Abstract
The chemical structure of PF-07321332, the first orally available Covid-19 clinical candidate, has recently been revealed by Pfizer. No information has been provided about the interaction pattern between PF-07321332 and its biomolecular counterpart, the SARS-CoV-2 main protease (Mpro). In the present work, we exploited Supervised Molecular Dynamics (SuMD) simulations to elucidate the key features that characterise the interaction between this drug candidate and the protease, emphasising similarities and differences with other structurally related inhibitors such as Boceprevir and PF-07304814. The structural insights provided by SuMD will hopefully be able to inspire the rational discovery of other potent and selective protease inhibitors.
Keywords:
Covid-19; PF-07321332; SARS-CoV-2; SuMD.
MeSH terms
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Antiviral Agents / chemistry*
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Antiviral Agents / pharmacology
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Humans
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Lactams / chemistry*
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Lactams / pharmacology
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Leucine / chemistry*
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Leucine / pharmacology
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Ligands
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Molecular Dynamics Simulation*
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Nitriles / chemistry*
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Nitriles / pharmacology
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Peptide Hydrolases / metabolism
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Proline / chemistry*
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Proline / pharmacology
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacology
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SARS-CoV-2 / drug effects
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SARS-CoV-2 / enzymology
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Software
Substances
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Antiviral Agents
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Lactams
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Ligands
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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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Peptide Hydrolases
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Leucine
Grants and funding
This scientific work has been financially supported by MIUR [PRIN2017, No. 2017MT3993] and by Fondazione Cariparo (An Integrated Strategy for the Fast Discovery of SARS-CoV-2 Main Protease (Mpro) Inhibitors, No. 55812].