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

• Published in: International journal of molecular sciences Vol. 22; no. 17; p. 9124
• Main Authors: Ahmad, Bilal, Batool, Maria, Ain, Qurat Ul, Kim, Moon Suk, Choi, Sangdun
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24-08-2021; MDPI
• Subjects: 3CL protease; Acquired immune deficiency syndrome; Affinity; AIDS; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Binding energy; Binding sites; Bonding strength; Catalytic Domain - drug effects; Chymotrypsin; Coronavirus 3C Proteases - antagonists & inhibitors; Coronavirus 3C Proteases - metabolism; Coronavirus Protease Inhibitors - pharmacology; Coronavirus Protease Inhibitors - therapeutic use; Coronaviruses; COVID-19; COVID-19 Drug Treatment; COVID-19 vaccines; Drugs; Free energy; Genomes; Humans; Hydrogen bonds; Lactams - pharmacology; Lactams - therapeutic use; Leucine - pharmacology; Leucine - therapeutic use; Ligands; Lopinavir; Lopinavir - pharmacology; main protease; Middle East respiratory syndrome; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Nitriles - pharmacology; Nitriles - therapeutic use; PF-07321332; Polypeptides; Proline - pharmacology; Proline - therapeutic use; Protease; Protease inhibitors; Proteinase inhibitors; Proteins; Public health; Ritonavir; Ritonavir - pharmacology; RNA polymerase; SARS-CoV-2; SARS-CoV-2 - drug effects; SARS-CoV-2 - enzymology; Severe acute respiratory syndrome coronavirus 2; Simulation; Thermodynamics; Trajectory analysis; α-ketoamide; COVID-19; 3CL protease; SARS-CoV-2; PF-07321332; main protease; α-ketoamide
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22179124

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 (3CL
) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CL
with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CL
-PF-07321332 and 3CL
-α-ketoamide complexes remained stable compared with 3CL
-ritonavir and 3CL
-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 3CL
. 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 3CL
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.