Chem Phys Lett . 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

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Chem Phys Lett


. 2021 Dec 18;139294.
doi: 10.1016/j.cplett.2021.139294. Online ahead of print.
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


Julia J Liang ^{1 2} , Eleni Pitsillou ^{1 2} , Katherine Ververis ¹ , Victor Guallar ^{3 4} , Andrew **** ² , Tom C Karagiannis ^{1 5}



Affiliations

• PMID: 34961797
• PMCID: PMC8693950
• DOI: 10.1016/j.cplett.2021.139294

Abstract

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 1.6µM 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.

Keywords: COVID-19; Coronavirus; GRL0617; SARS-CoV-2; hypericin; molecular modelling; papain-like protease.