agents.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Phytochemicals/therapeutic use , Phytotherapy , Alkaloids/therapeutic use , Benzaldehydes/therapeutic use , Benzoquinones/therapeutic use , Caffeic Acids/therapeutic use , Cinnamates/therapeutic use , Depsides/therapeutic use , Ellagic Acid/therapeutic use , Humans , Quercetin/therapeutic use , SARS-CoV-2 , Thymol/therapeutic use , Triterpenes/therapeutic use
7.
PLoS One ; 16(12): e0261497, 2021.
Article in English | MEDLINE | ID: covidwho-1581739

ABSTRACT

Since the emergence of yellow fever in the Americas and the devastating 1918 influenza pandemic, biologists and clinicians have been drawn to human infecting viruses to understand their mechanisms of infection better and develop effective therapeutics against them. However, the complex molecular and cellular processes that these viruses use to infect and multiply in human cells have been a source of great concern for the scientific community since the discovery of the first human infecting virus. Viral disease outbreaks, such as the recent COVID-19 pandemic caused by a novel coronavirus, have claimed millions of lives and caused significant economic damage worldwide. In this study, we investigated the mechanisms of host-virus interaction and the molecular machinery involved in the pathogenesis of some common human viruses. We also performed a phylogenetic analysis of viral proteins involved in host-virus interaction to understand the changes in the sequence organization of these proteins during evolution for various strains of viruses to gain insights into the viral origin's evolutionary perspectives.


Subject(s)
Host-Pathogen Interactions , Phylogeny , Viral Proteins/genetics , Virus Diseases/virology , HIV Envelope Protein gp160/genetics , Humans
8.
Curr Pharm Des ; 27(41): 4223-4231, 2021.
Article in English | MEDLINE | ID: covidwho-1502208

ABSTRACT

Coronavirus disease-2019 (COVID-19) is a respiratory tract infection accompanied by severe or fatal pneumonia-like symptoms and sometimes death. It has posed to be an ongoing global health emergency caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to a sudden outbreak and a large number of infections and deaths, it became a major concern all over the world. The options available as effective therapeutics should be urgently exercised to handle this pandemic. So far, no specific and accurate anti- SARS-CoV-2 treatment is recommended because of the absence of sufficient clinical evidence. In such cases, the clinical use of available drugs is always considered to be on top priority. A broad-spectrum antiviral agent, remdesivir, is found effective in many cases and recommended by many clinicians in many countries. This drug acts as a potential inhibitor of viral RNA-dependent RNA polymerase protein and thus likely to be efficacious in SARS-CoV-2 infection. Tocilizumab is currently recommended by many hospitals as an alternative treatment for critically ill COVID-19 patients. Tocilizumab has been administered to control cytokine storms that occur due to the release of proinflammatory cytokine, including interleukin 6. Chloroquine and hydroxychloroquine are also used in hospitals to handle severe COVID-19 patients. Currently, plasma therapy has been exercised as a therapeutic alternative, especially to handle severe COVID-19 patients. In addition, herbal medicines are expected to play a significant role in the control and prevention of COVID-19. All these therapeutic options have their advantages and limitations. This review highlights the therapeutic potential of these available drugs, along with their mechanism of action and shortcomings. We have provided detailed information on available therapeutic options, which have proved to be effective in improving clinical symptoms of severe COVID-19 patients.


Subject(s)
Antiviral Agents , COVID-19 , Antiviral Agents/therapeutic use , COVID-19/therapy , Cytokine Release Syndrome , Humans , Hydroxychloroquine , Immunization, Passive , Pandemics , Phytotherapy
9.
Int J Biochem Cell Biol ; 142: 106114, 2022 01.
Article in English | MEDLINE | ID: covidwho-1499649

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged from Wuhan in China before it spread to the entire globe. It causes coronavirus disease of 2019 (COVID-19) where mostly individuals present mild symptoms, some remain asymptomatic and some show severe lung inflammation and pneumonia in the host through the induction of a marked inflammatory 'cytokine storm'. New and efficacious vaccines have been developed and put into clinical practice in record time, however, there is a still a need for effective treatments for those who are not vaccinated or remain susceptible to emerging SARS-CoV-2 variant strains. Despite this, effective therapeutic interventions against COVID-19 remain elusive. Here, we have reviewed potential drugs for COVID-19 classified on the basis of their mode of action. The mechanisms of action of each are discussed in detail to highlight the therapeutic targets that may help in reducing the global pandemic. The review was done up to July 2021 and the data was assessed through the official websites of WHO and CDC for collecting the information on the clinical trials. Moreover, the recent research papers were also assessed for the relevant data. The search was mainly based on keywords like Coronavirus, SARS-CoV-2, drugs (specific name of the drugs), COVID-19, clinical efficiency, safety profile, side-effects etc.This review outlines potential areas for future research into COVID-19 treatment strategies.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning , SARS-CoV-2/drug effects , Adaptive Immunity/immunology , Antibodies, Viral/immunology , Antimalarials/pharmacology , Antiparasitic Agents/pharmacology , CD4-Positive T-Lymphocytes/immunology , COVID-19/therapy , Humans , Immunity, Innate/immunology , Immunization, Passive/methods , Probiotics/pharmacology , SARS-CoV-2/immunology
10.
Front Cell Infect Microbiol ; 11: 765039, 2021.
Article in English | MEDLINE | ID: covidwho-1497027

ABSTRACT

A continual rise in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease (COVID-19) has become a global threat. The main problem comes when SARS-CoV-2 gets mutated with the rising infection and becomes more lethal for humankind than ever. Mutations in the structural proteins of SARS-CoV-2, i.e., the spike surface glycoprotein (S), envelope (E), membrane (M) and nucleocapsid (N), and replication machinery enzymes, i.e., main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) creating more complexities towards pathogenesis and the available COVID-19 therapeutic strategies. This study analyzes how a minimal variation in these enzymes, especially in S protein at the genomic/proteomic level, affects pathogenesis. The structural variations are discussed in light of the failure of small molecule development in COVID-19 therapeutic strategies. We have performed in-depth sequence- and structure-based analyses of these proteins to get deeper insights into the mechanism of pathogenesis, structure-function relationships, and development of modern therapeutic approaches. Structural and functional consequences of the selected mutations on these proteins and their association with SARS-CoV-2 virulency and human health are discussed in detail in the light of our comparative genomics analysis.


Subject(s)
COVID-19 , SARS-CoV-2 , Genomics , Humans , Proteomics , Spike Glycoprotein, Coronavirus/genetics
13.
Am J Physiol Endocrinol Metab ; 321(2): E246-E251, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1285097

ABSTRACT

Vitamin D deficiency significantly correlates with the severity of SARS-CoV-2 infection. Molecular docking-based virtual screening studies predict that novel vitamin D and related lumisterol hydroxymetabolites are able to bind to the active sites of two SARS-CoV-2 transcription machinery enzymes with high affinity. These enzymes are the main protease (Mpro) and RNA-dependent RNA polymerase (RdRP), which play important roles in viral replication and establishing infection. Based on predicted binding affinities and specific interactions, we identified 10 vitamin D3 (D3) and lumisterol (L3) analogs as likely binding partners of SARS-CoV-2 Mpro and RdRP and, therefore, tested their ability to inhibit these enzymes. Activity measurements demonstrated that 25(OH)L3, 24(OH)L3, and 20(OH)7DHC are the most effective of the hydroxymetabolites tested at inhibiting the activity of SARS-CoV-2 Mpro causing 10%-19% inhibition. These same derivatives as well as other hydroxylumisterols and hydroxyvitamin D3 metabolites inhibited RdRP by 50%-60%. Thus, inhibition of these enzymes by vitamin D and lumisterol metabolites may provide a novel approach to hindering the SARS-CoV-2 infection.NEW & NOTEWORTHY Active forms of vitamin D and lumisterol can inhibit SARS-CoV-2 replication machinery enzymes, which indicates that novel vitamin D and lumisterol metabolites are candidates for antiviral drug research.


Subject(s)
Antiviral Agents/pharmacology , Ergosterol/metabolism , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/drug effects , Virus Replication/drug effects , Vitamin D/pharmacology , Antiviral Agents/chemistry , Ergosterol/analogs & derivatives , Ergosterol/chemistry , Ergosterol/pharmacology , Molecular Docking Simulation , RNA-Dependent RNA Polymerase/chemistry , SARS-CoV-2/physiology , Vitamin D/chemistry
14.
Biosci Rep ; 40(6)2020 06 26.
Article in English | MEDLINE | ID: covidwho-1099357

ABSTRACT

Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.


Subject(s)
Betacoronavirus/enzymology , Maraviroc/pharmacology , Protease Inhibitors/pharmacology , Quinoxalines/pharmacology , Sulfonamides/pharmacology , Aminoisobutyric Acids , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Computer Simulation , Cyclopropanes , Drug Evaluation, Preclinical/methods , Lactams, Macrocyclic , Leucine/analogs & derivatives , Maraviroc/chemistry , Maraviroc/metabolism , Molecular Structure , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Quinoxalines/chemistry , Quinoxalines/metabolism , SARS-CoV-2 , Sulfonamides/chemistry , Sulfonamides/metabolism
15.
Risk Manag Healthc Policy ; 14: 379-389, 2021.
Article in English | MEDLINE | ID: covidwho-1079421

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an emerging challenging area for the researchers to buckle up against the spread and control of the virus. Since earlier times, the diagnosis has been an important procedure in estimating the fate of epidemics by indicating the extent to which disease has been spread and to the extent, further disease prognosis would occur. The absence of anti-viral therapies and vaccines for COVID-19 at present suggests early diagnosis and isolation of the patients as the only smart approach available as of now. Presently, the increasing death rates, faster rates of transmission, non-availability of vaccines, and treatment have over-pressurized the researchers, health professionals, and government officials to develop effective clinical strategies in diagnosis and to come up with guidelines to be followed during conduction of each diagnostic procedure for maintaining healthcare systems. Since the incubation period of this virus is 2-14 days, a patient can transmit the infection without showing symptoms. Therefore, early diagnosis and isolation of susceptible individuals are the only way to limit the spread of the virus. Significance of diagnosis and triaging, information on specimen collection, safety considerations while handling, transport, and storage of samples have been highlighted in this paper to make people more aware and develop better clinical strategies in the future.

16.
Int J Biol Macromol ; 177: 1-9, 2021 Apr 30.
Article in English | MEDLINE | ID: covidwho-1071367

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from China has become a global threat due to the continuous rise in cases of Coronavirus disease 2019 (COVID-19). The problem with COVID-19 therapeutics is due to complexity of the mechanism of the pathogenesis of this virus. In this review, an extensive analysis of genome architecture and mode of pathogenesis of SARS-CoV-2 with an emphasis on therapeutic approaches is performed. SARS-CoV-2 genome consists of a single, ~29.9 kb long RNA having significant sequence similarity to BAT-CoV, SARS-CoV and MERS-CoV genome. Two-third part of SARS-Cov-2 genome comprises of ORF (ORF1ab) resulting in the formation of 2 polyproteins, pp1a and pp1ab, later processed into 16 smaller non-structural proteins (NSPs). The four major structural proteins of SARS-CoV-2 are the spike surface glycoprotein (S), a small envelope (E), membrane (M), and nucleocapsid (N) proteins. S protein helps in receptor binding and membrane fusion and hence plays the most important role in the transmission of CoVs. Priming of S protein is done by serine 2 transmembrane protease and thus plays a key role in virus and host cell fusion. This review highlights the possible mechanism of action of SARS-CoV-2 to search for possible therapeutic options.


Subject(s)
COVID-19/drug therapy , Genome, Viral , SARS-CoV-2/genetics , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Humans , Nucleocapsid Proteins/chemistry , Nucleocapsid Proteins/metabolism , Peptide Hydrolases/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , Viral Envelope Proteins/chemistry , Viral Envelope Proteins/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
17.
Curr Pharm Des ; 27(31): 3370-3388, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1069679

ABSTRACT

Coronavirus disease (COVID-19) is caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), which is a positive single-stranded RNA virus having a large genome ~30 kb. SARSCoV- 2 is zoonotic and highly contagious, causing severe pneumonia-like symptoms. The efficacy of the different potential drug and drug candidates against COVID-19 has been investigated, which are under various stages of clinical trials. The drugs effective against SARS, and Middle east respiratory syndrome (MERS), have been proposed to have a high potential for the treatment of COVID-19. Here, we selected plant-based materials implicated in the prevention and therapy of COVID-19. The plant produces secondary metabolites in response to viral infection. Different classes of secondary metabolites have different mechanisms to counter virus attacks. Many nanomaterials produced by carbohydrates and lipids have been exploited for their in-vitro and in-vivo delivery of antiviral therapeutics. The vaccine has shown impressive results in producing antibodies against SARS-CoV2 and has been evaluated for safety, tolerance, and preliminary immunogenicity. Similarly, DNA/RNA-based therapy has shown high clinical significance. Various forms of vitamins, minerals, herbs, and phytonutrients help to enhance immunity and be implicated in the control of COVID-19. However, such measures should not replace social distancing, quarantine and special care.


Subject(s)
COVID-19 , Vaccines , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , RNA, Viral , SARS-CoV-2
18.
Virus Res ; 288: 198102, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-1003124

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by a newly emerged highly pathogenic virus called novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Targeting the main protease (Mpro, 3CLpro) of SARS-CoV-2 is an appealing approach for drug development because this enzyme plays a significant role in the viral replication and transcription. The available crystal structures of SARS-CoV-2 Mpro determined in the presence of different ligands and inhibitor-like compounds provide a platform for the quick development of selective inhibitors of SARS-CoV-2 Mpro. In this study, we utilized the structural information of co-crystallized SARS-CoV-2 Mpro for the structure-guided drug discovery of high-affinity inhibitors from the PubChem database. The screened compounds were selected on the basis of their physicochemical properties, drug-likeliness, and strength of affinity to the SARS-CoV-2 Mpro. Finally, we have identified 6-Deaminosinefungin (PubChem ID: 10428963) and UNII-O9H5KY11SV (PubChem ID: 71481120) as potential inhibitors of SARS-CoV-2 Mpro which may be further exploited in drug development to address SARS-CoV-2 pathogenesis. Both compounds are structural analogs of known antivirals, having considerable protease inhibitory potential with improved pharmacological properties. All-atom molecular dynamics simulations suggested SARS-CoV-2 Mpro in complex with these compounds is stable during the simulation period with minimal structural changes. This work provides enough evidence for further implementation of the identified compounds in the development of effective therapeutics of COVID-19.


Subject(s)
Aminoglycosides/chemistry , Antiviral Agents/chemistry , Betacoronavirus/chemistry , Protease Inhibitors/chemistry , Pyrrolidines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Aminoglycosides/metabolism , Antiviral Agents/metabolism , Betacoronavirus/enzymology , COVID-19 , Catalytic Domain , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/metabolism , Drug Discovery , Gene Expression , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Pneumonia, Viral/drug therapy , Protease Inhibitors/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Pyrrolidines/metabolism , SARS-CoV-2 , Substrate Specificity , Sulfonic Acids , Thermodynamics , User-Computer Interface , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
20.
Mol Cell Biochem ; 476(2): 675-687, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-871519

ABSTRACT

The recent exposure of novel coronavirus strain, severe acute respiratory syndrome (SARS-CoV-2) has spread to different countries at an alarming rate. Faster transmission rate and genetic modifications have provoked scientists to search for an immediate solution. With an increasing death rate, it becomes important to throw some light on the life cycle of the virus and its associated pathogenesis in the form of lung inflammation through cytokine storm (CS) production. This paper highlights the different stages of viral-mediated inflammatory responses in the host respiratory system. Previously, known anti-inflammatory drugs and therapeutic strategies that might show potential in controlling the CS of Coronavirus disease-2019 (COVID-19) is also mentioned in this study. Our critical analysis provides insights into the inflammation cycle induced in the lungs by early virus replication, downregulation and shedding of angiotensin-converting enzyme 2 (ACE2), and in the CS production. Identification of suitable targets within the inflammatory pathways for devising the therapeutic strategies useful in controlling the prognosis of COVID-19 finds a special mention in this article. However, antibody-dependent enhancement is the key aspect to consider before testing any drug/compound for therapeutic purposes. Our in-depth analysis would provide similarities and differences between the inflammatory responses induced by SARS-CoV and SARS-CoV-2, providing an excellent avenue to further look at how earlier outbreaks of coronaviruses were controlled and where new steps are required?


Subject(s)
COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Inflammation/drug therapy , Lung/pathology , Antibodies/immunology , Antibodies/therapeutic use , Antibody-Dependent Enhancement/immunology , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Humans , Inflammation/pathology , Inflammation/virology , Lung/metabolism , Lung/virology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Virus Replication/drug effects
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