Computational chemistry
Modelled peptides inhibit SARS-CoV-2 main protease
Open access · cc by · source: Europe PMC
Simulations prefer a neutral His41/Cys145 dyad and guided four designed peptides that bind the Mpro dimer and inhibit substrate cleavage with IC50 values of 3–5 μM.
How this study connects
Role on claims
Each row is a claim on a concept or method page where this paper supports, challenges, or qualifies the statement. Roles are hand-checked — not a model guess.
MD plus docking can design peptides that then meet a wet IC₅₀, which is a stronger claim than MD that cannot rank sites. SARS-CoV-2 Mpro peptides p12–p16 have IC₅₀ 3.11–5.36 μM; at 8-fold excess they cut s01 depletion from >98% to 70–95%; the ion-pair dyad lies 28.5 kJ mol⁻¹ above the neutral state. On dimethylated lysozyme, short MD at each Lys-Me₂ and a crystal of sclx4 encapsulating Lys116-Me₂ still left MM-PBSA unable to rank sites; precipitation limited solution stoichiometry.
Evidence for the claim as stated.
MD that is later tested in a cuvette is not the same deliverable as MD that stays inside the computer. Mpro peptides have micromolar IC₅₀ values; GFP AIMD proton-transfer times disagree with 3/10 ps FSRS phases; UiO-66 proton hops are invisible to time-averaged XRD. A student who says 'MD showed the mechanism' must say whether a wet observable confirmed it.
Evidence for the claim as stated.
Open questions
Tensions this paper is part of
From concept pages' “where studies disagree.” Disagreement means the same question; scope means different assays, populations, or outcomes.
MD that is later tested in a cuvette is not the same deliverable as MD that stays inside the computer. Mpro peptides have micromolar IC₅₀ values; GFP AIMD proton-transfer times disagree with 3/10 ps FSRS phases; UiO-66 proton hops are invisible to time-averaged XRD. A student who says 'MD showed the mechanism' must say whether a wet observable confirmed it.
- Supports · AIMD maps GFP's excited-state proton shuttle
- Supports · Defect hydroxides in UiO-66 shuttle protons
Study at a glance
- Design
- Other — Computational design plus biochemical IC50 assays of Mpro peptide inhibitors
- N
- Four designed peptides assayed in vitro — no sample cohort N
- Population
- SARS-CoV-2 main protease with designed peptide inhibitors
- Outcome
- Peptide IC50 values and substrate-depletion inhibition of Mpro
Structured fields used in claim comparison tables when every cited study has a complete layer.
Inspect source passages
Modelled peptides inhibit SARS-CoV-2 main protease
These passages occur verbatim in the stored paper text. They support the points listed below; they do not verify every statement in the explanation.
The ion-pair dyad is 28.5 kJ mol−1 higher than the neutral state.
Applying the free energy difference between ωB97X-D/6-31G(d) and DFTB3 at each reaction coordinate value as a correction to the combined QM/MM free energy profile in the case of HIE-163, the neutral catalytic dyad is preferred, with the ion pair being 28.5 kJ mol −1 higher in energy than the neutral state ().
Designed peptides had IC50 values from 3.11 μM to 5.36 μM.
All four designed peptides manifested similar potency with IC 50 values ranging from 3.11 μM to 5.36 μM ( and Fig.
Key findings
The ion-pair dyad lies 28.5 kJ mol−1 above the neutral state. Designed peptides have IC50 3.11–5.36 μM; at 8-fold excess they cut s01 depletion from >98% to 70–95%. Binding modes mimic cluster-5 fragments and H-bond His-163/Glu-166.
Methodology
Authors combined docking, MD, QM/MM and fragment clustering on SARS-CoV-2 Mpro, synthesised peptides p12, p13, p15 and p16, and measured inhibition and non-denaturing MS complexes versus 11-mer substrates.
Limitations
These are micromolar peptides, not optimized oral antivirals, and the preferred dyad protonation is a computed free-energy result.
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