COMPARATIVE MOLECULAR-FIELD ANALYSIS OF A SERIES OF PACLITAXEL ANALOGS

A series of 94 paclitaxel analogues exhibiting antitumor activity by p romoting the assembly of microtubules and inhibiting the disassembly p rocess of microtubules to tubulin were investigated using the comparat ive molecular field analysis (CoMFA) method. These compounds belonging to 10 structural classes were randomly divided into a training set of 80 compounds and a test set of 14 compounds. Since the three-dimensio n structure of ligand-receptor complex is unknown, from X-ray and NMR data we rationally selected the three-dimension structure of paclitaxe l in a polar solution as the active conformation and starting structur e for molecule modeling, the other molecules were aligned using this m olecule model as the template. The most optimal CoMFA yielded a two-co mponents model, with significant cross-validation r(cv)(2) of 0.640 an d conventional r(2) of 0.868. The predictive ability of training set m odel was tested on the test set of 14 compounds. The tests not only re vealed the robustness of the CoMFA model but demonstrated that for our model r(pred)(2) based on the mean activity of test set compounds can accurately estimate external predictivity but r(pred)(2) based on the mean activity of training set compounds overestimated the model. The CoMFA model explained why the activity of taxoid is sensitive to the s tereochemistry of the atoms at C-2' and C-3' positions and the presenc e of hydroxyl group at C-2' position. The other factors affecting acti vity were also elucidated according to standard coefficient contour ma ps of steric and electrostatic fields derived from the CoMFA model.