4.7 Article

Computational simulations on the binding and reactivity of a nitrile inhibitor of the SARS-CoV-2 main protease

Journal

CHEMICAL COMMUNICATIONS
Volume 57, Issue 72, Pages 9096-9099

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/d1cc03953a

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Funding

  1. Generalitat Valenciana [GVCOV19/Decreto180/2020]
  2. Barcelona Supercomputing Center

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A computational analysis was conducted on the binding mode and reactivity of the novel oral inhibitor PF-07321332 against SARS-CoV-2 3CL protease, revealing potential improvements in binding strength at positions P3 and P4. QM/MM simulations unveiled the reaction mechanism for covalent inhibition, highlighting the role of the nitrile warhead in facilitating the recruitment of a water molecule for the proton transfer step.
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.

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