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

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Autores principales: Liang, Julia J., Pitsillou, Eleni, Ververis, Katherine, Guallar, Victor, Hung, Andrew, Karagiannis, Tom C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier B.V. 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8693950/
https://www.ncbi.nlm.nih.gov/pubmed/34961797
http://dx.doi.org/10.1016/j.cplett.2021.139294
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author Liang, Julia J.
Pitsillou, Eleni
Ververis, Katherine
Guallar, Victor
Hung, Andrew
Karagiannis, Tom C.
author_facet Liang, Julia J.
Pitsillou, Eleni
Ververis, Katherine
Guallar, Victor
Hung, Andrew
Karagiannis, Tom C.
author_sort Liang, Julia J.
collection PubMed
description The SARS-CoV-2 papain-like (PL(pro)) protease is essential for viral replication. We investigated potential antiviral effects of hypericin relative to the well-known noncovalent PL(pro) inhibitor GRL-0617. Molecular dynamics and PELE Monte Carlo simulations highlight favourable binding of hypericin and GRL-0617 to the naphthalene binding pocket of PL(pro). 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 PL(pro) 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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spelling pubmed-86939502021-12-23 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 Liang, Julia J. Pitsillou, Eleni Ververis, Katherine Guallar, Victor Hung, Andrew Karagiannis, Tom C. Chem Phys Lett Article The SARS-CoV-2 papain-like (PL(pro)) protease is essential for viral replication. We investigated potential antiviral effects of hypericin relative to the well-known noncovalent PL(pro) inhibitor GRL-0617. Molecular dynamics and PELE Monte Carlo simulations highlight favourable binding of hypericin and GRL-0617 to the naphthalene binding pocket of PL(pro). 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 PL(pro) 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. Elsevier B.V. 2022-02-16 2021-12-18 /pmc/articles/PMC8693950/ /pubmed/34961797 http://dx.doi.org/10.1016/j.cplett.2021.139294 Text en © 2021 Elsevier B.V. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Liang, Julia J.
Pitsillou, Eleni
Ververis, Katherine
Guallar, Victor
Hung, Andrew
Karagiannis, Tom C.
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8693950/
https://www.ncbi.nlm.nih.gov/pubmed/34961797
http://dx.doi.org/10.1016/j.cplett.2021.139294
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