A unified and quantitative receptor model for the microtubule binding of paclitaxel and epothilone.
[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.
Wang
M
M
Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
Xia
X
X
Kim
Y
Y
Hwang
D
D
Jansen
J M
JM
Botta
M
M
Liotta
D C
DC
Snyder
J P
JP
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D034261:Epothilones; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D009010:Monte Carlo Method; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011955:Receptors, Drug / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D034261:Epothilones; D004852:Epoxy Compounds; D011955:Receptors, Drug; D013844:Thiazoles; D014404:Tubulin; D017239:Paclitaxel; C093788:epothilone B