Docking studies reveal zerumbone targets ß-catenin of the Wnt–ß-catenin pathway in breast cancer

SUMMARY

Breast cancer is the second most common cancer among women worldwide. The Wnt–ß-catenin pathway appears to be deregulated in most can­cer cells including breast cancer. The role of zerumbone, the active sesquiter­pene from Zingiber zerumbet Roscoe, on the Wnt–ß-catenin pathway is relat­ively unknown, especially detailed molecular studies have yet to be published. Using the Chemistry at HARvard Macromolecular Mechanics (CHARMm) force field-based docking protocol, CDOCKER, the molecular interactions between zerumbone and key proteins of the Wnt–ß-catenin pathway were eval­uated in this study. The results suggest that zerumbone has a strong affinity for free ß-catenin in the cytoplasm, as well as the ß-catenin–transcription factor 4 complex in the nucleus. The overall hydrophobic nature of zerumbone allowed its interaction with other hydrophobic residues, such as Trp383, while its active a,ß-unsaturated carbonyl facilitated its interaction with positively charged residues, such as Lys345, Arg386 and Asn415 in the ß-catenin binding pocket. However, the Wnt protein and its frizzled receptor showed no attraction to zer­umbone.