Molecular docking-aided identification of small molecule inhibitors targeting β-catenin-TCF4 interaction
| Autor: | Gokce Oguz, Srdan Masirevic, Gocha Tenzin, Xiaoqian Zhang, Ramanuj DasGupta, Hao Fan, Joo-Leng Low, Ming Wei Chen, Weina Du, Daniel Guo Rong Yim, Iain Beehuat Tan, Adaikalavan Ramasamy |
|---|---|
| Přispěvatelé: | School of Biological Sciences, BioSciences Research Centre |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Science In silico Omics 02 engineering and technology Computational biology Biochemistry Article 03 medical and health sciences In vivo Cancer Pharmacology Multidisciplinary Chemistry Effector Wnt signaling pathway Biological sciences [Science] 021001 nanoscience & nanotechnology Small molecule In vitro 030104 developmental biology Structural biology Catenin 0210 nano-technology |
| Zdroj: | iScience, Vol 24, Iss 6, Pp 102544-(2021) iScience |
| ISSN: | 2589-0042 |
| DOI: | 10.1016/j.isci.2021.102544 |
| Popis: | Summary Here we report a molecular docking-based approach to identify small molecules that can target the β-catenin (β-cat)-TCF4 protein-protein interaction (PPI), a key effector complex for nuclear Wnt signaling activity. Specifically, we developed and optimized a computational model of β-cat using publicly available β-cat protein crystal structures, and existing β-cat-TCF4 interaction inhibitors as the training set. Using our computational model to an in silico screen predicted 27 compounds as good binders to β-cat, of which 3 were identified to be effective against a Wnt-responsive luciferase reporter. In vitro functional validation experiments revealed GB1874 as an inhibitor of the Wnt pathway that targets the β-cat-TCF4 PPI. GB1874 also affected the proliferation and stemness of Wnt-addicted colorectal cancer (CRC) cells in vitro. Encouragingly, GB1874 inhibited the growth of CRC tumor xenografts in vivo, thus demonstrating its potential for further development into therapeutics against Wnt-associated cancer indications. Graphical abstract Highlights • A computational docking model for β-catenin was developed and optimized. • The model was trained using protein crystal structures and known inhibitor compounds. • Compound GB1874 was identified by in silico screening and functionally validated. • GB1874 inhibited colon cancer growth in vitro and in vivo by blocking Wnt activity. Pharmacology; Biochemistry; Structural biology; Cancer; Omics |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|