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

Abstract

[formula: see text] 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 beta-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 Ki's with r = 0.99 and rms(delta Gcalc-delta Gexp) = 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.

Nordihydroguaiaretic Acid, of a New Family of Microtubule-stabilizing Agents, Shows Effects Differentiated from Paclitaxel

“…Structurally diŠerent kinds of microtubule-stabilizing drugs have been found, but they stabilize microtubules in a paclitaxel-like way and competitively inhibit [ 3 H]paclitaxel binding to microtubules. [9][10][11][12][13][14] However, NDGA did not aŠect [ 3 H]paclitaxel binding to microtubules, and this characteristic indicates that NDGA stabilizes microtubules in a diŠerent way from paclitaxel and also diŠerentiates NDGA from other microtubule-stabilizing drugs.…”

“…[9][10][11][12][13][14] Atˆrst, we addressed the question of whether NDGA bound to tubulin. Radiolabeled NDGA was not available, and another choice was to analyze whether tubulin interferes with a-glycosidase inhibition by NDGA.…”

“…Recently, this structure-activity relationship was explained in terms of a common pharmacophore. 13,14) Nordihydroguaiaretic acid (NDGA; Fig. 1) fragments the Golgi apparatus and causes retrograde movement of Golgi resident proteins to the endoplasmic reticulum.…”

The bioactive Taxol conformation on β-tubulin: Experimental evidence from highly active constrained analogs

“…In addition, studies have compared the conformations of Taxol and epothilone B by molecular modeling and other methods (29,(31)(32)(33). Separate investigations have proposed distinguishable conformations of the Taxol side chain, with a T-shaped conformation being favored on the basis of its fit with the election-density map of zinc-induced tubulin sheets (34,35). In the present work, we provide experimental evidence that Taxol can be constrained to the T-conformation in solution, and that this form both stabilizes genuine microtubules and induces cell death.…”

The High‐Resolution Solution Structure of Epothilone A Bound to Tubulin: An Understanding of the Structure–Activity Relationships for a Powerful Class of Antitumor Agents

“…[17] However, in the absence of information on the bioactive conformation of epothilones any 3D model of the tubulinepothilone complex remains uncertain. [18][19][20][21][22][23] Herein we describe the conformation of epothilone A bound to tubulin, as determined by NMR spectroscopy in aqueous solution. This structure provides the first piece of experimental information on the active conformation of this class of microtubule stabilizers.…”