Discovery of Multitarget-Directed Ligands Against Influenza A Virus From Compound Yizhihao Through a Predictive System for Compound-Protein Interactions
Influenza A virus (IAV) is a threat to public health due to its high mutation rate and resistance to existing drugs. In this investigation, 15 targets selected from an influenza virus–host interaction network were successfully constructed as a multitarget virtual screening system for new drug discov...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-02-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fcimb.2020.00016/full |
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| author | Lvjie Xu Wen Jiang Hao Jia Lishu Zheng Jianguo Xing Ailin Liu Guanhua Du |
| author_facet | Lvjie Xu Wen Jiang Hao Jia Lishu Zheng Jianguo Xing Ailin Liu Guanhua Du |
| author_sort | Lvjie Xu |
| collection | DOAJ |
| description | Influenza A virus (IAV) is a threat to public health due to its high mutation rate and resistance to existing drugs. In this investigation, 15 targets selected from an influenza virus–host interaction network were successfully constructed as a multitarget virtual screening system for new drug discovery against IAV using Naïve Bayesian, recursive partitioning, and CDOCKER methods. The predictive accuracies of the models were evaluated using training sets and test sets. The system was then used to predict active constituents of Compound Yizhihao (CYZH), a Chinese medicinal compound used to treat influenza. Twenty-eight compounds with multitarget activities were selected for subsequent in vitro evaluation. Of the four compounds predicted to be active on neuraminidase (NA), chlorogenic acid, and orientin showed inhibitory activity in vitro. Linarin, sinensetin, cedar acid, isoliquiritigenin, sinigrin, luteolin, chlorogenic acid, orientin, epigoitrin, and rupestonic acid exhibited significant effects on TNF-α expression, which is almost consistent with predicted results. Results from a cytopathic effect (CPE) reduction assay revealed acacetin, indirubin, tryptanthrin, quercetin, luteolin, emodin, and apigenin had protective effects against wild-type strains of IAV. Quercetin, luteolin, and apigenin had good efficacy against resistant IAV strains in CPE reduction assays. Finally, with the aid of Gene Ontology biological process analysis, the potential mechanisms of CYZH action were revealed. In conclusion, a compound-protein interaction-prediction system was an efficient tool for the discovery of novel compounds against influenza, and the findings from CYZH provide important information for its usage and development. |
| first_indexed | 2024-12-22T11:03:44Z |
| format | Article |
| id | doaj.art-6cf05588019242e0a84c1fd1afc66442 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-12-22T11:03:44Z |
| publishDate | 2020-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-6cf05588019242e0a84c1fd1afc664422022-12-21T18:28:23ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882020-02-011010.3389/fcimb.2020.00016506264Discovery of Multitarget-Directed Ligands Against Influenza A Virus From Compound Yizhihao Through a Predictive System for Compound-Protein InteractionsLvjie Xu0Wen Jiang1Hao Jia2Lishu Zheng3Jianguo Xing4Ailin Liu5Guanhua Du6Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, ChinaThe Sixth Clinical Hospital of Xinjiang Medical University, Ürümqi, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, ChinaChinese Center for Disease Control and Prevention, National Institute for Viral Disease Control and Prevention, Beijing, ChinaXinjiang Institute of Materia Medica, Ürümqi, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, ChinaInfluenza A virus (IAV) is a threat to public health due to its high mutation rate and resistance to existing drugs. In this investigation, 15 targets selected from an influenza virus–host interaction network were successfully constructed as a multitarget virtual screening system for new drug discovery against IAV using Naïve Bayesian, recursive partitioning, and CDOCKER methods. The predictive accuracies of the models were evaluated using training sets and test sets. The system was then used to predict active constituents of Compound Yizhihao (CYZH), a Chinese medicinal compound used to treat influenza. Twenty-eight compounds with multitarget activities were selected for subsequent in vitro evaluation. Of the four compounds predicted to be active on neuraminidase (NA), chlorogenic acid, and orientin showed inhibitory activity in vitro. Linarin, sinensetin, cedar acid, isoliquiritigenin, sinigrin, luteolin, chlorogenic acid, orientin, epigoitrin, and rupestonic acid exhibited significant effects on TNF-α expression, which is almost consistent with predicted results. Results from a cytopathic effect (CPE) reduction assay revealed acacetin, indirubin, tryptanthrin, quercetin, luteolin, emodin, and apigenin had protective effects against wild-type strains of IAV. Quercetin, luteolin, and apigenin had good efficacy against resistant IAV strains in CPE reduction assays. Finally, with the aid of Gene Ontology biological process analysis, the potential mechanisms of CYZH action were revealed. In conclusion, a compound-protein interaction-prediction system was an efficient tool for the discovery of novel compounds against influenza, and the findings from CYZH provide important information for its usage and development.https://www.frontiersin.org/article/10.3389/fcimb.2020.00016/fullinfluenza A viruscompound yizhihaomultitargetvirtual screeningin vitro evaluationbiological process analysis |
| spellingShingle | Lvjie Xu Wen Jiang Hao Jia Lishu Zheng Jianguo Xing Ailin Liu Guanhua Du Discovery of Multitarget-Directed Ligands Against Influenza A Virus From Compound Yizhihao Through a Predictive System for Compound-Protein Interactions Frontiers in Cellular and Infection Microbiology influenza A virus compound yizhihao multitarget virtual screening in vitro evaluation biological process analysis |
| title | Discovery of Multitarget-Directed Ligands Against Influenza A Virus From Compound Yizhihao Through a Predictive System for Compound-Protein Interactions |
| title_full | Discovery of Multitarget-Directed Ligands Against Influenza A Virus From Compound Yizhihao Through a Predictive System for Compound-Protein Interactions |
| title_fullStr | Discovery of Multitarget-Directed Ligands Against Influenza A Virus From Compound Yizhihao Through a Predictive System for Compound-Protein Interactions |
| title_full_unstemmed | Discovery of Multitarget-Directed Ligands Against Influenza A Virus From Compound Yizhihao Through a Predictive System for Compound-Protein Interactions |
| title_short | Discovery of Multitarget-Directed Ligands Against Influenza A Virus From Compound Yizhihao Through a Predictive System for Compound-Protein Interactions |
| title_sort | discovery of multitarget directed ligands against influenza a virus from compound yizhihao through a predictive system for compound protein interactions |
| topic | influenza A virus compound yizhihao multitarget virtual screening in vitro evaluation biological process analysis |
| url | https://www.frontiersin.org/article/10.3389/fcimb.2020.00016/full |
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