Computational insights into β-catenin–tcf inhibition by bioactive compounds from Cucumis sativus for cancer treatment

Abstract 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 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 anti-cancer 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 anti-cancer 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 anti-cancer 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 anti-cancer agents targeting the Wnt/β-catenin signaling pathway.