Study Of Molecular Simulations On Antitumor Medicines-Discodermolide And Dictyostatin

Discodermolide and dictyostatin, acting on tubulin, are novel and anti-tumor compounds. They have good pharmaceutical prospect.Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out on discodermolide and its derivatives using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best predictions were obtained with the CoMFA steric, electrostatic fields (leave-one-out q2=0.592, no validation r2=0.982, standard error of estimate = 0.094, F = 119.761), and with the CoMSIA combined electrostatic, hydrophobic, H-bond donor and acceptor fields (leave-one-out q2=0.544, no validation r2=0.980, standard error of estimate=0.098, F=108.715). The two models have good predictable ability and can be used to direct the design of new compound. By analyzing CoMFA and CoMSIA models, we found it is favorable for activity that a large group which is electropositive and hydrophilic is introduced in the lactone, a small group which is electronegative and hydrophobic is introduced on C1 site, a large H-bond acceptor which is electropositive is introduced on C19 site.In addition, dictyostatin was docked into tubulin and then molecular dynamics simulation was run on the complex. After the simulation, a more reasonable structure of the complex was obtained. Then, we analysed the interactions between dictyostatin and tubulin. The analysis concluded that the main interactions between dictyostatin and tubulin are H-bond interaction and electrostatic interaction. There are three H-bonds between dictyostatin and tubulin: one between C1 site and THR273, one between C9 site and HIS226, another between C19 site and GLY 359. Dictyostatin is electropositive and the active site of tubulin is strongly electronegative, so the electrostatic interaction between them is very strong.