SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an import...
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| Format: | Article |
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MDPI AG
2021-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/8/3957 |
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| author | Adam Stasiulewicz Alicja W. Maksymiuk Mai Lan Nguyen Barbara Bełza Joanna I. Sulkowska |
| author_facet | Adam Stasiulewicz Alicja W. Maksymiuk Mai Lan Nguyen Barbara Bełza Joanna I. Sulkowska |
| author_sort | Adam Stasiulewicz |
| collection | DOAJ |
| description | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC<sub>50</sub> values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC<sub>50</sub> values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs. |
| first_indexed | 2024-03-10T12:24:47Z |
| format | Article |
| id | doaj.art-13d1cef9439e4b52942aaaabc875b462 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:24:47Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-13d1cef9439e4b52942aaaabc875b4622023-11-21T15:08:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01228395710.3390/ijms22083957SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative AssessmentAdam Stasiulewicz0Alicja W. Maksymiuk1Mai Lan Nguyen2Barbara Bełza3Joanna I. Sulkowska4Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, PolandCentre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, PolandCentre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, PolandCentre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, PolandCentre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, PolandSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC<sub>50</sub> values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC<sub>50</sub> values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs.https://www.mdpi.com/1422-0067/22/8/3957SARS-CoV-2COVID-19coronavirusPLpropapain-like proteaseUCH-L1 |
| spellingShingle | Adam Stasiulewicz Alicja W. Maksymiuk Mai Lan Nguyen Barbara Bełza Joanna I. Sulkowska SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment International Journal of Molecular Sciences SARS-CoV-2 COVID-19 coronavirus PLpro papain-like protease UCH-L1 |
| title | SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment |
| title_full | SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment |
| title_fullStr | SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment |
| title_full_unstemmed | SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment |
| title_short | SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment |
| title_sort | sars cov 2 papain like protease potential inhibitors in silico quantitative assessment |
| topic | SARS-CoV-2 COVID-19 coronavirus PLpro papain-like protease UCH-L1 |
| url | https://www.mdpi.com/1422-0067/22/8/3957 |
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