Premium
Combined Molecular Docking, 3D‐ QSAR , and Pharmacophore Model: Design of Novel Tubulin Polymerization Inhibitors by Binding to Colchicine‐binding Site
Author(s) -
Li DongDong,
Qin YaJuan,
Zhang Xin,
Yin Yong,
Zhu HaiLiang,
Zhao LinGuo
Publication year - 2015
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/cbdd.12545
Subject(s) - pharmacophore , tubulin , in silico , docking (animal) , chemistry , quantitative structure–activity relationship , microtubule , molecular model , combinatorial chemistry , rational design , binding site , computational biology , stereochemistry , biochemistry , biology , nanotechnology , materials science , microbiology and biotechnology , medicine , nursing , gene
Interference with dynamic equilibrium of microtubule–tubulin has proven to be a useful tactics in the clinic. Based on investigation into the structure–activity relationship ( SAR ) studies of tubulin polymerization inhibitors obtained from several worldwide groups, we attempted to design 691 compounds covering several main heterocyclic scaffolds as novel colchicine‐site inhibitors ( CSI s). Evaluated by a series of combination of commonly used computer methods such as molecular docking, 3D‐ QSAR , and pharmacophore model, we can obtain the ultimate 16 target compounds derived from five important basic scaffolds in the field of medicinal chemistry. Among these compounds, compound A‐132 with in silico moderate activity was synthesized, and subsequently validated for preliminary inhibition of tubulin polymerization by immunofluorescence assay. In additional, the work of synthesis and validation of biological activity for other 15 various structure compounds will be completed in our laboratory. This study not only developed a hierarchical strategy to screen novel tubulin inhibitors effectively, but also widened the spectrum of chemical structures of canonical CSI s.