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dc.contributor.authorLiang, Julia
dc.contributor.authorPitsillou, Eleni
dc.contributor.authorVerverisa, Katherine
dc.contributor.authorGuallar, Victor
dc.contributor.authorHung, Andrew
dc.contributor.authorKaragiannis, Tom C.
dc.contributor.otherBarcelona Supercomputing Center
dc.date.accessioned2021-12-09T13:29:54Z
dc.date.available2023-10-11T00:26:36Z
dc.date.issued2022
dc.identifier.citationLiang, J. [et al.]. Small molecule interactions with the SARS-CoV-2 main protease: In silico all-atom microsecond MD simulations, PELE Monte Carlo simulations, and determination of in vitro activity inhibition. "Journal of Molecular Graphics and Modelling", 2022, vol. 110, 108050.
dc.identifier.issn1093-3263
dc.identifier.urihttp://hdl.handle.net/2117/358009
dc.description.abstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing COVID-19 pandemic. With some notable exceptions, safe and effective vaccines, which are now being widely distributed globally, have largely begun to stabilise the situation. However, emerging variants of concern and vaccine hesitancy are apparent obstacles to eradication. Therefore, the need for the development of potent antivirals is still of importance. In this context, the SARS-CoV-2 main protease (Mpro) is a critical target and numerous clinical trials, predominantly in the private domain, are currently in progress. Here, our aim was to extend our previous studies, with hypericin and cyanidin-3-O-glucoside, as potential inhibitors of the SARS-CoV-2 Mpro. Firstly, we performed all-atom microsecond molecular dynamics simulations, which highlight the stability of the ligands in the Mpro active site over the duration of the trajectories. We also invoked PELE Monte Carlo simulations which indicate that both hypericin and cyanidin-3-O-glucoside preferentially interact with the Mpro active site and known allosteric sites. For further validation, we performed an in vitro enzymatic activity assay that demonstrated that hypericin and cyanidin-3-O-glucoside inhibit Mpro activity in a dose-dependent manner at biologically relevant (μM) concentrations. However, both ligands are much less potent than the well-known covalent antiviral GC376, which was used as a positive control in our experiments. Nevertheless, the biologically relevant activity of hypericin and cyanidin-3-O-glucoside is encouraging. In particular, a synthetic version of hypericin has FDA orphan drug designation, which could simplify potential clinical evaluation in the context of COVID-19. }
dc.description.sponsorshipWe would like to acknowledge intellectual and financial support by McCord Research (Iowa, USA). JL is supported by an Australian Government Research Training Program Scholarship. We are indebted to Alfonso Perez Escudero and the team at Crowdfight COVID-19 for enabling access to supercomputing facilities. We thank the National Computing Infrastructure (NCI), and the Pawsey Supercomputing Centre in Australia (funded by the Australian Government). Further, we thank the Spartan High Performance Computing service (University of Melbourne), and the Partnership for Advanced Computing in Europe (PRACE) for awarding the access to Piz Daint, hosted at the Swiss National Supercomputing Centre (CSCS), Switzerland.
dc.format.extent9 p.
dc.language.isoeng
dc.publisherElsevier
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 Spain
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
dc.subjectÀrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
dc.subject.lcshCOVID-19 (Disease)
dc.subject.lcshSimulació per ordinador
dc.subject.lcshIn vitro
dc.subject.lcshMolecules
dc.subject.otherCoronavirus
dc.subject.otherCOVID-19
dc.subject.otherSARS-CoV-2
dc.subject.otherMain protease
dc.subject.otherGC376
dc.subject.otherHypericin
dc.subject.otherCyanidin-3-O-glucoside
dc.subject.otherMolecular modelling
dc.titleSmall molecule interactions with the SARS-CoV-2 main protease: In silico all-atom microsecond MD simulations, PELE Monte Carlo simulations, and determination of in vitro activity inhibition
dc.typeArticle
dc.subject.lemacCOVID-19 (Malaltia)
dc.identifier.doi10.1016/j.jmgm.2021.108050
dc.description.peerreviewedPeer Reviewed
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S1093326321002217
dc.rights.accessOpen Access
dc.description.versionPostprint (author's final draft)
local.citation.other108050
local.citation.publicationNameJournal of Molecular Graphics and Modelling
local.citation.volume110


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