Identification of highly effective inhibitors against SARS-CoV-2 main protease: From virtual screening to in vitro study
Background and Objective: The public’s safety has been significantly jeopardized by the pandemic of COVID-19, which is brought on by the highly virulent and contagious SARS-CoV-2 virus. Finding novel antiviral drugs is currently of utmost importance for the treatment of patients with COVID-19. Main...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1036208/full |
| _version_ | 1811307585368752128 |
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| author | Hu Wang Jun Wen Yang Yang Hailin Liu Song Wang Xiaoli Ding Chunqiao Zhou Xuelin Zhang |
| author_facet | Hu Wang Jun Wen Yang Yang Hailin Liu Song Wang Xiaoli Ding Chunqiao Zhou Xuelin Zhang |
| author_sort | Hu Wang |
| collection | DOAJ |
| description | Background and Objective: The public’s safety has been significantly jeopardized by the pandemic of COVID-19, which is brought on by the highly virulent and contagious SARS-CoV-2 virus. Finding novel antiviral drugs is currently of utmost importance for the treatment of patients with COVID-19. Main protease (3CLpro) of SARS-CoV-2 is involved in replication of virus, so it is considered as a promising target. Using small molecules to inhibit SARS-CoV-2-3CLpro activity may be an effective way to prevent viral replication to fight COVID-19. Despite the fact that some SARS-CoV-2-3CLpro inhibitors have been described, only few of them have high levels of inhibition at nanomolar concentrations. In this study, we aimed to screen out effective SARS-CoV-2-3CLpro inhibitors.Methods: To identify highly effective SARS-CoV-2-3CLpro inhibitors, a pharmacophore mapping and multiple-conformation docking were efficiently applied to find novel hit compounds from a database. Then, the stability of the 3CLpro-hit complexes was validated by using molecular dynamics simulation. Finally, biological assay was used to assess the inhibition effects of hit compounds on SARS-CoV-2-3CLpro.Results: Four hit compounds were identified by using computer-assisted strategy. Molecular dynamics simulation suggested that these hits bound stably to the 3CLpro-active pocket. Bioassay showed that all the hits had potent inhibition against SARS-CoV-2-3CLpro with IC50 values in the range of 0.017–0.83 μM. Particularly, hit one was the best 3CLpro inhibitor and its inhibition effect of SARS-CoV-2-3CLpro (IC50 = 0.017 ± 0.003 µM) was about 236 times stronger than that of ML300 (IC50 = 4.01 ± 0.66 µM).Conclusion: These data indicate that hit one could be regarded as an anti-SARS-CoV-2 candidate worth exploring further for the treatment of COVID-19. |
| first_indexed | 2024-04-13T09:07:00Z |
| format | Article |
| id | doaj.art-9562ae29309b45548587914046ff0df1 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T09:07:00Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-9562ae29309b45548587914046ff0df12022-12-22T02:52:58ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-11-011310.3389/fphar.2022.10362081036208Identification of highly effective inhibitors against SARS-CoV-2 main protease: From virtual screening to in vitro studyHu Wang0Jun Wen1Yang Yang2Hailin Liu3Song Wang4Xiaoli Ding5Chunqiao Zhou6Xuelin Zhang7Department of Pharmacy, The First People’s Hospital of Chongqing Liang Jiang New Area, Chongqing, ChinaDepartment of Pharmacy, The First People’s Hospital of Chongqing Liang Jiang New Area, Chongqing, ChinaDepartment of Pharmacy, The First People’s Hospital of Chongqing Liang Jiang New Area, Chongqing, ChinaDepartment of Pharmacy, The First People’s Hospital of Chongqing Liang Jiang New Area, Chongqing, ChinaDepartment of Pharmacy, The First People’s Hospital of Chongqing Liang Jiang New Area, Chongqing, ChinaDepartment of Pharmacy, The First People’s Hospital of Chongqing Liang Jiang New Area, Chongqing, ChinaDepartment of Pharmacy, The First People’s Hospital of Chongqing Liang Jiang New Area, Chongqing, ChinaDepartment of Pharmacy, The First People’s Hospital of Chongqing Liang Jiang New Area, Chongqing, ChinaBackground and Objective: The public’s safety has been significantly jeopardized by the pandemic of COVID-19, which is brought on by the highly virulent and contagious SARS-CoV-2 virus. Finding novel antiviral drugs is currently of utmost importance for the treatment of patients with COVID-19. Main protease (3CLpro) of SARS-CoV-2 is involved in replication of virus, so it is considered as a promising target. Using small molecules to inhibit SARS-CoV-2-3CLpro activity may be an effective way to prevent viral replication to fight COVID-19. Despite the fact that some SARS-CoV-2-3CLpro inhibitors have been described, only few of them have high levels of inhibition at nanomolar concentrations. In this study, we aimed to screen out effective SARS-CoV-2-3CLpro inhibitors.Methods: To identify highly effective SARS-CoV-2-3CLpro inhibitors, a pharmacophore mapping and multiple-conformation docking were efficiently applied to find novel hit compounds from a database. Then, the stability of the 3CLpro-hit complexes was validated by using molecular dynamics simulation. Finally, biological assay was used to assess the inhibition effects of hit compounds on SARS-CoV-2-3CLpro.Results: Four hit compounds were identified by using computer-assisted strategy. Molecular dynamics simulation suggested that these hits bound stably to the 3CLpro-active pocket. Bioassay showed that all the hits had potent inhibition against SARS-CoV-2-3CLpro with IC50 values in the range of 0.017–0.83 μM. Particularly, hit one was the best 3CLpro inhibitor and its inhibition effect of SARS-CoV-2-3CLpro (IC50 = 0.017 ± 0.003 µM) was about 236 times stronger than that of ML300 (IC50 = 4.01 ± 0.66 µM).Conclusion: These data indicate that hit one could be regarded as an anti-SARS-CoV-2 candidate worth exploring further for the treatment of COVID-19.https://www.frontiersin.org/articles/10.3389/fphar.2022.1036208/fullSARS CoV-2main proteasevirtual screeningmolecular dynamics simulationinhibitor |
| spellingShingle | Hu Wang Jun Wen Yang Yang Hailin Liu Song Wang Xiaoli Ding Chunqiao Zhou Xuelin Zhang Identification of highly effective inhibitors against SARS-CoV-2 main protease: From virtual screening to in vitro study Frontiers in Pharmacology SARS CoV-2 main protease virtual screening molecular dynamics simulation inhibitor |
| title | Identification of highly effective inhibitors against SARS-CoV-2 main protease: From virtual screening to in vitro study |
| title_full | Identification of highly effective inhibitors against SARS-CoV-2 main protease: From virtual screening to in vitro study |
| title_fullStr | Identification of highly effective inhibitors against SARS-CoV-2 main protease: From virtual screening to in vitro study |
| title_full_unstemmed | Identification of highly effective inhibitors against SARS-CoV-2 main protease: From virtual screening to in vitro study |
| title_short | Identification of highly effective inhibitors against SARS-CoV-2 main protease: From virtual screening to in vitro study |
| title_sort | identification of highly effective inhibitors against sars cov 2 main protease from virtual screening to in vitro study |
| topic | SARS CoV-2 main protease virtual screening molecular dynamics simulation inhibitor |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1036208/full |
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