The mechanism of action of the scorpion toxin, chlorotoxin, a bioinformatics approach

Glioblastoma is a very invasive and metastatic cancer with low patient survival-rate and high resistance to current treatment. Matrix metalloproteinase 2 (MMP2) is upregulated in glioblastoma multiforme (GBM) and its high expression is directly correlated with invasion and metastasis of GBM cells. Annexin A2 is involved in angiogenesis, and it is overexpressed in GBM. MMP2 and annexin A2 are potential targets for effective glioma therapy. Chlorotoxin is a promising toxin peptide for glioma targeted therapy. Chlorotoxin decreased migration and metastasis of GBM cells, although mechanism of action of the toxin is unclear due to the complicated nature of GBM, slow and costly experiments and challenging techniques. The relationship of chlorotoxin binding to both MMP2 and annexin A2 is controversial and further work is needed to clarify a complex situation. Chlorotoxin-like short toxins are homologous peptides that may also have potential therapeutic effects for glioma. In this study homology modelling was used to predict 3D models of chlorotoxin-like short toxins. Stereochemical quality estimation of 3D models was performed with QMEAN, Z-Score and Procheck server. ClusPro docking programme was used to dock 3D structures of chlorotoxin and chlorotoxin homologues with their putative binding partners MMP2 and annexin A2 to provide a first step to understand the mechanism of action of the toxin. Chlorotoxin shows binding interaction with both MMP2 and annexin A2. Chlorotoxin-like short toxins also showed stronger binding interaction with activated MMP2 than annexin A2. The positively charged surface of chlorotoxin is mainly involved in interaction with MMP2. All three chlorotoxin-like short toxins bind to a similar site on MMP2 but on separate sites on annexin A2 hence suggesting the significance of observed interaction between chlorotoxin and MMP2.