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.
Highlights
The recent outbreak of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affected more than 192 million people and killed 4.1 million across the globe [1,2]
To elucidate the mechanism of binding of PF-07321332 (PF), α-ketoamide, lopinavir, and ritonavir with 3-chymotrypsin like protease (3CLpro), all complexes were subjected to 100 ns simulations in Gromacs
We have explored the binding of PF-07321332, α-ketoamide, lopinavir, and ritonavir to SARS-CoV-2 3CLpro through molecular dynamic (MD) simulation and molecular mechanics Poisson–Boltzmann surface area (MMPBSA) calculation
Summary
The recent outbreak of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affected more than 192 million people and killed 4.1 million across the globe (as of 23 July 2021) [1,2]. The genomic organizations of SARS-CoV and MERSCoV are similar [7] and both viruses comprise two polypeptides, pp1a and pp1ab. These polypeptides are processed into nonstructural proteins that play a fundamental part in the replication of these viruses, and the whole process is mediated by two kinds of main proteases: 3-chymotrypsin like protease (3CLpro) and papain-like proteases [8,9]. Antiretroviral drugs have been tested in past human coronavirus infections and against SARS-CoV-2, but a recent clinical trial of lopinavir and ritonavir failed to show any clinical benefit in COVID-19 disease. The bespoke clinical candidate PF-07321332 (NCT04756531) is a potent protease inhibitor with potent antiviral activity against SARS-CoV-2
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