Molecular docking studies of flavonoids for their inhibition pattern against β‑catenin and pharmacophore model generation from experimentally known flavonoids to fabricate more potent inhibitors for Wnt signaling pathway

Background: Canonical Wnt signaling plays a key role in tumor cell proliferation, which correlates with the accumulation of β‑catenin in cell due to inactivation of glycogen synthetase kinase‑3 β. However, uncontrolled expression of β‑catenin leads to fibromatosis, sarcoma and mesenchymal tumor formation. Recently, a number of polyphenolic compounds of naturally occurring flavonoid family have been screened for the inhibition of Wnt signaling. Objective: Elucidation of the binding mode of inhibitors to β‑catenin, reporting more potent inhibitors for the disease‑causing protein and designing a pharmacophore model based on naturally occurring compounds, flavonoids. Materials and Methods: In this study, a comparative molecular docking analysis was performed to elucidate the binding mode of experimentally reported and unknown inhibitors. Based on the knowledge of geometry, binding affinity and drug score, we described a subset of novel inhibitors. Results: The binding energy of known inhibitors (isorhamnetin, fisetin, genistein and silibinin) was observed in a range of −5.68 to −4.98 kcal/mol, while novel inhibitors (catechin, luteolin, coumestrol and β‑naphthoflavone) exhibited −6.50 to −5.22 kcal/mol. We observed good placement and strong interactions of selected compounds inside the binding pocket of β‑catenin. Moreover, flavonoid family members and T cell factors 4 (TCF4) compete for β‑catenin binding by sharing common binding residues. Conclusion: This study will largely help in understanding the molecular basis of β‑catenin/TCF4 inhibition through flavonoids by exploring their structural details. Finally, the novel inhibitors proposed in this study need further attention to uncover cancer treatment and with the generated pharmacophore model, more and potent β‑catenin inhibitors can be easily screened.