Structure based pharmacophore modeling, virtual screening and molecular docking approaches for identification of natural anti-cancer metastasis agents targeting Wnt/β- catenin pathway

Cancer metastasis is a multi-stage process in which a cancer cell spreads from the primary site of the lesion,passes through the circulatory system, and establishes a secondary tumor at a new nonadjacent organ.Dietary phytochemicals (DPs) modulate numerous biological events including epigenetic changes andsignaling transduction pathways such as Wnt/β-catenin. Some of these compounds which stabilize cell-celladhesions are controversial topics that change the expression of a variety of Wnt target genes. So they mayinduce cell-cycle arrest, apoptosis, and/or inhibition of Epithelial-Mesenchymal Transition (EMT) andmetastasis. Natural molecules that target the Wnt/β-catenin pathway include flavonoids, polyphenols,terpenes and terpenoids, secosteroids, and alkaloids.In this study, we aimed to discover novel potent WNT/β-catenin pathway inhibitors through β-catenin (PDBID: ۱JDH) structure-based virtual screening and pharmacophore modeling. ۲۸ bioactive molecules wereselected from different plants, after which we performed analyzes such as molecular docking, pharmacophoremodeling, and Lipinski's Rule of Five (RO۵) filter. The Camptothecin molecule had the best ligand-basedpharmacophore model and docking energy. This model was applied to screen Pubchem molecular librarywith more than ۹.۳ million compounds for the novel β-catenin inhibitor. The hits were subsequently subjectedto molecular docking after being filtered by Lipinski’s rules. After screening the molecular library throughmolecular docking, pharmacophore modeling, and Lipinski's Rule of Five (RO۵) filter, we proposed eightcompounds out of ۵۳۹ structurally representative top hits as the most potent inhibitors (Compound CID:۱۱۳۱۷۶۴۷; ۱۰۲۳۳۵۶۰۱; ۱۳۷۳۱۳۶۲۵; ۱۲۹۶۷۰۵۱۶; ۵۷۲۴۴۱۴۹; ۹۰۶۸۰۰۹۷; ۹۰۶۸۰۰۹۸; ۵۷۰۱۶۱۰۴).Finally, the novel inhibitors proposed in this study need further consideration to uncovering cancer treatmentand with the generated pharmacophore model, more potent β-catenin inhibitors can be easily screened.

کلیدواژه ها:

β-catenin inhibitors ، Cancer metastasis ، molecular docking ، pharmacophore modeling