Exploring the potential of thiazole derivatives in modulating the Wnt/β-catenin pathway for colon cancer therapy

Colon cancer is one of the second leading death-causing diseases among cancer in the whole world. The majority of colon cancers are Adenocarcinomas, which is due to the mutation of the APC gene that leads to uncontrolled activation of the Wnt/β-catenin pathway. This present study attempts to discover a thiazole derivative as a potential anti-cancer agent using structural and ligand-based in-silico approaches. To begin with, a set of thiazole derivatives was identified from a literature survey, and a molecule was selected as the lead component by using pharmacophore modeling. Then, lead optimization was done by substituting various substituents to the chosen molecule, approximately 144 molecules were obtained, and these molecules were filtered using a 3D-QSAR study based on the IC50 value and about 88 of them were selected for molecular docking with standard drug trifluridine. After docking with β-catenin protein (PDB ID:1JDH) only 17 potential molecules were selected for ADMET analysis based on the binding energy. Compound 8l: 4-hydroxyphenyl)(4-(4-methoxyphenyl)thiazole-2-yl)methanone displayed substantial pharmacokinetic and drug-like properties and was chosen for further investigation. This chosen compound was subjected to molecular dynamics simulation and molecular mechanics (MM-GBSA) analysis, and its results were compared with Trifluridine to evaluate complex stability, protein–ligand interactions, and its potential as an anti-cancer agent.