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

  1. Maria Bzówka
  2. Karolina Mitusińska
  3. Agata Raczyńska
  4. Aleksandra Samol
  5. Jack A. Tuszyński
  6. Artur Góra

Reviewed by

Read the full article

Listed in

Log in to save this article

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.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2020.02.27.968008: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The chemical structures of cosolvents molecules were downloaded from the ChemSpider database [49] and a dedicated set of parameters was prepared.
    ChemSpider
    suggested: (ChemSpider, RRID:SCR_006360)
    The mixed-solvent MD simulation procedures (minimization, equilibration, and production) carried out using the AMBER 18 package were identical as for the classical MD simulations.
    AMBER
    suggested: (AMBER, RRID:SCR_016151)
    All visualisations were made in PyMol [54].
    PyMol
    suggested: (PyMOL, RRID:SCR_000305)
    Those so-called hot-spots could be calculated as local and/or global, based on the distribution of tracked molecules which visited the Object (local) or just the Scope without visiting the Object (global); here, they are considered as potential binding sites.
    Scope
    suggested: (Scope, RRID:SCR_017454)
    Tblastn [55] was run based on the protein amino acid sequence.
    Tblastn
    suggested: (TBLASTN, RRID:SCR_011822)
    Blastx [56] calculations were run with the selected region, and orf1a polyprotein (NCBI Reference Sequence: YP_009725295.1
    Blastx
    suggested: (BLASTX, RRID:SCR_001653)
    If a substitution of a single nucleotide caused translation to a different amino acid than the corresponding residue in the wild-type structure, an appropriate mutation was proposed with FoldX software.
    FoldX
    suggested: (FoldX, RRID:SCR_008522)
    Clustal Omega [58] was used to prepare an alignment of those sequences.
    Clustal Omega
    suggested: (Clustal Omega, RRID:SCR_001591)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.02.27.968008v3 on bioRxiv
  3. Version published to 10.1101/2020.02.27.968008v2 on bioRxiv
  4. Version published to 10.1101/2020.02.27.968008v1 on bioRxiv