Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease

Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro by formin...

Descripción completa

Detalles Bibliográficos
Autores: Marazzi, Marco Dino Maurizio|||0000-0001-7158-7994, García Iriepa, Cristina|||0000-0002-7577-8242, Hognon, Cécilia
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad de Alcalá (UAH)
Repositorio:e_Buah Biblioteca Digital Universidad de Alcalá
Idioma:inglés
OAI Identifier:oai:ebuah.uah.es:10017/59907
Acceso en línea:http://hdl.handle.net/10017/59907
https://dx.doi.org/10.3390/ijms23105855
Access Level:acceso abierto
Palabra clave:SARS-CoV-2
papain-like protease
covalent inhibitor
molecular dynamics
free energy calculations
Química
Chemistry
id ES_b9936fdd31fd2ee04fb4553bfcdca06a
oai_identifier_str oai:ebuah.uah.es:10017/59907
network_acronym_str ES
network_name_str España
repository_id_str
spelling Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like ProteaseMarazzi, Marco Dino Maurizio|||0000-0001-7158-7994García Iriepa, Cristina|||0000-0002-7577-8242Hognon, CéciliaSARS-CoV-2papain-like proteasecovalent inhibitormolecular dynamicsfree energy calculationsQuímicaChemistryInhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro by forming a covalent bond with a specific residue of the catalytic site (Cys(111)), through a Michael addition reaction. An inhibition mechanism can therefore be proposed, including four steps: (i) ligand entry into the protease pocket; (ii) Cys(111) deprotonation of the thiol group by a Bronsted-Lowry base; (iii) Cys(111)-S- addition to the ligand; and (iv) proton transfer from the protonated base to the covalently bound ligand. Evaluating the energetics and PLpro conformational changes at each of these steps could aid the design of more efficient and selective covalent inhibitors. For this aim, we have studied by means of MD simulations and QM/MM calculations the whole mechanism. Regarding the first step, we show that the inhibitor entry in the PLpro pocket is thermodynamically favorable only when considering the neutral Cys(111), that is, prior to the Cys(111) deprotonation. For the second step, MD simulations revealed that His(272) would deprotonate Cys(111) after overcoming an energy barrier of ca. 32 kcal/mol (at the QM/MM level), but implying a decrease of the inhibitor stability inside the protease pocket. This information points to a reversible Cys(111) deprotonation, whose equilibrium is largely shifted toward the neutral Cys(111) form. Although thermodynamically disfavored, if Cys(111) is deprotonated in close proximity to the vinylic carbon of the ligand, then covalent binding takes place in an irreversible way (third step) to form the enolate intermediate. Finally, due to Cys(111)-S- negative charge redistribution over the bound ligand, proton transfer from the initially protonated His(272) is favored, finally leading to an irreversibly modified Cys(111) and a restored His(272). These results elucidate the selectivity of Cys(111) to enable formation of a covalent bond, even if a weak proton acceptor is available, as His(272).20222022-05-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10017/59907https://dx.doi.org/10.3390/ijms23105855reponame:e_Buah Biblioteca Digital Universidad de Alcaláinstname:Universidad de Alcalá (UAH)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ebuah.uah.es:10017/599072026-06-18T11:13:07Z
dc.title.none.fl_str_mv Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease
title Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease
spellingShingle Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease
Marazzi, Marco Dino Maurizio|||0000-0001-7158-7994
SARS-CoV-2
papain-like protease
covalent inhibitor
molecular dynamics
free energy calculations
Química
Chemistry
title_short Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease
title_full Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease
title_fullStr Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease
title_full_unstemmed Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease
title_sort Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease
dc.creator.none.fl_str_mv Marazzi, Marco Dino Maurizio|||0000-0001-7158-7994
García Iriepa, Cristina|||0000-0002-7577-8242
Hognon, Cécilia
author Marazzi, Marco Dino Maurizio|||0000-0001-7158-7994
author_facet Marazzi, Marco Dino Maurizio|||0000-0001-7158-7994
García Iriepa, Cristina|||0000-0002-7577-8242
Hognon, Cécilia
author_role author
author2 García Iriepa, Cristina|||0000-0002-7577-8242
Hognon, Cécilia
author2_role author
author
dc.subject.none.fl_str_mv SARS-CoV-2
papain-like protease
covalent inhibitor
molecular dynamics
free energy calculations
Química
Chemistry
topic SARS-CoV-2
papain-like protease
covalent inhibitor
molecular dynamics
free energy calculations
Química
Chemistry
description Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro by forming a covalent bond with a specific residue of the catalytic site (Cys(111)), through a Michael addition reaction. An inhibition mechanism can therefore be proposed, including four steps: (i) ligand entry into the protease pocket; (ii) Cys(111) deprotonation of the thiol group by a Bronsted-Lowry base; (iii) Cys(111)-S- addition to the ligand; and (iv) proton transfer from the protonated base to the covalently bound ligand. Evaluating the energetics and PLpro conformational changes at each of these steps could aid the design of more efficient and selective covalent inhibitors. For this aim, we have studied by means of MD simulations and QM/MM calculations the whole mechanism. Regarding the first step, we show that the inhibitor entry in the PLpro pocket is thermodynamically favorable only when considering the neutral Cys(111), that is, prior to the Cys(111) deprotonation. For the second step, MD simulations revealed that His(272) would deprotonate Cys(111) after overcoming an energy barrier of ca. 32 kcal/mol (at the QM/MM level), but implying a decrease of the inhibitor stability inside the protease pocket. This information points to a reversible Cys(111) deprotonation, whose equilibrium is largely shifted toward the neutral Cys(111) form. Although thermodynamically disfavored, if Cys(111) is deprotonated in close proximity to the vinylic carbon of the ligand, then covalent binding takes place in an irreversible way (third step) to form the enolate intermediate. Finally, due to Cys(111)-S- negative charge redistribution over the bound ligand, proton transfer from the initially protonated His(272) is favored, finally leading to an irreversibly modified Cys(111) and a restored His(272). These results elucidate the selectivity of Cys(111) to enable formation of a covalent bond, even if a weak proton acceptor is available, as His(272).
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-05-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10017/59907
https://dx.doi.org/10.3390/ijms23105855
url http://hdl.handle.net/10017/59907
https://dx.doi.org/10.3390/ijms23105855
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:e_Buah Biblioteca Digital Universidad de Alcalá
instname:Universidad de Alcalá (UAH)
instname_str Universidad de Alcalá (UAH)
reponame_str e_Buah Biblioteca Digital Universidad de Alcalá
collection e_Buah Biblioteca Digital Universidad de Alcalá
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869417784512872448
score 15,300719

Similares en LA Referencia