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Antioxidants
Volume 14
Issue 5
10.3390/antiox14050546
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Identification of Food-Derived Electrophilic Chalcones as Nrf2 Activators Using Comprehensive Virtual Screening Techniques

by
Bingyu Bai
1,2,
Piaohan Tu
1,3,
Jiayi Weng
1,2,
Yan Zhang
1,2,
Quan Lin
1,2,
Mitchell N. Muskat
4,
Jie Wang
1,2,
Xue Tang
1,2 and
Xiangrong Cheng
1,2,*
1
School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
2
State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
3
Beilun Market Supervision Administration, Ningbo 315800, China
4
Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
*
Author to whom correspondence should be addressed.
Antioxidants 2025, 14(5), 546; https://doi.org/10.3390/antiox14050546
Submission received: 8 April 2025 / Revised: 28 April 2025 / Accepted: 28 April 2025 / Published: 30 April 2025
Versions Notes

Abstract

Electrophilic compounds are bioactive components commonly found in foods that are capable of covalently modifying nucleophilic sites on biologically functional macromolecules. These compounds may elicit positive bioactivity or negative biotoxicity, posing significant challenges in terms of time and resource expenditure in the de novo characterization of their biological activity. In this study, we developed a database of 332 food-derived electrophilic compounds and used a semi-supervised k-nearest neighbors (KNN) machine learning model to predict their bioactivity. Molecular docking analysis identified the three chalcone compounds with the highest potential positive activity—4-hydroxyderricin (4HD), isoliquiritigenin (ISO), and butein. Furthermore, in cell experiments, treatment with 4HD, ISO, and butein significantly reduced reactive oxygen species (ROS) levels. An RT-qPCR analysis demonstrated that these chalcones significantly upregulated the mRNA expression of Nrf2 and its downstream antioxidant genes, including Nqo1, HO-1, Gsr, Gclc, and Gclm. ISO’s cytoprotective and antioxidant effects were abolished following these findings, which highlight that 4HD, ISO, and butein are effective Nrf2 activators and suggest that comprehensive virtual technology is a promising strategy for identifying functional bioactive compounds.
Keywords: electrophilic compounds; machine learning; molecular docking; Nrf2 activators; chalcones electrophilic compounds; machine learning; molecular docking; Nrf2 activators; chalcones

Share and Cite

MDPI and ACS Style

Bai, B.; Tu, P.; Weng, J.; Zhang, Y.; Lin, Q.; Muskat, M.N.; Wang, J.; Tang, X.; Cheng, X. Identification of Food-Derived Electrophilic Chalcones as Nrf2 Activators Using Comprehensive Virtual Screening Techniques. Antioxidants 2025, 14, 546. https://doi.org/10.3390/antiox14050546

AMA Style

Bai B, Tu P, Weng J, Zhang Y, Lin Q, Muskat MN, Wang J, Tang X, Cheng X. Identification of Food-Derived Electrophilic Chalcones as Nrf2 Activators Using Comprehensive Virtual Screening Techniques. Antioxidants. 2025; 14(5):546. https://doi.org/10.3390/antiox14050546

Chicago/Turabian Style

Bai, Bingyu, Piaohan Tu, Jiayi Weng, Yan Zhang, Quan Lin, Mitchell N. Muskat, Jie Wang, Xue Tang, and Xiangrong Cheng. 2025. "Identification of Food-Derived Electrophilic Chalcones as Nrf2 Activators Using Comprehensive Virtual Screening Techniques" Antioxidants 14, no. 5: 546. https://doi.org/10.3390/antiox14050546

APA Style

Bai, B., Tu, P., Weng, J., Zhang, Y., Lin, Q., Muskat, M. N., Wang, J., Tang, X., & Cheng, X. (2025). Identification of Food-Derived Electrophilic Chalcones as Nrf2 Activators Using Comprehensive Virtual Screening Techniques. Antioxidants, 14(5), 546. https://doi.org/10.3390/antiox14050546

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