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Structural and Evolutionary Analysis Indicate that the SARS-CoV-2 Mpro is an Inconvenient Target for Small-Molecule Inhibitors Design

View ORCID ProfileMaria Bzówka, View ORCID ProfileKarolina Mitusińska, View ORCID ProfileAgata Raczyńska, View ORCID ProfileAleksandra Samol, View ORCID ProfileJack A. Tuszyński, View ORCID ProfileArtur Góra
doi: https://doi.org/10.1101/2020.02.27.968008
Maria Bzówka
1Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, Gliwice, 44-100, Poland
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Karolina Mitusińska
1Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, Gliwice, 44-100, Poland
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Agata Raczyńska
1Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, Gliwice, 44-100, Poland
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Aleksandra Samol
1Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, Gliwice, 44-100, Poland
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Jack A. Tuszyński
2Department of Physics, University of Alberta, Edmont, AB, T6G 2E1, Canada
3DIMEAS, Politecnino di Torino, Corso Duca degli Abruzzi, 24, Turin, 10129, Italy
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Artur Góra
1Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, Gliwice, 44-100, Poland
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  • For correspondence: a.gora@tunnelinggroup.pl
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Abstract

The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mix-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar SARS Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins show major differences in both shape and size indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site’s conformational changes during the simulation time indicates its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicates that the virus’ mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.

Footnotes

  • The extended version of the manuscript with detailed description of methods and improved supplementary informations.

  • Abbreviations

    Mpro
    Main protease
    CoVs
    Coronaviruses
    ORFs
    Open reading frames
    3CLpro
    Chymotrypsin-like cysteine protease
    S
    Spike surface glycoprotein
    E
    Small envelope protein
    M
    Matrix protein
    N
    Nucleocapsid protein
    N3
    N-[(5 methylisoxazol-3-yl)carbonyl] alanyl-L-valyl-N~1-((1R,2Z)-4-(benzyloxy)-4-oxo-1--{[(3R)-2-oxopyrrolidin-3-yl]methyl}but-2-enyl)-L-leucinamide
    cMD
    Classical molecular dynamics simulations
    MixMD
    Mixed-solvent molecular dynamics simulations
    PDB
    Protein Data Bank
    MAV
    Maximal accessible volume
    ACN
    Acetonitrile
    BNZ
    Benzene
    DMSO
    Dimethylsulfoxide
    MEO
    Methanol
    PHN
    Phenol
    URE
    Urea
    CMA
    Correlated mutation analysis
  • Copyright 
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    Posted April 06, 2020.
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    Structural and Evolutionary Analysis Indicate that the SARS-CoV-2 Mpro is an Inconvenient Target for Small-Molecule Inhibitors Design
    Maria Bzówka, Karolina Mitusińska, Agata Raczyńska, Aleksandra Samol, Jack A. Tuszyński, Artur Góra
    bioRxiv 2020.02.27.968008; doi: https://doi.org/10.1101/2020.02.27.968008
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    Structural and Evolutionary Analysis Indicate that the SARS-CoV-2 Mpro is an Inconvenient Target for Small-Molecule Inhibitors Design
    Maria Bzówka, Karolina Mitusińska, Agata Raczyńska, Aleksandra Samol, Jack A. Tuszyński, Artur Góra
    bioRxiv 2020.02.27.968008; doi: https://doi.org/10.1101/2020.02.27.968008

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