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In silico and in vitro studies of organoselenium compounds interaction with Mpro and PLpro from SARS-CoV-2
| dc.creator | Omage, Folorunsho Bright | |
| dc.date.accessioned | 2023-04-14T11:16:32Z | |
| dc.date.available | 2023-04-14T11:16:32Z | |
| dc.date.issued | 2023-02-24 | |
| dc.identifier.uri | http://repositorio.ufsm.br/handle/1/28689 | |
| dc.description.abstract | - | eng |
| dc.description.sponsorship | Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES | por |
| dc.language | eng | por |
| dc.publisher | Universidade Federal de Santa Maria | por |
| dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | * |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
| dc.subject | Density Functional Theory (DFT) | eng |
| dc.subject | Molecular Dynamics (MD) | eng |
| dc.subject | ARS-CoV-2 | por |
| dc.subject | Main protease (Mpro) | eng |
| dc.subject | Papain-like protease (PLpro) | eng |
| dc.subject | Covalent inhibition | eng |
| dc.subject | Non-covalent inhibition | eng |
| dc.title | In silico and in vitro studies of organoselenium compounds interaction with Mpro and PLpro from SARS-CoV-2 | eng |
| dc.type | Tese | por |
| dc.description.resumo | The SARS-CoV-2 pandemic has prompted global efforts to develop therapeutics. The main protease of SARS-CoV- 2 (Mpro) and the papain-like protease (PLpro) are essential for viral replication and are key targets for therapeutic development. These two proteases have no equivalent enzymatic analogs in humans and thus no similar cleavage specificity, implying that their inhibition will likely have low or no toxicity. The Mpro activity has more than 11 cleavage sites on larger polyproteins, cleaving the C-terminus of replicase polyproteins with recognition sequence Ile-Leu-Met-Val-Phe-Gln**Ser-Gly-Ala,Cys-Asn where the symbol ** marks the cleavage sites. Inhibiting the activity of Mpro will block viral replication. The enzyme mechanism is via a catalytic dyad formed by a nucleophilic Cysteine (Cys145) activated by a His41 residue. Attacks on substrate leads to a tetrahedral intermediate from which the actual peptide bond cleavage occurs thanks to the back-proton-transfer from His45 of Mpro leading to a thioester after a preliminary proton transfer from Cys145 to His41, which greatly increases the nucleophilic strength of the former residue. PLpro is responsible for cleavages located at the N-terminus of the replicase polyprotein, possessing deubiquitinating/deISGylating activity. Cys111, His272, and Asp286 residues form a catalytic triad in the active site of PLpro, with Cys111 acting as the critical nucleophile in the peptide bond cleavage from the pp1a and pp1ab. The two proteases have very similar mechanisms, and as our results show, there is more to these proteases than meets the eye. Several in vitro assays have revealed that organochalcogen compounds, such as ebselen, inhibit Mpro and PLpro as well as having antiviral activity. However, much remains unknown about the whys and the important role that organochalcogen plays in these mechanisms, which are embedded within the binding site’s structure, dynamics, and energetics. To investigate this, we use a wide range of computational chemistry approaches, including molecular docking, virtual screening, kmeans analysis, molecular dynamics, molecular mechanics, quantum mechanics, and hybrid methods focusing on reactivity. Among the organochalcogens explored, diphenyldiselenide (PhSe)2, a parent compound of diaryl diselenide with a low electrophilic potential, serves as a prototype model for a diselenide as well as a potential therapeutic agent. In Vero cells, the inhibitory concentration of (PhSe)2against SARS-CoV-2 is in the low micromolar range. The free energy landscape for the mechanism of inhibition was computed using a combined molecular dynamic and Density Functional Theory (DFT) approach. We investigated two possible routes of diselenide inhibition in proteases: non-covalent inhibition via pi-stacking interactions with His-41 of Mpro and His-272 of PLpro, and covalent inhibition via the protease-Cys-SePh inhibitor complex. The findings highlight the benefits and drawbacks of diselenide and offer recommendations for rational drug design of bioorganic selenium-based inhibitors. | eng |
| dc.contributor.advisor1 | Rocha, Joao Batista Teixeira da | |
| dc.contributor.advisor1Lattes | http://lattes.cnpq.br/3935055744673018 | por |
| dc.contributor.advisor-co1 | Orian, Laura | |
| dc.contributor.referee1 | Rodriguez, Ihosvany Camps | |
| dc.contributor.referee2 | Bellanda, Massimo | |
| dc.contributor.referee3 | Scott, Ana Ligia Barbour | |
| dc.contributor.referee4 | Sancineto, Luca | |
| dc.creator.Lattes | http://lattes.cnpq.br/6847222536072305 | por |
| dc.publisher.country | Brasil | por |
| dc.publisher.department | Bioquímica | por |
| dc.publisher.initials | UFSM | por |
| dc.publisher.program | Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica | por |
| dc.subject.cnpq | CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA | por |
| dc.publisher.unidade | Centro de Ciências Naturais e Exatas | por |
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