Selected article for: "accurate mechanism and action mechanism"
Author: Chunlong Ma; Brett Hurst; Yanmei Hu; Tommy Szeto; Bart Tarbet; Jun Wang
Title: Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease
  • Document date: 2020_4_20
    • ID: 047xpt2c_12
    Snippet: To elucidate the mechanism of action of hits against SARS-CoV-2 M pro , we focus on five most potent compounds prioritized from the primary and secondary screenings including boceprevir The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.20.051581 doi: bioRxiv preprint proceeded beyond 90 minutes, we therefore chose the first 90 minutes of the progression curves for curve fitting (Fig. 4 m.....
    Document: To elucidate the mechanism of action of hits against SARS-CoV-2 M pro , we focus on five most potent compounds prioritized from the primary and secondary screenings including boceprevir The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.20.051581 doi: bioRxiv preprint proceeded beyond 90 minutes, we therefore chose the first 90 minutes of the progression curves for curve fitting (Fig. 4 middle column) . We fit the progression curves in the presence different concentrations of GC-376 (64) with the two-step Morrison equation (equation 3 in methods section). GC-376 (64) binds to SARS-CoV-2 M pro with an equilibrium dissociation constant for the inhibitor (KI) of 59.9 ± 21.7 nM in the first step. After initial binding, a slower covalent bond is formed between GC-376 (64) and M pro with the second reaction rate constant (k2) being 0.00245 ± 0.00047 s -1 , resulting an overall k2/KI value of 4.08 x 10 4 M -1 s -1 (Fig. 4A) . However, when we tried to fit the proteolytic progression curves for boceprevir (28) , MG-132 (43), calpain inhibitors II (61) and XII (62) using the same two-step reaction mechanism, we could not obtain accurate values for the second rate constant k2. This is presumably due to significant substrate depletion before the equilibrium between EI and EI*, leading to very small values of k2. Accordingly, for these four inhibitors

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