An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mpro inhibitor

  1. Daniel Zaidman
  2. Paul Gehrtz
  3. Mihajlo Filep
  4. Daren Fearon
  5. Ronen Gabizon
  6. Alice Douangamath
  7. Jaime Prilusky
  8. Shirly Duberstein
  9. Galit Cohen
  10. C. David Owen
  11. Efrat Resnick
  12. Claire Strain-Damerell
  13. Petra Lukacik
  14. Haim Barr
  15. Martin A. Walsh
  16. Frank von Delft
  17. Nir London

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Abstract

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  1. Version published to 10.1016/j.chembiol.2021.05.018
  2. ScreenIT

    SciScore for 10.1101/2020.09.21.299776: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Marvin was used in the process of preparing the molecules for docking, Marvin 17.21.0, ChemAxon (https://www.chemaxon.com).
    https://www.chemaxon.com
    suggested: (ChemAxon, RRID:SCR_004111)
    Curating target structures from the PDB: Using pymol scripts (The PyMOL Molecular Graphics System, Version 2.0.4 Schrödinger, LLC), we filtered only the structures that have a ligand in which one of its atoms is within 6 Å cysteine residue.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    Computational optimisation of the Mpro inhibitor: We used the RDKit reaction functionalities, as well as OpenBabel (http://openbabel.org/wiki/Main_Page) to prepare virtual libraries of analogs of compound 10.
    http://openbabel.org/wiki/Main_Page
    suggested: (Open Babel, RRID:SCR_014920)

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Despite the success of our protocol, several caveats remain. First is the fact that currently the protocol does not take into account the synthetic feasibility of the proposed designs. When selecting candidates for prospective evaluation, we found that some of the molecules required complicated synthesis. Incorporating into our pipeline a strategy such as DOTS33,48, other retrosynthesis algorithms49–51 or even the use of synthetic feasibility scores52–54, can significantly improve the quality of proposed candidates in the future. Another point for improvement is the relatively weak potency of our prospective designs in comparison to their parent compounds. One likely explanation for these lower affinities is the removal of non-covalent affinity elements which are not sufficiently compensated by the gains from covalent bond formation. For example, in compound 2 (derived from PDB: 4QTA) more than 350 Da of the original compound55 is removed (Supp. Fig. 2), resulting in three orders of magnitude loss in potency. However the remaining covalent fragment still shows significant inhibition of ERK2. Another example is compound 1, its parent compound (PDB: 4QP9) has an IC50 of 71 nM, however the propyl-pyrazole group we have omitted in order to accommodate the electrophile (Supp. Fig. 2) improved the parent reversible binder by more than 150-fold. Lastly the loss of a hydrogen bond between the Mpro backbone NH of Gly143 and the furanyl oxygen of ML188 (PDB: 3V3M), decreased potency, u...

    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.

  3. Version published to 10.1101/2020.09.21.299776v1 on bioRxiv