Quantitative structure-activity relationship (5D-QSAR) study of combretastatin-like analogues as inhibitors of tubulin assembly.
A molecular modeling study was carried out to develop a predictive model for combretastatin-like analogues populating the colchicine-binding site of beta-tubulin. A series of compounds built around a framework including two aromatic groups linked by various moieties such as alkenes (stilbenes), enones (chalcones), or ethers was selected for the study. The 5D-QSAR model was developed stepwise. First a model was generated for the chalcone series (19 compounds, 71 conformations), then for the stilbene series (18 compounds, 59 conformations), and finally for the combined dataset (47 ligands, 160 conformers). Although the models for the chalcone and stilbene series appeared slightly different when represented by QSAR colored surfaces, the combined model seems to reconcile the differences without compromise and represents a highly predictive model for compounds that bind to the colchicine-binding site of tubulin.
Ducki
Sylvie
S
Centre for Molecular Drug Design, Cockcroft Building, University of Salford, Salford M5 4WT, UK. s.ducki@salford.ac.uk
Mackenzie
Grant
G
Lawrence
Nicholas J
NJ
Snyder
James P
JP
D000970:Antineoplastic Agents / Q000737:chemistry*; D001632:Bibenzyls / Q000737:chemistry*; D001665:Binding Sites; D003078:Colchicine / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D021281:Quantitative Structure-Activity Relationship; D013267:Stilbenes / Q000737:chemistry*; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators
D000970:Antineoplastic Agents; D001632:Bibenzyls; D008024:Ligands; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C040105:combretastatin; D003078:Colchicine