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.
Matesanz
Ruth
R
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Barasoain
Isabel
I
Yang
Chun-Gang
CG
Wang
Lei
L
Li
Xuan
X
de Inés
Concepción
C
Coderch
Claire
C
Gago
Federico
F
Barbero
Jesús Jiménez
JJ
Andreu
José Manuel
JM
Fang
Wei-Shuo
WS
Díaz
José Fernando
JF
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