title: Binding orientations, QSAR, and molecular design of thiophene derivative inhibitors.
abstract: 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.
authors.affiliation: School of Chemistry and Chemical Engineering, Zhongshan (Sun Yat-Sen) University, Guangzhou 510275, China.
authors.forename: Si Yan
authors.initials: SY
authors.lastname: Liao
authors.forename: Tao Ju
authors.initials: TJ
authors.lastname: Chen
authors.forename: Ti Fang
authors.initials: TF
authors.lastname: Miao
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.forename: Kang Cheng
authors.initials: KC
authors.lastname: Zheng
mesh_terms: 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
chemical_list: D013876:Thiophenes; D014404:Tubulin; D050257:Tubulin Modulators