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Discovery of Small Molecule Inhibitors that Interact with γ‐Tubulin
Author(s) -
Friesen Douglas E.,
Barakat Khaled H.,
Semenchenko Valentyna,
PerezPineiro Rolando,
Fenske Bruce W.,
Mane Jonathan,
Wishart David S.,
Tuszynski Jack A.
Publication year - 2012
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2012.01340.x
Subject(s) - tubulin , combretastatin , microtubule , colchicine , docking (animal) , drug discovery , computational biology , small molecule , biology , glioblastoma , chemistry , microbiology and biotechnology , biochemistry , cancer research , genetics , medicine , nursing
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.