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

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...

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Autores principales: Ahmad, Bilal, Batool, Maria, Ain, Qurat ul, Kim, Moon Suk, Choi, Sangdun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430524/
https://www.ncbi.nlm.nih.gov/pubmed/34502033
http://dx.doi.org/10.3390/ijms22179124
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author Ahmad, Bilal
Batool, Maria
Ain, Qurat ul
Kim, Moon Suk
Choi, Sangdun
author_facet Ahmad, Bilal
Batool, Maria
Ain, Qurat ul
Kim, Moon Suk
Choi, Sangdun
author_sort Ahmad, Bilal
collection PubMed
description 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.
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spelling pubmed-84305242021-09-11 Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations Ahmad, Bilal Batool, Maria Ain, Qurat ul Kim, Moon Suk Choi, Sangdun Int J Mol Sci Article 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. MDPI 2021-08-24 /pmc/articles/PMC8430524/ /pubmed/34502033 http://dx.doi.org/10.3390/ijms22179124 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ahmad, Bilal
Batool, Maria
Ain, Qurat ul
Kim, Moon Suk
Choi, Sangdun
Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations
title Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations
title_full Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations
title_fullStr Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations
title_full_unstemmed Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations
title_short Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations
title_sort exploring the binding mechanism of pf-07321332 sars-cov-2 protease inhibitor through molecular dynamics and binding free energy simulations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430524/
https://www.ncbi.nlm.nih.gov/pubmed/34502033
http://dx.doi.org/10.3390/ijms22179124
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