Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation Studies
Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1) is an orphan nuclear receptor encoded by the <i>NR0B1</i> gene. The functional study showed that DAX1 is a physiologically significant target for EWS/FLI1-mediated oncogenesis, particularly...
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MDPI AG
2023-05-01
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| author | Muhammad Yasir Jinyoung Park Eun-Taek Han Won Sun Park Jin-Hee Han Yong-Soo Kwon Hee-Jae Lee Mubashir Hassan Andrzej Kloczkowski Wanjoo Chun |
| author_facet | Muhammad Yasir Jinyoung Park Eun-Taek Han Won Sun Park Jin-Hee Han Yong-Soo Kwon Hee-Jae Lee Mubashir Hassan Andrzej Kloczkowski Wanjoo Chun |
| author_sort | Muhammad Yasir |
| collection | DOAJ |
| description | Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1) is an orphan nuclear receptor encoded by the <i>NR0B1</i> gene. The functional study showed that DAX1 is a physiologically significant target for EWS/FLI1-mediated oncogenesis, particularly Ewing Sarcoma (ES). In this study, a three-dimensional DAX1 structure was modeled by employing a homology modeling approach. Furthermore, the network analysis of genes involved in Ewing Sarcoma was also carried out to evaluate the association of DAX1 and other genes with ES. Moreover, a molecular docking study was carried out to check the binding profile of screened flavonoid compounds against DAX1. Therefore, 132 flavonoids were docked in the predicted active binding pocket of DAX1. Moreover, the pharmacogenomics analysis was performed for the top ten docked compounds to evaluate the ES-related gene clusters. As a result, the five best flavonoid-docked complexes were selected and further evaluated by Molecular Dynamics (MD) simulation studies at 100 ns. The MD simulation trajectories were evaluated by generating RMSD, hydrogen bond plot analysis, and interaction energy graphs. Our results demonstrate that flavonoids showed interactive profiles in the active region of DAX1 and can be used as potential therapeutic agents against DAX1-mediated augmentation of ES after in-vitro and in-vivo evaluations. |
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| issn | 1661-6596 1422-0067 |
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| last_indexed | 2024-03-11T03:05:31Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-41613c7d097d4e60a8d15a00ca0ab6bc2023-11-18T07:57:34ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012411933210.3390/ijms24119332Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation StudiesMuhammad Yasir0Jinyoung Park1Eun-Taek Han2Won Sun Park3Jin-Hee Han4Yong-Soo Kwon5Hee-Jae Lee6Mubashir Hassan7Andrzej Kloczkowski8Wanjoo Chun9Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of KoreaDepartment of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of KoreaDepartment of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon 24341, Republic of KoreaDepartment of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of KoreaDepartment of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon 24341, Republic of KoreaCollege of Pharmacy, Kangwon National University School of Medicine, Chuncheon 24341, Republic of KoreaDepartment of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of KoreaThe Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH 43205, USAThe Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH 43205, USADepartment of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of KoreaDosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1) is an orphan nuclear receptor encoded by the <i>NR0B1</i> gene. The functional study showed that DAX1 is a physiologically significant target for EWS/FLI1-mediated oncogenesis, particularly Ewing Sarcoma (ES). In this study, a three-dimensional DAX1 structure was modeled by employing a homology modeling approach. Furthermore, the network analysis of genes involved in Ewing Sarcoma was also carried out to evaluate the association of DAX1 and other genes with ES. Moreover, a molecular docking study was carried out to check the binding profile of screened flavonoid compounds against DAX1. Therefore, 132 flavonoids were docked in the predicted active binding pocket of DAX1. Moreover, the pharmacogenomics analysis was performed for the top ten docked compounds to evaluate the ES-related gene clusters. As a result, the five best flavonoid-docked complexes were selected and further evaluated by Molecular Dynamics (MD) simulation studies at 100 ns. The MD simulation trajectories were evaluated by generating RMSD, hydrogen bond plot analysis, and interaction energy graphs. Our results demonstrate that flavonoids showed interactive profiles in the active region of DAX1 and can be used as potential therapeutic agents against DAX1-mediated augmentation of ES after in-vitro and in-vivo evaluations.https://www.mdpi.com/1422-0067/24/11/9332Ewing sarcomaDAX1flavonoidsmolecular dockingpharmacogenomicsmolecular dynamics simulation |
| spellingShingle | Muhammad Yasir Jinyoung Park Eun-Taek Han Won Sun Park Jin-Hee Han Yong-Soo Kwon Hee-Jae Lee Mubashir Hassan Andrzej Kloczkowski Wanjoo Chun Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation Studies International Journal of Molecular Sciences Ewing sarcoma DAX1 flavonoids molecular docking pharmacogenomics molecular dynamics simulation |
| title | Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation Studies |
| title_full | Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation Studies |
| title_fullStr | Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation Studies |
| title_full_unstemmed | Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation Studies |
| title_short | Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation Studies |
| title_sort | investigation of flavonoid scaffolds as dax1 inhibitors against ewing sarcoma through pharmacoinformatic and dynamic simulation studies |
| topic | Ewing sarcoma DAX1 flavonoids molecular docking pharmacogenomics molecular dynamics simulation |
| url | https://www.mdpi.com/1422-0067/24/11/9332 |
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