Molecular simulation strategies for the discovery of selective inhibitors of β-catenin

Tumor dissemination and relapse in lung cancer were found to be due to the existence of cancer stem cells. In particular, the beta-catenin pathway is found to be one of the crucial pathways in maintaining the stem-like properties of the cells. Thus, targeting the beta-catenin family of proteins is a significant therapeutic route in the treatment of lung cancer. Therefore, in the present study, a pharmacophore-based drug repurposing approach was accomplished to pinpoint potent beta-catenin inhibitors from the DrugBank database. Primarily, ligand-based pharmacophore hypothesis (AAHHR) was generated using existing -catenin inhibitors available in the literature and utilized for library screening. Subsequently, the inhibitory activity of the screened compounds was examined by the hierarchical docking process and the Prime MM-GBSA algorithm. Moreover, quantum chemical calculations and molecular dynamics simulations were executed to analyze the inhibitory effects of the screened hit molecule. The results indicate that hit molecule, DB08047 was found to possess better binding free energy, favorable ligand strain energy, satisfactory pharmacokinetic properties and superior free energy landscape profile. Eventually, the pIC(50) values of the lead compounds were predicted by the AutoQSAR algorithm. It is noteworthy to mention that DB08047 was found to possess pyrazole scaffolds which could downregulate beta-catenin pathway and thus facilitate the controlled cell growth/inhibit tumor growth.