Binding and Reactivity of a Nitrile Oral Inhibitor of SARS-CoV-2 Main Protease Revealed by Computational Simulations

23 July 2021, Version 1
This content is an early or alternative research output and has not been peer-reviewed by Cambridge University Press at the time of posting.


We present a detailed analysis of the binding mode and reactivity of the novel oral inhibitor PF-07321332 developed against SARS-CoV-2 3CL protease. Classical and QM/MM Molecular Dynamics simulations are used to quantify the contributions to the binding free energy and the reaction mechanism for covalent inhibition. The small size of the nitrile warhead conferes additional advantadges to this inhibitor.


3CL protease
Minimum Free Energy Path
Binding Free Energy
nitrile-based inhibitor


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