Discovery of Small Molecule Inhibitors that Interact with gamma-Tubulin

作者：Friesen Douglas E; Barakat Khaled H; Semenchenko Valentyna; Perez Pineiro Rolando; Fenske Bruce W; Mane Jonathan; Wishart David S; Tuszynski Jack A^*

来源：Chemical Biology & Drug Design, 2012, 79(5): 639-652.

DOI：10.1111/j.1747-0285.2012.01340.x

• colchicine
• combretastatin A-4
• drug discovery
• glioblastoma multiforme
• therapeutic target
• -tubulin

Recent studies have shown an overexpression of ?-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 ?-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 ?-tubulin, which are to our knowledge the first drug-like compounds known to interact with ?-tubulin. Molecular dynamics simulations and docking studies were used to analyze the hypothesized ?-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 ?-tubulin.

• 出版日期2012-5