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A theoretical study on the binding conformations and the quantitative structure-activity relationship (QSAR) of combretastatin A4 (CA-4) analogs as inhibitors toward tubulin has been carried out using docking analysis and comparative molecular field analysis (CoMFA). The appropriate binding orientations and conformations of these compounds interacting with tubulin were revealed by the docking study; and a 3D-QSAR model showing significant statistical quality and satisfactory predictive ability was established, in which the correlation coefficient (R(2)) and cross-validation coefficient (q(2)) were 0.955 and 0.66, respectively. The same model was further applied to predict the pIC(50) values for 16 congeneric compounds as external test set, and the predictive correlation coefficient R(2)(pred) reached 0.883. Other tests on additional validations further confirmed the satisfactory predictive power of the model. In this work, it was very interesting to find that the 3D topology structure of the active site of tubulin from the docking analysis was in good agreement with the 3D-QSAR model from CoMFA for this series of compounds. Some key structural factors of the compounds responsible for cytotoxicity were reasonably presented. These theoretical results can offer useful references for understanding the action mechanism and directing the molecular design of this kind of inhibitor with improved activity.

The theoretical studies on three-dimensional quantitative structure activity relationship (3D-QSAR) and action mechanism of a series of 2-indolinone derivatives as tubulin inhibitors against human breast cancer cell line MDA-MB-231 have been carried out. The established 3D-QSAR model from the comparative molecular field analysis (CoMFA) shows not only significant statistical quality but also predictive ability, with high correlation coefficient (R 2 ϭ 0.986) and cross-validation coefficient (q 2 ϭ 0.683). In particular, the appropriate binding orientations and conformations of these 2-indolinone derivatives interacting with tubulin are located by docking study, and it is very interesting to find that the plot of the energy scores of these compounds in DOCK versus the corresponding experimental pIC 50 values exhibits a considerable linear correlation. Therefore, the inhibition mechanism that 2-indolinone derivatives were regarded as tubulin inhibitors can be theoretically confirmed. Based on such an inhibition mechanism along with 3D-QSAR results, some important factors improving the activities of these compounds were discussed in detail. These factors can be summarized as follows: the H atom adopted as substituent R 1 , the substituent R 2 with higher electropositivity and smaller bulk, the substituents R 4 -R 6 (on the phenyl ring) with higher electropositivity and larger bulk, and so on. These results can offer useful theoretical references for understanding the action mechanism, designing more potent inhibitors, and predicting their activities prior to synthesis.

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.

Three-dimensional (3D) quantitative structure–activity relationships (QSARs) of 36 apoptosis inducers, substituted 4-aryl/heteroaryl-4H-chromenes with anticancer activity against human breast cancer cell lines T47D, have been studied by using methods of comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA). The established 3D-QSAR models in training set show not only significant statistical quality, but also predictive ability, with high correlation coefficient (R2) values and cross-validation coefficient (q2) values: CoMFA (R2, q2: 0.944, 0.747), CoMSIA (R2, q2: 0.944, 0.704). Moreover, the predictive abilities of the CoMFA and CoMSIA models were further confirmed by a test set, giving the predictive correlation coefficients ([Formula: see text] values) of 0.845 and 0.851, respectively. Based on the CoMFA and CoMSIA contour map analyses, some key factors responsible for anticancer activity of this series of compounds have been found as follows: the steric interaction plays a decisive role in determining the anticancer activities of these compounds; bulky groups as substituent R 1 are not tolerated; in addition to a steric moderation, higher degree of electropositivity and hydrophobicity on the terminal alkyl of substituent R 2 might be favorable to the activity; the substituent R 3 should be hydrophobic; bulky and strong electron withdrawing groups for the substituent R 4 are not advantageous to the activity; simultaneously introducing large electronegative atoms as hydrogen-acceptors to the first atoms of the substituents R 5 and R 6 may increase the activity, but substituents R 5 and R 6 with a linking group – OCH 2 O – may decrease the activity. Such results can offer some useful theoretical references for understanding the action mechanism, designing more potent derivatives, and predicting their activities prior to synthesis.