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Closed Access item Optimization of Taxane Binding to Microtubules: Binding Affinity Dissection and Incremental Construction of a High-Affinity Analog of Paclitaxel

Authors:Matesanz, Ruth
Barasoain, Isabel
Yang, C.G.
Wan, L.
Li, X.
Inés, C. de
Coderch, Claire
Gago, Federico
Jiménez-Barbero, Jesús
Andreu Morales, José Manuel
Fang, Wei-shuo S.
Díaz, José Fernando
Keywords:Chembio, Cellbio
Issue Date:23-Jun-2008
Citation:Chemistry and Biology, 15 (6) : 573-585 (2008)
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
Description:13 páginas, 5 figuras, 2 tablas -- PAGS nro.s 573-585
Publisher version (URL):http://dx.doi.org/10.1016/j.chembiol.2008.05.008
E-ISSNmetadata.dc.identifier.doi = DOI:1879-1301
Appears in Collections:(CIB) Artículos

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