Targeting the β-catenin–TCF binding interface for cancer therapy: In silico exploration of Cucumis sativus phytochemicals using Induced-Fit Docking, Molecular Dynamics and ADMET analysis

Background The Wnt/β-catenin signaling pathway plays a vital role in embryogenesis, stem cell regulation, and tissue homeostasis. Aberrant activation of this pathway has been linked to the initiation and progression of various cancers. β-Catenin, a key transcriptional coactivator in this pathway, interacts with T cell factor/Lymphoid enhancer-binding factor (TCF/LEF) transcription factors to drive gene expression critical for oncogenesis. Disrupting this protein–protein interaction (PPI) by directly targeting β-catenin presents a promising therapeutic approach for suppressing oncogenic Wnt signaling. Cucumis sativus contains a variety of phytochemicals—such as flavonoids, triterpenoids, and cucurbitacins—known for their anti-inflammatory, antioxidant, and anticancer activities. In this study, computational techniques, including molecular docking and molecular dynamics (MD) simulations, were employed to identify potential β-catenin–TCF interaction inhibitors among bioactive compounds from C. sativus . Additionally, absorption, distribution, metabolism, excretion, toxicity (ADMET) predictions were carried out to assess the pharmacokinetic and toxicity profiles of the most promising candidates, offering insights into their potential as lead compounds in anticancer drug development. Results The results from binding affinity scores, docking poses, and interaction analyses indicate that Isovitexin-7-O-(6-O-glucosyl)-glucoside (− 9.811 kcal/mol), Cucumerin C (− 8.454 kcal/mol), Kaempferol 3-O-glucoside (− 7.869 kcal/mol), and Kaempferol 3-O-rhamnoside (− 7.738 kcal/mol) are promising inhibitors of the β-catenin–TCF protein–protein interaction. MD simulations showed the stability of the β-catenin–Cucumerin C complex over time. Furthermore, ADMET predictions supported the drug-likeness and favorable pharmacokinetic properties of Cucumerin C, Kaempferol 3-O-rhamnoside, and Isovitexin, highlighting their potential as lead compounds for further anticancer drug development. Conclusion This study demonstrates the potential of C. sativus phytocompounds as inhibitors of the β-catenin–TCF interaction, suggesting that this plant may serve as a valuable natural source of lead compounds for the development of anticancer agents targeting the Wnt/β-catenin signaling pathway.