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 pro ) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CL pro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CL pro –PF-07321332 and 3CL pro –α-ketoamide complexes remained stable compared with 3CL pro –ritonavir and 3CL pro –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 pro . 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 pro 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.
【저자키워드】 COVID-19, SARS-CoV-2, main protease, 3CL Protease, PF-07321332, α-ketoamide, 【초록키워드】 coronavirus disease, coronavirus, Antiviral, Lopinavir, Ritonavir, 3CL pro, docking, protease, novel coronavirus disease, binding affinity, MD simulation, binding energy, Novel coronavirus, trajectory, PF-07321332, molecular, respiratory, optimization, affinity, binding, Ligand, Interaction, Analysis, severe acute respiratory coronavirus 2, low potency, global public health, SARS-CoV-2 protease, severe acute respiratory coronavirus, residue, Compound, chymotrypsin, catalytic dyad, Cys145, His41, binding mechanism, LOPINAVIR AND RITONAVIR, Respiratory Coronavirus, caused, remained, calculated, demonstrated, complexes, disrupt, 【제목키워드】 Dynamics, Simulation, energy, Free,