Discovery of the Cryptic Sites of SARS-CoV-2 Papain-like Protease and Analysis of Its Druggability
In late 2019, a new coronavirus (CoV) caused the outbreak of a deadly respiratory disease, resulting in the COVID-19 pandemic. In view of the ongoing pandemic, there is an immediate need to find drugs to treat patients. SARS-CoV-2 papain-like cysteine protease (PLpro) not only plays an important rol...
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| Format: | Article |
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/19/11265 |
| _version_ | 1797479097395314688 |
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| author | Yue Qiu Qing Liu Gao Tu Xiao-Jun Yao |
| author_facet | Yue Qiu Qing Liu Gao Tu Xiao-Jun Yao |
| author_sort | Yue Qiu |
| collection | DOAJ |
| description | In late 2019, a new coronavirus (CoV) caused the outbreak of a deadly respiratory disease, resulting in the COVID-19 pandemic. In view of the ongoing pandemic, there is an immediate need to find drugs to treat patients. SARS-CoV-2 papain-like cysteine protease (PLpro) not only plays an important role in the pathogenesis of the virus but is also a target protein for the development of inhibitor drugs. Therefore, to develop targeted inhibitors, it is necessary to analyse and verify PLpro sites and explore whether there are other cryptic binding pockets with better activity. In this study, first, we detected the site of the whole PLpro protein by sitemap of Schrödinger (version 2018), the cavity of LigBuilder V3, and DeepSite, and roughly judged the possible activated binding site area. Then, we used the mixed solvent dynamics simulation (MixMD) of probe molecules to induce conformational changes in the protein to find the possible cryptic active sites. Finally, the TRAPP method was used to predict the druggability of cryptic pockets and analyse the changes in the physicochemical properties of residues around these sites. This work will help promote the research of SARS-CoV-2 PLpro inhibitors. |
| first_indexed | 2024-03-09T21:40:52Z |
| format | Article |
| id | doaj.art-25bce4ea34094471b126c03ca9cae0c2 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:40:52Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-25bce4ea34094471b126c03ca9cae0c22023-11-23T20:30:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123191126510.3390/ijms231911265Discovery of the Cryptic Sites of SARS-CoV-2 Papain-like Protease and Analysis of Its DruggabilityYue Qiu0Qing Liu1Gao Tu2Xiao-Jun Yao3Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, ChinaDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, ChinaDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, ChinaDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, ChinaIn late 2019, a new coronavirus (CoV) caused the outbreak of a deadly respiratory disease, resulting in the COVID-19 pandemic. In view of the ongoing pandemic, there is an immediate need to find drugs to treat patients. SARS-CoV-2 papain-like cysteine protease (PLpro) not only plays an important role in the pathogenesis of the virus but is also a target protein for the development of inhibitor drugs. Therefore, to develop targeted inhibitors, it is necessary to analyse and verify PLpro sites and explore whether there are other cryptic binding pockets with better activity. In this study, first, we detected the site of the whole PLpro protein by sitemap of Schrödinger (version 2018), the cavity of LigBuilder V3, and DeepSite, and roughly judged the possible activated binding site area. Then, we used the mixed solvent dynamics simulation (MixMD) of probe molecules to induce conformational changes in the protein to find the possible cryptic active sites. Finally, the TRAPP method was used to predict the druggability of cryptic pockets and analyse the changes in the physicochemical properties of residues around these sites. This work will help promote the research of SARS-CoV-2 PLpro inhibitors.https://www.mdpi.com/1422-0067/23/19/11265COVID-19SARS-CoV-2 PLproMixMDProbeviewTRAPPdruggability |
| spellingShingle | Yue Qiu Qing Liu Gao Tu Xiao-Jun Yao Discovery of the Cryptic Sites of SARS-CoV-2 Papain-like Protease and Analysis of Its Druggability International Journal of Molecular Sciences COVID-19 SARS-CoV-2 PLpro MixMD Probeview TRAPP druggability |
| title | Discovery of the Cryptic Sites of SARS-CoV-2 Papain-like Protease and Analysis of Its Druggability |
| title_full | Discovery of the Cryptic Sites of SARS-CoV-2 Papain-like Protease and Analysis of Its Druggability |
| title_fullStr | Discovery of the Cryptic Sites of SARS-CoV-2 Papain-like Protease and Analysis of Its Druggability |
| title_full_unstemmed | Discovery of the Cryptic Sites of SARS-CoV-2 Papain-like Protease and Analysis of Its Druggability |
| title_short | Discovery of the Cryptic Sites of SARS-CoV-2 Papain-like Protease and Analysis of Its Druggability |
| title_sort | discovery of the cryptic sites of sars cov 2 papain like protease and analysis of its druggability |
| topic | COVID-19 SARS-CoV-2 PLpro MixMD Probeview TRAPP druggability |
| url | https://www.mdpi.com/1422-0067/23/19/11265 |
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