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

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.