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Binding Orientations, QSAR, and Molecular Design of Thiophene Derivative Inhibitors
Author(s) -
Liao Si Yan,
Chen Tao Ju,
Miao Ti Fang,
Qian Li,
Zheng Kang Cheng
Publication year - 2009
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.1747-0285.2009.00861.x
Subject(s) - quantitative structure–activity relationship , thiophene , docking (animal) , chemistry , correlation coefficient , stereochemistry , molecular dynamics , computational chemistry , biological system , mathematics , biology , organic chemistry , medicine , nursing , statistics
A theoretical study on binding orientations and quantitative structure–activity relationship of thiophene derivatives as inhibitors towards tubulin has been carried out by using the docking analysis and the comparative molecular field analysis. The appropriate binding orientations and conformations of these compounds interacting with tubulin were revealed by docking study; and a 3D‐quantitative structure–activity relationship model showing significant statistical quality and satisfying predictive ability was established, in which the correlation coefficient ( R 2 ) and cross‐validation coefficient ( q 2 ) are 0.949 and 0.743, respectively. The same model was further applied to predict the pIC 50 values for nine congeneric compounds as external test set, and the predictive correlation coefficient reaches 0.929, thus the predictive ability of this 3D‐quantitative structure–activity relationship model can be further confirmed. Some key structural factors of the compounds responsible for cytotoxicity were discussed in detail. Based on these structural factors, three new compounds with higher activity have been designed, and their cytotoxicities were also predicted by the established 3D‐quantitative structure–activity relationship model from comparative molecular field analysis as well as the docking analysis. We hope these theoretical results can be confirmed by experimental work.