Determination of the binding sites and binding modes of gatastatin and its novel derivatives

Glioblastoma Multiforme (GBM) is among the most aggressive forms of brain tumours. The prognosis for GBM patients remains poor despite advances in therapies, as they have proven unable to prolong patient survival more than a few months. The World Health Organization classification of GBM is a necrosis-predisposed grade IV cancer that is mitotically active, which means its cells are proliferating at a higher rate than normal tissue cells. During mitosis prophase, the cell prepares to divide by condensing its chromosomes and starting the formation of the mitotic spindle, of which microtubules are the main component. In vivo nucleation of microtubules begins with a complex called gamma-TuRC (gamma Tubulin Ring Complex) formed by accessory proteins recalled by gamma-tubulin, which is therefore essential for the formation of microtubules. As gamma-tubulin has been found to be overexpressed in GBM, identifying a compound that can inhibit its functions could benefit patients greatly. The present work aims at identifying the binding sites and binding modes of gatastatin, a potential gamma-tubulin inhibitor, and its recently developed derivatives. Computational modelling, particularly molecular docking simulations, has proven a valuable tool to explore and compare the compounds’ binding to gamma and alpha-beta tubulin.