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

13 páginas, 5 figuras, 2 tablas -- PAGS nro.s 573-585The 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 pumpsThis work was supported in part by grant BIO2007-61336 from M.E.C. to J.F.D., BIPPED-CM from Comunidad de Madrid to F.G., J.F.D., J.J.B., and J.M.A., and grants NSFC 20572135 and MOST 2006DFA31490 to W.S.FPeer reviewe