Optimization of taxane binding to microtubules: binding affinity dissection and incremental construction of a high-affinity analog of paclitaxel.
The microtubule binding affinities of a series of synthetic taxanes have been measured with the aims of dissecting individual group contributions and obtaining a rationale for the design of novel compounds with the ability to overcome drug resistance. As previously observed for epothilones, the positive and negative contributions of the different substituents to the binding free energies are cumulative. By combining the most favorable substitutions we increased the binding affinity of paclitaxel 500-fold. Insight into the structural basis for this improvement was gained with molecular modeling and NMR data obtained for microtubule-bound docetaxel. Taxanes with affinities for microtubules well above their affinities for P-glycoprotein are shown not to be affected by multidrug resistance. This finding strongly indicates that optimization of the ligand-target interaction is a good strategy to overcome multidrug resistance mediated by efflux pumps.
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Ruth
R
Matesanz
Isabel
I
Barasoain
Chun-Gang
CG
Yang
Lei
L
Wang
Xuan
X
Li
Concepción
C
de Inés
Claire
C
Coderch
Federico
F
Gago
Jesús Jiménez
JJ
Barbero
José Manuel
JM
Andreu
Wei-Shuo
WS
Fang
José Fernando
JF
Díaz
D001665:Binding Sites; D045744:Cell Line, Tumor; D000077143:Docetaxel; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D043823:Taxoids / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
D043823:Taxoids; D000077143:Docetaxel