Discovery of Small Molecule Inhibitors that Interact with γ-Tubulin

Recent studies have shown an overexpression of γ‐tubulin in human glioblastomas and glioblastoma cell lines. As the 2‐year survival rate for glioblastoma is very poor, potential benefit exists for discovering novel chemotherapeutic agents that can inhibit γ‐tubulin, which is known to form a ring complex that acts as a microtubule nucleation center. We present experimental evidence that colchicine and combretastatin A‐4 bind to γ‐tubulin, which are to our knowledge the first drug‐like compounds known to interact with γ‐tubulin. Molecular dynamics simulations and docking studies were used to analyze the hypothesized γ‐tubulin binding domain of these compounds. The suitability of the potential binding modes was evaluated and suggests the subsequent rational design of novel targeted inhibitors of γ‐tubulin. We present experimental evidence that colchicine and combretastatin A‐4 bind to γ‐tubulin, which are to our knowledge the first drug‐like compounds known to interact with γ‐tubulin, a protein key to nucleating microtubules. Molecular dynamics (MD) simulations and docking studies were used to analyze the hypothesized γ‐tubulin binding domain of these compounds. This discovery is a significant first step in the rational drug design of an effective small molecule inhibitor of γ‐tubulin.