Activity Evaluation, Pharmacophore Modeling And Molecular Docking Studies For A Series Of Microtubule Inhibitors

Microtubules are ubiquitous, essential cytoskeletal polymers in all eukaryotic cells controlling various cellular functions, transport of material within the cell, movement of cytoplasmic organelles, and proper progression through cell division. The function of microtubules is strongly associated with their stability, the interference with the dynamics of tubulin and cell division has been proven clinically useful for designing anticancer agents, which provide an interesting target for further designing of new anticancer agents.A series of novel podophyllotoxin derivatives were evaluated for biological activities and molecule simulation studies. The antiproliferative activities were tested against a panel of human cancer cell lines and the inhibition of tubulin polymerization was also evaluated. All Compounds displayed significant antiproliferative activities and strong levels of tubulin depolymerization effect. Combined with cell apoptosis and cell cycle analysis, it demonstrated that All Compounds that effectively interfere with tubulin dynamics prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually dose dependent apoptosis. All experimental measurements were also supported by molecular docking simulations of colchicine binding site, which revealed the governing forces for the binding behavior and a good relationship with anti-tubulin activity and antiproliferative activities.Moreover, Chemical features based3D pharmacophore models were developed for the known antitubule inhibitors. An optimal pharmacophore model was brought forth and validated using a external test set and Fischer’s randomization method. The best five features pharmacophore model, includes one hydrogen bond acceptors, four hydrophobic features,which has the highest correlation coefficient (0.96), cost difference (52.86), low RMS (0.87), as well as it shows a high goodness of fit and enrichment factor. The best model was used as a3D query for virtual screening to retrieve potential inhibitors from Maybridge and NCI2000databases. The hit compounds were obtained subsequently subjected to molecular docking studies,which based on consensus scoring function.In conclusion, we based on microtubule protein, the biological evaluation and molecule simulation studies were investigated for a series of small molecule inhibitors of microtubule polymerization. Then pharmacophore modeling based on some known active small molecules and verified the reliability of the model. The above work has important significance to microtubule polymerization mechanism, which provided an interesting new class of antitubule agents for development of lead compounds and also a direction for further structure modification to obtain more potent anti-cancer drugs.