Supercomputing Multi-Ligand Modeling, Simulation, Wavelet Analysis and Surface Plasmon Resonance to Develop Novel Combination Drugs: A Case Study of Arbidol and Baicalein Against Main Protease of SARS-CoV-2
<b>Background/Objectives</b>: Combination therapies using traditional Chinese medicine and Western drugs have gained attention for their enhanced therapeutic effects and reduced side effects. Toujie Quwen Granules (TQG), known for its antiviral properties, particularly against respirator...
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2025-07-01
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| author | Hong Li Hailong Su Akari Komori Shuxuan Yang Hailang Luo Angela Wei Hong Yang Xiaomin Sun Hongwei Li Andrew Hung Xiaoshan Zhao |
| author_facet | Hong Li Hailong Su Akari Komori Shuxuan Yang Hailang Luo Angela Wei Hong Yang Xiaomin Sun Hongwei Li Andrew Hung Xiaoshan Zhao |
| author_sort | Hong Li |
| collection | DOAJ |
| description | <b>Background/Objectives</b>: Combination therapies using traditional Chinese medicine and Western drugs have gained attention for their enhanced therapeutic effects and reduced side effects. Toujie Quwen Granules (TQG), known for its antiviral properties, particularly against respiratory viruses, could offer new treatment strategies when combined with antiviral drugs like arbidol, especially for diseases such as Coronavirus disease. This study investigates the synergistic mechanisms between arbidol and components from TQG against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M<sup>pro</sup>). <b>Methods</b>: We identified compounds from TQG via existing data. Multi-ligand molecular docking, pharmacokinetic/toxicity screening, and preliminary simulations were performed to assess potential synergistic compounds with arbidol. UPLC-Q-Exactive Orbitrap-MS verified the presence of these compounds. Extended simulations and in vitro assays, including Luciferase and surface plasmon resonance, validated the findings. <b>Results</b>: Five compounds interacted with arbidol in synergy based on docking and preliminary dynamics simulation results. Only Baicalein (HQA004) could be identified in the herbal remedy by untargeted metabolomics, with ideal pharmacokinetic properties, and as a non-toxic compound. Extended simulations revealed that HQA004 enhanced arbidol’s antiviral activity via a <i>“Far” Addition Mechanism #2</i>, with an optimal 2:1 arbidol:HQA004 ratio. The movements of arbidol (diffusion and intramolecular conformational shifts) in the system were significantly reduced by HQA004, which may be the main reason for the synergism that occurred. In vitro experiments confirmed an increased inhibition of M<sup>pro</sup> by the combination. <b>Conclusions</b>: HQA004 demonstrated synergistic potential with arbidol in inhibiting M<sup>pro</sup>. The development of combination therapies integrating Western and herbal medicine is supported by these findings for effective antiviral treatments. |
| format | Article |
| id | doaj-art-25fa5b0b44fc462cb4d5eafa53b3bbdc |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj-art-25fa5b0b44fc462cb4d5eafa53b3bbdc2025-08-20T03:32:17ZengMDPI AGPharmaceuticals1424-82472025-07-01187105410.3390/ph18071054Supercomputing Multi-Ligand Modeling, Simulation, Wavelet Analysis and Surface Plasmon Resonance to Develop Novel Combination Drugs: A Case Study of Arbidol and Baicalein Against Main Protease of SARS-CoV-2Hong Li0Hailong Su1Akari Komori2Shuxuan Yang3Hailang Luo4Angela Wei Hong Yang5Xiaomin Sun6Hongwei Li7Andrew Hung8Xiaoshan Zhao9Department of Traditional Chinese Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, ChinaSchool of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, ChinaSchool of Science, STEM College, RMIT University, Melbourne, VIC 3000, AustraliaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, ChinaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, ChinaSchool of Health and Biomedical Sciences, STEM College, RMIT University, Bundoora, VIC 3083, AustraliaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, ChinaSchool of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, ChinaSchool of Science, STEM College, RMIT University, Melbourne, VIC 3000, AustraliaDepartment of Traditional Chinese Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China<b>Background/Objectives</b>: Combination therapies using traditional Chinese medicine and Western drugs have gained attention for their enhanced therapeutic effects and reduced side effects. Toujie Quwen Granules (TQG), known for its antiviral properties, particularly against respiratory viruses, could offer new treatment strategies when combined with antiviral drugs like arbidol, especially for diseases such as Coronavirus disease. This study investigates the synergistic mechanisms between arbidol and components from TQG against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M<sup>pro</sup>). <b>Methods</b>: We identified compounds from TQG via existing data. Multi-ligand molecular docking, pharmacokinetic/toxicity screening, and preliminary simulations were performed to assess potential synergistic compounds with arbidol. UPLC-Q-Exactive Orbitrap-MS verified the presence of these compounds. Extended simulations and in vitro assays, including Luciferase and surface plasmon resonance, validated the findings. <b>Results</b>: Five compounds interacted with arbidol in synergy based on docking and preliminary dynamics simulation results. Only Baicalein (HQA004) could be identified in the herbal remedy by untargeted metabolomics, with ideal pharmacokinetic properties, and as a non-toxic compound. Extended simulations revealed that HQA004 enhanced arbidol’s antiviral activity via a <i>“Far” Addition Mechanism #2</i>, with an optimal 2:1 arbidol:HQA004 ratio. The movements of arbidol (diffusion and intramolecular conformational shifts) in the system were significantly reduced by HQA004, which may be the main reason for the synergism that occurred. In vitro experiments confirmed an increased inhibition of M<sup>pro</sup> by the combination. <b>Conclusions</b>: HQA004 demonstrated synergistic potential with arbidol in inhibiting M<sup>pro</sup>. The development of combination therapies integrating Western and herbal medicine is supported by these findings for effective antiviral treatments.https://www.mdpi.com/1424-8247/18/7/1054synergismstructure-based multi-ligand molecular modelingumifenovirToujie Quwen GranulesCOVID-19 |
| spellingShingle | Hong Li Hailong Su Akari Komori Shuxuan Yang Hailang Luo Angela Wei Hong Yang Xiaomin Sun Hongwei Li Andrew Hung Xiaoshan Zhao Supercomputing Multi-Ligand Modeling, Simulation, Wavelet Analysis and Surface Plasmon Resonance to Develop Novel Combination Drugs: A Case Study of Arbidol and Baicalein Against Main Protease of SARS-CoV-2 Pharmaceuticals synergism structure-based multi-ligand molecular modeling umifenovir Toujie Quwen Granules COVID-19 |
| title | Supercomputing Multi-Ligand Modeling, Simulation, Wavelet Analysis and Surface Plasmon Resonance to Develop Novel Combination Drugs: A Case Study of Arbidol and Baicalein Against Main Protease of SARS-CoV-2 |
| title_full | Supercomputing Multi-Ligand Modeling, Simulation, Wavelet Analysis and Surface Plasmon Resonance to Develop Novel Combination Drugs: A Case Study of Arbidol and Baicalein Against Main Protease of SARS-CoV-2 |
| title_fullStr | Supercomputing Multi-Ligand Modeling, Simulation, Wavelet Analysis and Surface Plasmon Resonance to Develop Novel Combination Drugs: A Case Study of Arbidol and Baicalein Against Main Protease of SARS-CoV-2 |
| title_full_unstemmed | Supercomputing Multi-Ligand Modeling, Simulation, Wavelet Analysis and Surface Plasmon Resonance to Develop Novel Combination Drugs: A Case Study of Arbidol and Baicalein Against Main Protease of SARS-CoV-2 |
| title_short | Supercomputing Multi-Ligand Modeling, Simulation, Wavelet Analysis and Surface Plasmon Resonance to Develop Novel Combination Drugs: A Case Study of Arbidol and Baicalein Against Main Protease of SARS-CoV-2 |
| title_sort | supercomputing multi ligand modeling simulation wavelet analysis and surface plasmon resonance to develop novel combination drugs a case study of arbidol and baicalein against main protease of sars cov 2 |
| topic | synergism structure-based multi-ligand molecular modeling umifenovir Toujie Quwen Granules COVID-19 |
| url | https://www.mdpi.com/1424-8247/18/7/1054 |
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