Paclitaxel conformational analysis

Thus, the fluorine probe approach has proved useful for the conformational analysis of paclitaxel and taxoids in connection with the determination of possible bioactive conformations.77 The previously unrecognized conformer C might be the molecular structure first recognized by the P-tubulin binding site on microtubules. 

Boge, T. C. Heperle, M. Vander Velde, D. G. Gunn, C. W. Grunerwald, G. L. Georg, G. I. The oxetane conformational lock of paclitaxel structural analysis of D-secopa-clitaxel. Bioorg. Med. Chem. Lett., 1999, 9 3041-3046. 

Boge TC, Hepperle M, Vander Velde DG, Gunn CW, Grunewald GL, Georg GI (1999) The Oxetane Conformational Lock of Paclitaxel Structural Analysis of D-secopaclitaxel. Bioorg Med Chem Lett 9 3041... 

In another application, 19F NMR studies have provided critical information on the bioactive conformation of taxoids. Fluorine-containing taxoids have been used as probes for NMR analysis of the conformational dynamics of paclitaxel in conjunction with molecular modeling [166], The dependence of the 19F chemical shifts and the Jm--ny values of these fluorinated analogues is examined through 19F and H variable-temperature (VT) NMR measurements. The experiments clearly indicate highly dynamic behavior of these molecules and the existence of equilibrium between conformers. The analysis of the VT NMR data in combination with molecular modeling, including restrained molecular dynamics (RMD), has identified three key conformers, which were further confirmed by the 19F- H heteronuclear NOE measurements. 

Fluorine-probe protocol has been applied to solid-state magic-angle spinning (SSMAS) 19F NMR analysis with the radiofrequency-driven dipolar recoupling (RFDR) method to measure the F-F distance in the microtubule-bound conformation of F2-10-Ac-docetaxel (see Figure 1.29a) [167], Moreover, five intramolecular distances of the key atoms in the microtubule-bound l9I72II/l3(Mabeled paclitaxel were determined by the rotational echo double resonance (REDOR) method (see Figure 1.29b and c) [168, 169],... 

Recently, we proposed a new bioactive conformation of paclitaxel, RKDOR-Taxol [50], based on (i) the 19F-13C distances obtained by the REDOR experiment [49], (ii) the photoaffinity labeling of microtubules [51], (iii) the crystal structure (PDB code 1TUB) of the Zn2+-stabilized aP-tubulin dimer model determined by cryo-electron microscopy (cryo-EM) [52], and (iv) molecular modeling (Monte Carlo Macromodel) [50], In this computational biology analysis, we first docked a paclitaxel-photoaffinity label molecule to the position identified by our photoaffinity labeling study and then optimized the... 

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