Abstract
We present a detailed computational analysis of the binding mode and reactivity of the novel oral inhibitor PF-07321332 developed against the SARS-CoV-2 3CL protease. Alchemical free energy calculations suggest that positions P3 and P4 could be susceptible to improvement in order to get a larger binding strength. QM/MM simulations unveil the reaction mechanism for covalent inhibition, showing that the nitrile warhead facilitates the recruitment of a water molecule for the proton transfer step.
MeSH terms
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Binding Sites
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COVID-19 / pathology
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COVID-19 / virology
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Catalytic Domain
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Coronavirus 3C Proteases / antagonists & inhibitors*
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Coronavirus 3C Proteases / metabolism
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Humans
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Lactams / chemistry
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Lactams / metabolism
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Leucine / chemistry
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Leucine / metabolism
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Molecular Dynamics Simulation*
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Nitriles / chemistry*
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Nitriles / metabolism
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Proline / chemistry
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Proline / metabolism
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Protease Inhibitors / chemistry*
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Protease Inhibitors / metabolism
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Quantum Theory
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SARS-CoV-2 / enzymology*
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SARS-CoV-2 / isolation & purification
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Thermodynamics
Substances
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Lactams
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Nitriles
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Protease Inhibitors
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nirmatrelvir
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Proline
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3C-like proteinase, SARS-CoV-2
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Coronavirus 3C Proteases
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Leucine