Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations

Abstract

The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, α-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CLpro–PF-07321332 and 3CLpro–α-ketoamide complexes remained stable compared with 3CLpro–ritonavir and 3CLpro–lopinavir. Investigating the dynamic behavior of ligand–protein interaction, ligands PF-07321332 and α-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41–Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of α-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.

Design of SARS-CoV-2 Mpro, PLpro Dual-Target Inhibitors Based on Deep Reinforcement Learning and Virtual Screening

“…This demonstrated that all three compounds effectively occupy the catalytic dyad of the Mpro and prevent its substrate from binding to the Mpro. A recent study showed that PF-07321332 and α-ketoamide performed better than Lopinavir and Ritonavir, due to their ability to disrupt the catalytic dyad residue His41-Cys145 of Mpro [ 53 ]. These three compounds disrupt the catalytic dyad by interacting with His41-Cys145, which is similar to PF-07321332 and α-ketoamide.…”

Molecular Interactions of Tannic Acid with Proteins Associated with SARS-CoV-2 Infectivity

“…To date, remdesivir has been approved by the U.S. Food and Drug Administration (FDA), but it is not recommended by the World Health Organization due to insufficient evidence of its effectiveness against COVID-19. The mutagenic ribonucleoside molnupiravir [ 53 ] and the 3CLpro inhibitor nirmatrelvir/PF-07321332 (Paxlovid ® ) [ 54 ] are two recently FDA-approved oral antivirals for the treatment of COVID-19. However, there are some safety concerns regarding molnupiravir, as it can cause mutations in host cells [ 55 ].…”

Targeting SARS-CoV-2 Proteases for COVID-19 Antiviral Development

“…To examine the binding mode of the novel PLpro inhibitors, authors obtained co-crystal structures of XR8-24, XR8-65, XR8-69, XR8-83, and XR8-89 with SARS-CoV-2 PLpro (PDB: 7LBR, 7LBS, 7LLF, 7LLZ, and 7LOS) (Table 1). Superposition of the ligand-bound structures shows all inhibitors utilized the same binding mode similar to GRL0617, including closure of BL loop and H bond between amide of inhibitor and D164 and Q269 (Osipiuk et al, 2021a;Gao et al, 2021;Ratia et al, 2008;Ahmad et al, 2021). The analysis of the representative cocrystal structures of XR8-24 and XR8-89 found that the azetidine ring extends into Site I to interact with side chain of E168 (Figures 5B,C) (Shen et al, 2021).…”