Nelfinavir was predicted to be a potential inhibitor of 2019-nCov main protease by an integrative approach combining homology modelling, molecular docking and binding free energy calculation

  1. Zhijian Xu
  2. Cheng Peng
  3. Yulong Shi
  4. Zhengdan Zhu
  5. Kaijie Mu
  6. Xiaoyu Wang
  7. Weiliang Zhu

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Abstract

2019-nCov has caused more than 80 deaths as of 27 January 2020 in China, and infection cases have been reported in more than 10 countries. However, there is no approved drug to treat the disease. 2019-nCov M pro is a potential drug target to combat the virus. We built homology models based on SARS M pro structures, and docked 1903 small molecule drugs to the models. Based on the docking score and the 3D similarity of the binding mode to the known M pro ligands, 4 drugs were selected for binding free energy calculations. Both MM/GBSA and SIE methods voted for nelfinavir, with the binding free energy of −24.69±0.52 kcal/mol and −9.42±0.04 kcal/mol, respectively. Therefore, we suggested that nelfinavir might be a potential inhibitor against 2019-nCov M pro .

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    SciScore for 10.1101/2020.01.27.921627: (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
    2.1 Homology modelling: 43 Mpro complexes with ligands were downloaded from protein data bank6 (PDB IDs: 1WOF, 2A5I, 2A5K, 2ALV, 2AMD, 2GTB, 2GX4, 2GZ7, 2GZ8, 2OP9, 2QIQ, 2V6N, 2ZU4, 2ZU5, 3SN8, 3SND, 3SZN, 3TIT, 3TIU, 3TNS, 3TNT, 3V3M, 4F49, 4MDS, 4TWW, 4TWY, 4WY3, 4YLU, 4YOG, 4YOI, 4YOJ, 4ZRO, 5C5N, 5C5O, 5EU8, 5N5O, 5N19, 5NH0, 5WKJ, 5WKK, 5WKL, 5WKM,6FV1) and aligned to 2GTB in PyMOL.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    7 11 complexes (PDB IDs: 2A5K, 2GTB, 2GX4, 3SND, 3TNS, 3V3M, 4F49, 4YLU, 5NH0, 5WKJ, 5WKM) were served as templates to build 11 2019-nCov Mpro models in SWISS-MODEL server by “user template” mode.8 2.2 Approved Drugs: 1905 approved small molecule drugs with 3D coordinates were downloaded from DrugBank release version 5.1.5,9 while 1903 drugs could be converted to pdbqt format by prepare_ligand4.py script in MGLToos version 1.5.6.10 2.3 Molecular Docking: 1903 approved drugs in pdbqt format were docked to 2019-nCov Mpro model (template: 2GTB) by smina,11 which is a fork of AutoDock Vina12 with improving scoring and minimization.
    DrugBank
    suggested: (DrugBank, RRID:SCR_002700)
    AutoDock
    suggested: (AutoDock, RRID:SCR_012746)
    General Amber force field (GAFF)15 and Amber ff03 force field16 were used to parameterize the ligand and protein, respectively. 10,000 steps of minimization with constraints (10 kcal/mol/Å2) on heavy atoms of complex, including 5,000 steps of steepest descent minimization and 5,000 steps of conjugate gradient minimization, was used to optimize each system.
    Amber
    suggested: (AMBER, RRID:SCR_016151)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    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:
    • No conflict of interest statement was detected. If there are no conflicts, we encourage authors to explicit state so.
    • 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

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  2. Version published to 10.1101/2020.01.27.921627 on bioRxiv