Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulations
Abstract In the twenty-first century, we have witnessed multiple coronavirus pandemics. Despite declining SARS-CoV-2 cases, continued research remains vital. We report the discovery of sydowiol B, a natural product, as a dual inhibitor of SARS-CoV-2 main protease (Mpro) and papain-like protease (PLp...
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| Format: | Article |
| Language: | English |
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SpringerOpen
2025-01-01
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| Series: | Natural Products and Bioprospecting |
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| Online Access: | https://doi.org/10.1007/s13659-024-00486-4 |
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| _version_ | 1841559030991945728 |
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| author | Xiaoxia Gu Xiaotian Zhang Xueke Zhang Xinyu Wang Weiguang Sun Yonghui Zhang Zhengxi Hu |
| author_facet | Xiaoxia Gu Xiaotian Zhang Xueke Zhang Xinyu Wang Weiguang Sun Yonghui Zhang Zhengxi Hu |
| author_sort | Xiaoxia Gu |
| collection | DOAJ |
| description | Abstract In the twenty-first century, we have witnessed multiple coronavirus pandemics. Despite declining SARS-CoV-2 cases, continued research remains vital. We report the discovery of sydowiol B, a natural product, as a dual inhibitor of SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro). Sydowiol B interacts with the nano-channel at the Mpro dimer interface and the PLpro active site. Molecular dynamics simulations suggest that sydowiol B inhibits Mpro by limiting active site expansion rather than inducing collapse. Furthermore, sydowiol B binding may amplify the fluctuation of two loops coordinating with the structural Zn2+ in PLpro, displacing Zn2+ from the zinc finger domain to the S2 helix. Sydowiol B and its analogue, violaceol I, exhibit broad-spectrum antiviral activity against homologous coronaviruses. Given the conservation of Mpro and PLpro, sydowiol B and violaceol I are promising leads for designing and developing anti-coronavirus therapies. Graphical Abstract |
| format | Article |
| id | doaj-art-da16cd7e1cae42458a062bb04ceed82d |
| institution | Kabale University |
| issn | 2192-2195 2192-2209 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Natural Products and Bioprospecting |
| spelling | doaj-art-da16cd7e1cae42458a062bb04ceed82d2025-01-05T12:49:56ZengSpringerOpenNatural Products and Bioprospecting2192-21952192-22092025-01-0115112110.1007/s13659-024-00486-4Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulationsXiaoxia Gu0Xiaotian Zhang1Xueke Zhang2Xinyu Wang3Weiguang Sun4Yonghui Zhang5Zhengxi Hu6Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyAbstract In the twenty-first century, we have witnessed multiple coronavirus pandemics. Despite declining SARS-CoV-2 cases, continued research remains vital. We report the discovery of sydowiol B, a natural product, as a dual inhibitor of SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro). Sydowiol B interacts with the nano-channel at the Mpro dimer interface and the PLpro active site. Molecular dynamics simulations suggest that sydowiol B inhibits Mpro by limiting active site expansion rather than inducing collapse. Furthermore, sydowiol B binding may amplify the fluctuation of two loops coordinating with the structural Zn2+ in PLpro, displacing Zn2+ from the zinc finger domain to the S2 helix. Sydowiol B and its analogue, violaceol I, exhibit broad-spectrum antiviral activity against homologous coronaviruses. Given the conservation of Mpro and PLpro, sydowiol B and violaceol I are promising leads for designing and developing anti-coronavirus therapies. Graphical Abstracthttps://doi.org/10.1007/s13659-024-00486-4SARS-CoV-2PLproMproNatural productDual inhibitorNano-channel |
| spellingShingle | Xiaoxia Gu Xiaotian Zhang Xueke Zhang Xinyu Wang Weiguang Sun Yonghui Zhang Zhengxi Hu Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulations Natural Products and Bioprospecting SARS-CoV-2 PLpro Mpro Natural product Dual inhibitor Nano-channel |
| title | Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulations |
| title_full | Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulations |
| title_fullStr | Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulations |
| title_full_unstemmed | Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulations |
| title_short | Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulations |
| title_sort | unveiling the mechanism of action of a novel natural dual inhibitor of sars cov 2 mpro and plpro with molecular dynamics simulations |
| topic | SARS-CoV-2 PLpro Mpro Natural product Dual inhibitor Nano-channel |
| url | https://doi.org/10.1007/s13659-024-00486-4 |
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