| Title: | Ensemble Docking Coupled to Linear Interaction Energy Calculations for Identification of Coronavirus Main Protease (3CLpro) Non-Covalent Small-Molecule Inhibitors |
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| Authors: | ID Jukič, Marko, Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia (Author)
ID Janežič, Dušanka, Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagoljaška 8, SI-6000 Koper, Slovenia (Author)
ID Bren, Urban, Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia (Author) |
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| Files: |  Jukic-2020-Ensemble_Docking_Coupled_to_Linear.pdf (3,08 MB)
MD5: 328FB87242D418E631F17D563AB2F367
 https://doi.org/10.3390/molecules25245808
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| Language: | English |
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| Work type: | Scientific work |
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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: | SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new strain of Coronaviridae. In the closing 2019 to early 2020 months, the virus caused a global pandemic of COVID-19 disease. We performed a virtual screening study in order to identify potential inhibitors of the SARS-CoV-2 main viral protease (3CLpro or Mpro). For this purpose, we developed a novel approach using ensemble docking high-throughput virtual screening directly coupled with subsequent Linear Interaction Energy (LIE) calculations to maximize the conformational space sampling and to assess the binding affinity of identified inhibitors. A large database of small commercial compounds was prepared, and top-scoring hits were identified with two compounds singled out, namely 1-[(R)-2-(1,3-benzimidazol-2-yl)-1-pyrrolidinyl]-2-(4-methyl-1,4-diazepan-1-yl)-1-ethanone and [({(S)-1-[(1H-indol-2-yl)methyl]-3-pyrrolidinyl}methyl)amino](5-methyl-2H-pyrazol-3-yl)formaldehyde. Moreover, we obtained a favorable binding free energy of the identified compounds, and using contact analysis we confirmed their stable binding modes in the 3CLpro active site. These compounds will facilitate further 3CLpro inhibitor design. |
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| Keywords: | COVID-19, SARS-CoV-2, Mpro, 3CLpro, 3C-like protease, virtual screening, inhibitors, in silico drug design, free-energy calculations |
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| Publication status: | Published |
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| Publication version: | Version of Record |
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| Submitted for review: | 05.11.2020 |
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| Article acceptance date: | 06.12.2020 |
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| Publication date: | 09.12.2020 |
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| Publisher: | MDPI |
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| Year of publishing: | 2020 |
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| Number of pages: | Str. 1-11 |
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| Numbering: | Letn. 25, št. 24, št. članka 5808 |
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| PID: | 20.500.12556/DKUM-78347  |
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| UDC: | 578.834 |
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| ISSN on article: | 1420-3049 |
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| COBISS.SI-ID: | 42014467 |
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| DOI: | 10.3390/molecules25245808 |
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| NUK URN: | URN:SI:UM:DK:MPK4OGWH |
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| Publication date in DKUM: | 10.12.2020 |
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| Views: | 1252 |
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| Downloads: | 189 |
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| Metadata: |    |
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| Categories: | Misc.
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JUKIČ, Marko, JANEŽIČ, Dušanka and BREN, Urban, 2020, Ensemble Docking Coupled to Linear Interaction Energy Calculations for Identification of Coronavirus Main Protease (3CLpro) Non-Covalent Small-Molecule Inhibitors. Molecules [online]. 2020. Vol. 25, no. 24, članka 5808, p. 1–11. [Accessed 8 April 2025]. DOI 10.3390/molecules25245808. Retrieved from: https://dk.um.si/IzpisGradiva.php?lang=eng&id=78347
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