Molecular Modeling and Structure-Activity Relationship of Podophyllotoxin and Its Congeners

Abstract

A quantitative structure-activity relationship (QSAR) model has been developed between cytotoxic activity and structural properties by considering a data set of 119 podophyllotoxin analogs based on 2D and 3D structural descriptors. A systematic stepwise searching approach of zero tests, a missing value test, a simple correlation test, a multicollinearity test, and a genetic algorithm method of variable selection was used to generate the model. A statistically significant model ( r train2 = 0.906; q cv2 = 0.893) was obtained with the molecular descriptors. The robustness of the QSAR model was characterized by the values of the internal leave-one-out cross-validated regression coefficient ( q cv2) for the training set and r test2 for the test set. The overall root mean square error (RMSE) between the experimental and predicted pIC50 value was 0.265 and r test2 = 0.824, revealing good predictability of the QSAR model. For an external data set of 16 podophyllotoxin analogs, the QSAR model was able to predict the tubulin polymerization inhibition and mechanistically cytotoxic activity with an RMSE value of 0.295 in comparison to experimental values. The QSAR model developed in this study shall aid further design of novel potent podophyllotoxin derivatives.