| Title: | Identification of triazolopyrimidinyl scaffold SARS-CoV-2 papain-like protease (PLpro) inhibitor |
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| Authors: | ID Kralj, Sebastjan (Author)
ID Jukič, Marko (Author)
ID Bahun, Miha (Author)
ID Krajnc, Luka (Author)
ID Kolarič, Anja (Author)
ID Hodošček, Milan (Author)
ID Poklar Ulrih, Nataša (Author)
ID Bren, Urban (Author) |
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| Files: |  pharmaceutics-16-00169.pdf (6,86 MB)
MD5: 589EA9EE19F6AA2E9E2CDBD80BC06BD2
 https://www.mdpi.com/1999-4923/16/2/169
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| Language: | English |
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| Work type: | Article |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: | FKKT - Faculty of Chemistry and Chemical Engineering
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| Abstract: | The global impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
and its companion disease, COVID-19, has reminded us of the importance of basic coronaviral
research. In this study, a comprehensive approach using molecular docking, in vitro assays, and
molecular dynamics simulations was applied to identify potential inhibitors for SARS-CoV-2 papainlike protease (PLpro), a key and underexplored viral enzyme target. A focused protease inhibitor
library was initially created and molecular docking was performed using CmDock software (v0.2.0),
resulting in the selection of hit compounds for in vitro testing on the isolated enzyme. Among
them, compound 372 exhibited promising inhibitory properties against PLpro, with an IC50 value of
82 ± 34 µM. The compound also displayed a new triazolopyrimidinyl scaffold not yet represented
within protease inhibitors. Molecular dynamics simulations demonstrated the favorable binding
properties of compound 372. Structural analysis highlighted its key interactions with PLpro, and
we stress its potential for further optimization. Moreover, besides compound 372 as a candidate for
PLpro inhibitor development, this study elaborates on the PLpro binding site dynamics and provides
a valuable contribution for further efforts in pan-coronaviral PLpro inhibitor development. |
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| Keywords: | drug design, protease inhibitor, SARS-CoV-2, papain-like protease, PLpro, antiviral design, in silico drug design, CADD, virtual screening, HTVS, structure-based design |
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| Publication status: | Published |
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| Publication version: | Version of Record |
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| Submitted for review: | 11.12.2023 |
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| Article acceptance date: | 22.01.2024 |
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| Publication date: | 25.01.2024 |
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| Publisher: | MDPI |
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| Year of publishing: | 2024 |
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| Number of pages: | 13 str. |
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| Numbering: | Vol. 16, iss. 2, [article no.] 169 |
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| PID: | 20.500.12556/DKUM-86901  |
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| UDC: | 60:543.2/.9 |
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| ISSN on article: | 1999-4923 |
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| COBISS.SI-ID: | 182627331 |
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| DOI: | 10.3390/pharmaceutics16020169 |
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| Copyright: | © 2024 by the authors |
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| Publication date in DKUM: | 26.01.2024 |
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| Views: | 520 |
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| Downloads: | 51 |
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| Metadata: |    |
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| Categories: | Misc.
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