Investigation of small molecule inhibitors of the SARS-CoV-2 papain-like protease by all-atom microsecond modelling, PELE Monte Carlo simulations, and in vitro activity inhibition

The SARS-CoV-2 papain-like (PLpro) protease is essential for viral replication. We investigated potential antiviral effects of hypericin relative to the well-known noncovalent PLpro inhibitor GRL-0617. Molecular dynamics and PELE Monte Carlo simulations highlight favourable binding of hypericin and...

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Detalles Bibliográficos
Autores: Liang, Julia J., Pitsillou, Eleni, Ververis, Katherine, Guallar, Víctor|||0000-0002-4580-1114, Hung, Andrew, Karagiannis, Tom C.
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Politècnica de Catalunya (UPC)
Repositorio:UPCommons. Portal del coneixement obert de la UPC
Idioma:inglés
OAI Identifier:oai:upcommons.upc.edu:2117/367571
Acceso en línea:https://hdl.handle.net/2117/367571
https://dx.doi.org/10.1016/j.cplett.2021.139294
Access Level:acceso abierto
Palabra clave:COVID-19 (Disease)
Molecular dynamics
Acute respiratory syndrome, Severe
Pandemics & COVID-19
Coronavirus
COVID-19
SARS-CoV-2
Papain-like protease
GRL0617
Hypericin
Molecular modelling
COVID-19 (Malaltia)
Simulació per ordinador
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
Descripción
Sumario:The SARS-CoV-2 papain-like (PLpro) protease is essential for viral replication. We investigated potential antiviral effects of hypericin relative to the well-known noncovalent PLpro inhibitor GRL-0617. Molecular dynamics and PELE Monte Carlo simulations highlight favourable binding of hypericin and GRL-0617 to the naphthalene binding pocket of PLpro. Although not potent as GRL-0617 (45.8 vs 1.6 µM for protease activity, respectively), in vitro fluorogenic enzymatic assays with hypericin show concentration-dependent inhibition of both PLpro protease and deubiquitinating activities. Given its use in supplementations and the FDA conditional approval of a synthetic version, further evaluation of hypericin as a potential SARS-CoV-2 antiviral is warranted.

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