ArticleNature communications2025
Harnessing artificial intelligence to identify Bufalin as a molecular glue degrader of estrogen receptor alpha.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Bufalin-Loaded Multifunctional Nanodrugs for Cancer Therapy: Mechanisms, Delivery Strategies, and Translational Perspectives.Biomolecules · 2026Review
- Artificial intelligence empowers targeted protein degradation: Core technological innovations, multi-scenario applications, and translational prospects.Smart molecules : open access · 2026Review
- Dual targeting of ferroptosis and immune evasion: STAT3 inhibition as a one-two punch for breast cancer immunotherapy.Journal of translational internal medicine · 2026Article
- SIRT6-Mediated Deacetylation of ATF3 Promotes Silica-Induced Lung Fibrosis by Enhancing its Nuclear Import via Binding to Importin α.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The role of artificial intelligence in precision medicine for breast cancer.Discover oncology · 2026Review
- Bufalin targets E2F2 to transcriptionally inhibit LINC01410 and suppress Wnt/β-catenin signaling in esophageal squamous cell carcinoma.NPJ precision oncology · 2026Article
- Target discovery and drug design in the era of artificial intelligence.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- Virtual and CMC-Based Screening Identified Reticuline, an Intermediate of BIA Biosynthesis, as a Potential Agonist of D5R.Molecules (Basel, Switzerland) · 2026Article
- Targeted Degradation of eEF2K by a Structure-Guided PROTAC Strategy for the Treatment of Triple-Negative Breast Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- A Novel Paradigm for Targeting Challenging Targets: Advancing Technologies and Future Directions of Molecular Glue Degraders.Molecules (Basel, Switzerland) · 2026Review
- Article
- Advances in the Research and Development of Breast Cancer Organoids.Oncology research · 2026Review
- Integrative characterization of Huachansu against hepatocellular carcinoma: chemical profiling, Network pharmacology, andFrontiers in chemistry · 2026Article
- Na,K-ATPase mediated and cardiotonic induced signaling in health and disease.Frontiers in physiology · 2025Review
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
Target identification in natural products plays a critical role in the development of innovative drugs. Bufalin, a compound derived from traditional medicines, has shown promising anti-cancer activity; however, its precise molecular mechanism of action remains unclear. Here, we employ artificial intelligence, molecular docking, and molecular dynamics simulations to elucidate the molecular mechanism of Bufalin. Using an integrated multi-predictive strategy, we identify CYP17A1, ESR1, mTOR, AR, and PRKCD as the potential targets of Bufalin. Subsequent validation via surface plasmon resonance, biotin pulldown, and thermal shift assays confirms Bufalin's direct binding to ESR1, which encodes estrogen receptor alpha (ERα). Molecular docking analyses pinpoint Bufalin's selective interaction with Arg394 on ERα. Molecular dynamic simulations further show that Bufalin acts as a molecular glue, enhancing the interaction between ERα and the E3 ligase STUB1, thereby promoting proteasomal degradation of ERα. Given the therapeutic potential of ERα degradation in overcoming endocrine resistance, we investigate the inhibitory effect of Bufalin on endocrine-resistant models and prove Bufalin reverses Tamoxifen resistance in vitro, in vivo, and in patient-derived breast cancer organoids from tamoxifen-relapsed cases. Collectively, our findings indicate that Bufalin functions as a molecular glue to degrade ERα, offering a potential therapeutic strategy for reversing Tamoxifen resistance.
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Registered trials
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