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Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic
Muhammad Yasir1, Jinyoung Park1, Eun-Taek Han2
1Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea.
Abstract:
Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1) is an orphan nuclear receptor encoded by the NR0B1 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.
Insights
This study models the DAX1 protein structure and identifies potential flavonoid compounds that may inhibit its activity. These findings suggest new therapeutic strategies for Ewing Sarcoma (ES) by targeting DAX1.
Area of Science:
- Molecular biology
- Genomics
- Drug discovery
Background:
- DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), encoded by NR0B1, is an orphan nuclear receptor.
- DAX1 plays a significant role in EWS/FLI1-mediated oncogenesis, particularly in Ewing Sarcoma (ES).
Purpose of the Study:
- To model the three-dimensional structure of DAX1.
- To identify potential therapeutic agents, specifically flavonoids, that can interact with DAX1.
- To evaluate the association of DAX1 with other genes in Ewing Sarcoma.
Main Methods:
- Homology modeling was used to predict the DAX1 structure.
- Network analysis was performed on genes associated with Ewing Sarcoma.
- Molecular docking of 132 flavonoids against the DAX1 active site.
- Pharmacogenomics analysis of top docked compounds.
- Molecular Dynamics (MD) simulations for the top five flavonoid-DAX1 complexes.
Main Results:
- A 3D model of DAX1 was successfully generated.
- Molecular docking identified flavonoids with potential binding affinity to DAX1's active pocket.
- MD simulations confirmed stable interactions between selected flavonoids and DAX1.
- Flavonoids demonstrated interactive profiles within the DAX1 active region.
Conclusions:
- Flavonoids show potential as therapeutic agents against DAX1-mediated Ewing Sarcoma.
- Further in-vitro and in-vivo evaluations are warranted to confirm the therapeutic efficacy of these flavonoid-DAX1 interactions.
