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  1. Article ; Online: A comprehensive SARS-CoV-2 genomic analysis identifies potential targets for drug repurposing.

    Anand, Nithishwer Mouroug / Liya, Devang Haresh / Pradhan, Arpit Kumar / Tayal, Nitish / Bansal, Abhinav / Donakonda, Sainitin / Jainarayanan, Ashwin Kumar

    PloS one

    2021  Volume 16, Issue 3, Page(s) e0248553

    Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) was initially reported in December 2019 in Wuhan City, China. This acute infection caused pneumonia-like symptoms and other respiratory ... ...

    Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) was initially reported in December 2019 in Wuhan City, China. This acute infection caused pneumonia-like symptoms and other respiratory tract illness. Its higher transmission and infection rate has successfully enabled it to have a global spread over a matter of small time. One of the major concerns involving the SARS-COV-2 is the mutation rate, which enhances the virus evolution and genome variability, thereby making the design of therapeutics difficult. In this study, we identified the most common haplotypes from the haplotype network. The conserved genes and population level variants were analysed. Non-Structural Protein 10 (NSP10), Nucleoprotein, Papain-like protease (Plpro or NSP3) and 3-Chymotrypsin like protease (3CLpro or NSP5), which were conserved at the highest threshold, were used as drug targets for molecular dynamics simulations. Darifenacin, Nebivolol, Bictegravir, Alvimopan and Irbesartan are among the potential drugs, which are suggested for further pre-clinical and clinical trials. This particular study provides a comprehensive targeting of the conserved genes. We also identified the mutation frequencies across the viral genome.
    MeSH term(s) COVID-19/virology ; Drug Discovery/methods ; Drug Repositioning/methods ; Genome, Viral ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Mutation Rate ; SARS-CoV-2/drug effects ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Viral Proteins/genetics ; Viral Proteins/metabolism ; COVID-19 Drug Treatment
    Chemical Substances Viral Proteins
    Language English
    Publishing date 2021-03-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0248553
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Evolutionarily conserved and conformationally constrained short peptides might serve as DNA recognition elements in intrinsically disordered regions.

    Tayal, Nitish / Choudhary, Preeti / Pandit, Shashi B / Sandhu, Kuljeet Singh

    Molecular bioSystems

    2014  Volume 10, Issue 6, Page(s) 1469–1480

    Abstract: Despite recent advances, it is yet not clear how intrinsically disordered regions in proteins recognize their targets without any defined structures. Short linear motifs had been proposed to mediate molecular recognition by disordered regions; however, ... ...

    Abstract Despite recent advances, it is yet not clear how intrinsically disordered regions in proteins recognize their targets without any defined structures. Short linear motifs had been proposed to mediate molecular recognition by disordered regions; however, the underlying structural prerequisite remains elusive. Moreover, the role of short linear motifs in DNA recognition has not been studied. We report a repertoire of short evolutionarily Conserved Recognition Elements (CoREs) in long intrinsically disordered regions, which have very distinct amino-acid propensities from those of known motifs, and exhibit a strong tendency to retain their three-dimensional conformations compared to adjacent regions. The majority of CoREs directly interact with the DNA in the available 3D structures, which is further supported by literature evidence, analyses of ΔΔG values of DNA-binding energies and threading-based prediction of DNA binding potential. CoREs were enriched in cancer-associated missense mutations, further strengthening their functional nature. Significant enrichment of glycines in CoREs and the preference of glycyl ϕ-Ψ values within the left-handed bridge range in the l-disallowed region of the Ramachandran plot suggest that Gly-to-nonGly mutations within CoREs might alter the backbone conformation and consequently the function, a hypothesis that we reconciled using available mutation data. We conclude that CoREs might serve as bait for DNA recognition by long disordered regions and that certain mutations in these peptides can disrupt their DNA binding potential and consequently the protein function. We further hypothesize that the preferred conformations of CoREs and of glycyl residues therein might play an important role in DNA binding. The highly ordered nature of CoREs hints at a therapeutic strategy to inhibit malicious molecular interactions using small molecules mimicking CoRE conformations.
    MeSH term(s) Algorithms ; Amino Acid Motifs ; Binding Sites ; Computational Biology/methods ; Conserved Sequence ; DNA/metabolism ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/metabolism ; Intrinsically Disordered Proteins/chemistry ; Intrinsically Disordered Proteins/metabolism ; Models, Molecular ; Peptides/chemistry ; Peptides/metabolism ; Protein Conformation ; Sequence Analysis, Protein
    Chemical Substances DNA-Binding Proteins ; Intrinsically Disordered Proteins ; Peptides ; DNA (9007-49-2)
    Language English
    Publishing date 2014-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2188635-0
    ISSN 1742-2051 ; 1742-206X
    ISSN (online) 1742-2051
    ISSN 1742-206X
    DOI 10.1039/c3mb70539k
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Book ; Online: A Comprehensive SARS-CoV-2 Genomic Analysis Identifies Potential Targets for Drug Repurposing

    Mouroug Anand, Nithishwer / Haresh Liya, Devang / Pradhan, Arpit Kumar / Tayal, Nitish / Bansal, Abhinav / Donakonda, Sainitin / Jainarayanan, Ashwin Kumar

    2020  

    Abstract: ... Background: ... The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) initially reported in December 2019 in Wuhan City, China causing pneumonia-like symptoms and other respiratory tract ... ...

    Abstract

    Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) initially reported in December 2019 in Wuhan City, China causing pneumonia-like symptoms and other respiratory tract illness. It’s higher transmission and infection rate has successfully enabled it to have a global spread over a matter of small time. With 6,529,240 cases and about 385,264 deaths, this pandemic has become a global concern with certain drugs and vaccines failing at later clinical trials.

    Materials and Methods: Phylogenetic Analysis, Haplotype Network, Analysis of conserved genes and population-level variants, Using conserved genes as targets for drug designing, Docking studies and Molecular Dynamics (MD) simulations to predict the stability of Drug-Ligand Complex.

    Results: We identified the most common haplotypes from the haplotype network and at least seven different clusters were found signifying seven different viral lineages across the globe. We studied the mutation frequency across the SARS-CoV-2 viral genome. The conserved genes and population level variants were analyzed and NSP10, Nucleoprotein, Plpro and 3CLpro which were conserved at the highest threshold were used as drug targets for molecular dynamics simulations. Darifenacin, Nebivolol, Bictegravir, Alvimopan and Irbesartan are among the potential drugs which are suggested for further pre-clinical and clinical trials.

    Significance: This particular study provides a comprehensive targeting of the conserved genes as a novel approach for drug targeting. The conserved gene approach could also be of a big use while designing vaccines and cure. Mutations in the viral genome make the designing of the drugs a challenging task which has a higher risk of failure at later clinical trials. This approach of targeting the stable genes for drug discovery would provide a better therapeutic approach and confidence in the successive clinical trials. We also identified the global level spread of SARS-CoV-2 and mutation frequencies across the viral genome. Our study gives insights of the origin and global spread of the SARS-CoV-2. The data provided in this study can further be used by other groups to understand and combat Covid 19.


    Keywords covid19
    Publisher American Chemical Society (ACS)
    Publishing country us
    Document type Book ; Online
    DOI 10.26434/chemrxiv.12430919.v1
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Book ; Online: A Comprehensive SARS-CoV-2 Genomic Analysis Identifies Potential Targets for Drug Repurposing

    Mouroug Anand, Nithishwer / Haresh Liya, Devang / Pradhan, Arpit Kumar / Tayal, Nitish / Bansal, Abhinav / Donakonda, Sainitin / Jainarayanan, Ashwin Kumar

    2020  

    Abstract: ... Background: ... The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) initially reported in December 2019 in Wuhan City, China causing pneumonia-like symptoms and other respiratory tract ... ...

    Abstract

    Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) initially reported in December 2019 in Wuhan City, China causing pneumonia-like symptoms and other respiratory tract illness. It’s higher transmission and infection rate has successfully enabled it to have a global spread over a matter of small time. With 6,529,240 cases and about 385,264 deaths, this pandemic has become a global concern with certain drugs and vaccines failing at later clinical trials.

    Materials and Methods: Phylogenetic Analysis, Haplotype Network, Analysis of conserved genes and population-level variants, Using conserved genes as targets for drug designing, Docking studies and Molecular Dynamics (MD) simulations to predict the stability of Drug-Ligand Complex.

    Results: We identified the most common haplotypes from the haplotype network and at least seven different clusters were found signifying seven different viral lineages across the globe. We studied the mutation frequency across the SARS-CoV-2 viral genome. The conserved genes and population level variants were analyzed and NSP10, Nucleoprotein, Plpro and 3CLpro which were conserved at the highest threshold were used as drug targets for molecular dynamics simulations. Darifenacin, Nebivolol, Bictegravir, Alvimopan and Irbesartan are among the potential drugs which are suggested for further pre-clinical and clinical trials.

    Significance: This particular study provides a comprehensive targeting of the conserved genes as a novel approach for drug targeting. The conserved gene approach could also be of a big use while designing vaccines and cure. Mutations in the viral genome make the designing of the drugs a challenging task which has a higher risk of failure at later clinical trials. This approach of targeting the stable genes for drug discovery would provide a better therapeutic approach and confidence in the successive clinical trials. We also identified the global level spread of SARS-CoV-2 and mutation frequencies across the viral genome. Our study gives insights of the origin and global spread of the SARS-CoV-2. The data provided in this study can further be used by other groups to understand and combat Covid 19.


    Keywords covid19
    Publisher American Chemical Society (ACS)
    Publishing country us
    Document type Book ; Online
    DOI 10.26434/chemrxiv.12430919
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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