Paclitaxel/epothilone pharmacophore

Winkler JD, Axelsen PH (1996) A Model for the Taxol (Paclitaxel)/Epothilone Pharmacophore. Bioorg Med Chem Lett 6 2963... 

In 2000, Giannakakou et al. [86] proposed another common pharmacophore for taxanes and epothilones, based on biological activity and resistance data related to (3-tubulin mutations. In particular, the study focused on (3276Thr->Ile, (3284Arg->Gln and (3272Phe->Val mutations, affecting both paclitaxel and epothilones ability to induce tubulin polymerization and inhibition of cell proliferation [113]. To identify patterns of epothilone to be superposed to taxanes, the authors sampled 100... 

Fig. 8 Overlap of the three pharmacophores representing the interactions found for paclitaxel in the 1JFF structure (A), epothilone A in the NMR-derived structure (B), and epothilone A in the QSAR model from Botta and co-workers (C), respectively. Blue C7-OH (epothilones) oxetane ring (paclitaxel) red C13 carbon (epothilones) phenyl ring (paclitaxel) yellow Cl carbonyl oxygen (epothilones) Cl carbonyl oxygen (paclitaxel) purple thiazole ring (epothilone) C3 benzamide (paclitaxel). (3-tubulin monomer is represented as a green cartoon and residues involved in hydrogen bonds are in orange (hydrogens are omitted for sake of clarity)...

Banerjee, A. Kasmala, L. T. Differential assembly kinetics of a-tubulin isoforms in the presence of paclitaxel. Biochem. Biophys. Res. Commun., 1998, 245 349-351. Giannakakou, R Gussio, R. Nogales, E. Downing, K. H. Zaharevitz, D. Bollbuck, B. Poy, G. Sackett, D. Nicolaou, K. C. Fojo, T. A common pharmacophore for epothilone and taxanes molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Proc. Natl. Acad. Sci. USA, 2000, 97 2904-2909. 

The similarity in the mechanisms of action of paclitaxel (Section 1.1), the epothilones (Section 1.3), discodermolide and eleutherobin (section 1.2) has led to proposals that these structurally dissimilar substances possess common pharmacophores which could lead to the design and synthesis of analogs having substantially different structures and superior activities. 

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