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1.
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
2.
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.

3.
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
4.
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
5.
J Biomol Struct Dyn ; : 1-12, 2021 Mar 24.
Article in English | MEDLINE | ID: covidwho-1147890

ABSTRACT

A respiratory pandemic known as coronavirus disease-19 (COVID-19) has created havoc since it emerged from Wuhan, China. COVID-19 is caused by a newly emerged SARS coronavirus (SARS-CoV) with increased pathogenicity named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Due to the lack of understanding of the mechanism of pathogenesis, an effective therapeutic option is unavailable. Epidemics described in Unani ancient literature include nazla-e-wabai and humma-e-wabai, and most of the symptoms of COVID-19 resemble nazla-e-wabai. Hence, in light of Unani literature, the treatment of COVID-19 can be managed with the composites prescribed in Unani medicine for nazla-e-wabai. In this study, a structure-based drug design approach was carried out to check the effectiveness of the pharmacologically active constituents of the Unani composites prescribed to treat nazla-e-wabai against SARS-CoV-2. We performed molecular docking of the active constituents of these composites against the main protease (Mpro), a potential drug target in SARS-CoV-2. Using detailed molecular docking analysis, Habb-ul-aas and Tabasheer were identified as potential inhibitors of SARS-CoV-2 Mpro. The active constituents of both these composites bind to the substrate-binding pocket of SARS-CoV-2 Mpro, forming interactions with key residues of the binding pocket. Molecular dynamics (MD) simulation suggested the binding of active constituents of Habb-ul-aas with SARS-CoV-2 Mpro with a strong affinity as compared to the constituents of Tabasheer. Thus, this study sheds light on the use of these Unani composites in COVID-19 therapeutics.Communicated by Ramaswamy H. Sarma.

6.
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
7.
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
8.
Saudi J Biol Sci ; 28(4): 2423-2431, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1051946

ABSTRACT

Coronavirus disease 2019 (COVID-19) has emerged from China and globally affected the entire population through the human-to-human transmission of a newly emerged virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The genome of SARS-CoV-2 encodes several proteins that are essential for multiplication and pathogenesis. The main protease (Mpro or 3CLpro) of SARS-CoV-2 plays a central role in its pathogenesis and thus is considered as an attractive drug target for the drug design and development of small-molecule inhibitors. We have employed an extensive structure-based high-throughput virtual screening to discover potential natural compounds from the ZINC database which could inhibit the Mpro of SARS-CoV-2. Initially, the hits were selected on the basis of their physicochemical and drug-like properties. Subsequently, the PAINS filter, estimation of binding affinities using molecular docking, and interaction analyses were performed to find safe and potential inhibitors of SARS-CoV-2 Mpro. We have identified ZINC02123811 (1-(3-(2,5,9-trimethyl-7-oxo-3-phenyl-7H-furo[3,2-g]chromen-6-yl)propanoyl)piperidine-4-carboxamide), a natural compound bearing appreciable affinity, efficiency, and specificity towards the binding pocket of SARS-CoV-2 Mpro. The identified compound showed a set of drug-like properties and preferentially binds to the active site of SARS-CoV-2 Mpro. All-atom molecular dynamics (MD) simulations were performed to evaluate the conformational dynamics, stability and interaction mechanism of Mpro with ZINC02123811. MD simulation results indicated that Mpro with ZINC02123811 forms a stable complex throughout the trajectory of 100 ns. These findings suggest that ZINC02123811 may be further exploited as a promising scaffold for the development of potential inhibitors of SARS-CoV-2 Mpro to address COVID-19.

9.
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
10.
Biochim Biophys Acta Mol Basis Dis ; 1866(10): 165878, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-597413

ABSTRACT

The sudden emergence of severe respiratory disease, caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently become a public health emergency. Genome sequence analysis of SARS-CoV-2 revealed its close resemblance to the earlier reported SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). However, initial testing of the drugs used against SARS-CoV and MERS-CoV has been ineffective in controlling SARS-CoV-2. The present study highlights the genomic, proteomic, pathogenesis, and therapeutic strategies in SARS-CoV-2 infection. We have carried out sequence analysis of potential drug target proteins in SARS-CoV-2 and, compared them with SARS-CoV and MERS viruses. Analysis of mutations in the coding and non-coding regions, genetic diversity, and pathogenicity of SARS-CoV-2 has also been done. A detailed structural analysis of drug target proteins has been performed to gain insights into the mechanism of pathogenesis, structure-function relationships, and the development of structure-guided therapeutic approaches. The cytokine profiling and inflammatory signalling are different in the case of SARS-CoV-2 infection. We also highlighted possible therapies and their mechanism of action followed by clinical manifestation. Our analysis suggests a minimal variation in the genome sequence of SARS-CoV-2, may be responsible for a drastic change in the structures of target proteins, which makes available drugs ineffective.


Subject(s)
Betacoronavirus/genetics , Genome, Viral , Betacoronavirus/isolation & purification , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/metabolism , Genetic Variation , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/isolation & purification , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , RNA-Dependent RNA Polymerase/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry
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