title: Discovery of small molecule inhibitors that interact with γ-tubulin.
abstract: 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.
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Friesen
authors.forename: Khaled H
authors.initials: KH
authors.lastname: Barakat
authors.forename: Valentyna
authors.initials: V
authors.lastname: Semenchenko
authors.forename: Rolando
authors.initials: R
authors.lastname: Perez-Pineiro
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Fenske
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mane
authors.forename: David S
authors.initials: DS
authors.lastname: Wishart
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
mesh_terms: D001665:Binding Sites; D003078:Colchicine / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D056004:Molecular Dynamics Simulation; D013267:Stilbenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C058728:fosbretabulin; D003078:Colchicine