Supervised Molecular Dynamics (SuMD) Insights into the mechanism of action of SARS-CoV-2 main protease inhibitor PF-07321332

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 (M^pro). 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.

Figure 1.

This panel encompasses the recognition pathway between PF-07321332 and the SARS-CoV-2 main protease predicted by SuMD. (A) PF-07321332 conformation within the binding site, sampled in the last SuMD trajectory frame (orange). Binding site residues within 4 Å of the ligand are depicted in ice-blue. (B) Profile of the distance between the centre of mass of the ligand and the M^pro catalytic site during SuMD simulation. (C) Interaction Energy Landscape describing the protein-ligand binding pathway; values are arranged according to distances between the centre of mass of the ligand the one of the M^pro catalytic site. (D) Dynamic total interaction energy (sum of electrostatic and van der Waals contribution) computed for the 25 most contacted residues throughout the SuMD trajectory.

Figure 2.

This panel illustrates the similarities between PF-07321332 conformation in the final SuMD trajectory frame and the crystallographic complexes of two structurally related covalent inhibitors of SARS-CoV-2 M^pro: Boceprevir and PF-00835231 (active metabolite of PF-07304814). (A) superposition between the binding mode predicted by SuMD for PF-07321332 (orange) and the crystallographic complex of Boceprevir within the catalytic site of SARS-CoV-2 M^pro (cyan, PDB ID: 6WNP). (B) superposition between the binding mode predicted by SuMD for PF-07321332 (orange) and the crystallographic complex of PF-00835231 within the catalytic site of SARS-CoV-2 M^pro (green, PDB ID: 6XHM).