Discovery of small molecule modulators targeting β-catenin interactions using molecular docking and molecular dynamics strategy

Abstract

The rapid activation of signaling pathways is the primary factor responsible for the progression of serious malignancies. Particularly, overexpression of β-catenin is one of the preventative oncogenic biomarkers that is widely present in many tumor types. Therefore, we have designed an integrated pharmacophore strategy to discover the potential inhibitor against β-catenin. Primarily, the ligand-, energy-optimized and the receptor cavity-based pharmacophore hypothesis AAHHR, ADR and ANNNRRR were constructed to screen the active molecules from the database. In order to improve the screening efficacy, the resultant molecules were scrutinized by integrating the results obtained through docking and MM/GBSA calculations. Further, the common hit molecules were subjected to a pharmacokinetic and toxicity study which resulted in two potent β-catenin inhibitors: BAS03014832 and BAS01077671. The existence of thiazole and pyrazole moiety is responsible for the anti-neoplastic activity of these molecules. Finally, a deep neural network technique was used to assess the inhibitory action of these compounds across 66 colorectal cancer cell lines. Overall, the results of our study portray a pathway for the experimental biologist in developing selective β-catenin inhibitors.