Molecular modelling evaluation of the cytotoxic activity of podophyllotoxin analogues

Podophyllotoxin and its structural derivatives, a class of tubulin polymerization inhibitors, have been the objective of numerous studies to prepare better and safer anti-cancer drugs. A library of podophyllotoxin analogues has been designed consisting of 154 analogues. Their molecular interactions and binding affinities with tubulin protein (1SA1) have been studied using the docking-molecular mechanics based on generalized Born/surface area (MM-GBSA) solvation model. Quantitative structure activity relationships were developed between the cytotoxic activity (pIC(50)) of these compounds and molecular descriptors like docking score and binding free energy. For both the cases the r(2) was in the range of 0.642-0.728 indicating good data fit and r(cv)(2) was in the range of 0.631-0.719 indicating that the predictive capabilities of the models were acceptable. In addition, a linear correlation was observed between the predicted and experimented pIC(50) for the validation data set with correlation coefficient r(2) of 0.806 and 0.887, suggesting that the docked structure orientation and the interaction energies are reasonable. Low levels of root mean square error for the majority of inhibitors establish the docking and Prime/MM-GBSA based prediction model as an efficient tool for generating more potent and specific inhibitors of tubulin protein by testing rationally designed lead compounds based on podophyllotoxin derivatization.