QSAR Study On Epothilones

Epothilones are a class of novel microtubule stabilizing and anti-mitotic agents that have a paclitaxel-like mechanism of action. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was conducted on epothilones by the method of comparative molecular field analyses (CoMFA) combined with flexible docking technology. The flexible docking program FlexX 1.13.2 interfaced with Sybyl6.92 was used for the determination of the "active" conformation and the molecular alignment according to the property of the binding pocket ofα,β-tubulin. At the same time, we considered the different definitions of partial charges and the grid spacing, which have important influence on the final CoMFA model. At last, the docking CoMFA model was investigated with the partial least square (PLS) contour maps complemented with MOLCAD-generated active site potential surface.Based on the CoMFA result, we study further the stability of 4 important active sites (O(C1),O(C3),O(C7) and N(thiazole)) for epothilones by molecule dynamics and quantum chemistry. After the multiple linear regression analysis for the calculated descriptors and active data, the result shows that the influence factors on the activities of epothilones include Vdw area (S) or Vdw volume (V), nuclear repulsive potentials (Ep), the dipole polarizability (DIPO), the charge density for oxygen at C7 and that for N at thiazole group in C15 sidechain. At last, the QSAR model was established between the chief ingredients and active data using PLS. The correlation coefficient was 0.861 between the predicted and observed data, and standard error was 11.096, such results show the model has a good predicted capability. It is important for epothilones' bioactivities increasing to revise the structure at C12 and C15 sidechain to change their DIPO and Ep. At the same time, increasing the negative charge of O at C7 and N at thiazole in C15 sidechain is favorable. However, the charge density of O at C1 and at C3 has little influence on the bioactivities though they are important active sites, so there is little possibility to improve the bioactivity by changing their charge density at these sites.