Binding orientations, QSAR, and molecular design of thiophene derivative inhibitors.
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 R(pred)(2) 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.
Liao
Si Yan
SY
School of Chemistry and Chemical Engineering, Zhongshan (Sun Yat-Sen) University, Guangzhou 510275, China.
Chen
Tao Ju
TJ
Miao
Ti Fang
TF
Qian
Li
L
Zheng
Kang Cheng
KC
D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D012984:Software; D013876:Thiophenes / Q000737:chemistry* / Q000633:toxicity; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000633:toxicity
D013876:Thiophenes; D014404:Tubulin; D050257:Tubulin Modulators