A Unified and Quantitative Receptor Model for the Microtubule Binding of Paclitaxel and Epothilone

Paclitaxel and epothilone represent the two major classes of antimicrotubule agents that promote tubulin polymerization and, presumably, mitotic arrest during cell division. A common minireceptor binding site model at β-tubulin has been constructed for these structurally divergent compounds. Utilizing 20 amino acids identified in photoaffinity labeling experiments, the 3-D model correlates measured and predicted K i's with r = 0.99 and rms(ΔG calc − ΔG exp) = 0.2 kcal/mol. In addition, the model predicts the affinity of compounds not used in the training set and explains much of the SAR for the paclitaxel and epothilone families.