Optimization of taxane binding to microtubules: binding affinity dissection and incremental construction of a high-affinity analog of paclitaxel.

Article Details

Citation

Copy to clipboard

Matesanz R, Barasoain I, Yang CG, Wang L, Li X, de Ines C, Coderch C, Gago F, Barbero JJ, Andreu JM, Fang WS, Diaz JF

Optimization of taxane binding to microtubules: binding affinity dissection and incremental construction of a high-affinity analog of paclitaxel.

Chem Biol. 2008 Jun;15(6):573-85. doi: 10.1016/j.chembiol.2008.05.008.

PubMed ID

18559268 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Docetaxel	Tubulin beta-1 chain	Protein	Humans	Yes	Not Available	Details