Molecular Docking And QSAR Study On Antitumor Medicine-Discodermolide

Discodermolide is a multiple-hydroxyl-δ-lactone compound, which is isolated from marine sponge Discodermia dissolute. Similar with paclitaxel, discodermolide is a new-style microtubule-stabilizing agent. Molecular docking has been adopted in order to investigate the mechanism of action of discodermolide in detail. On the basis of docking, research on quantitative structure activity relationship (QSAR) has been employed here to provide suggestions for modifying the structure of discodermolide.Molecular docking studies were performed using FlexX in order to systematically investigate the binding model of discodermolide withβ-tubulin. Based on the docking conclusions, the main important interactions between discodermolide andβ-tubulin are hydrogen bond interaction, hydrophobic interaction and electrostatic interaction. The docking results also indicated that there were four possible binding models according to the orientation of discodermolide within theβ-tubulin structure, in which modelⅠandⅡare in agreement with reference and modelⅢandⅣare new models brought forward by us for the first time. ModelⅢandⅣare more rational according to the position of hydrogen bond, the successfully docking number, SAS Score, and so on.On the basis of the docking, 33 discodermolide analogues have been applied as the objective of research to establish two models of CoMFA QSAR: docking CoMFA model and database align CoMFA model. By analyzing the results of calculation, docking CoMFA model shows preferable prediction ability with a cross-validated coefficient q~2 of 0.418, a non-cross validated conventional coefficient r~2 of 0.993 and standard error of estimate (SEE) of 0.051. By analyzing contour maps of steric and electrostatic fields of docking CoMFA model, we found that placing a large group onδ-lactone was favorable for activity, but if the group was too large, activity would decrease. A small group on C19 side chain was advantaged and a large one on C24 was favorable. In addition, a positive charge onδ-lactone and C19 side chain was favorable for increasing activity, but a negative charge on C24 was good for activity. Overall, effect of electrostatic field was stronger than that of steric field.