The T-Taxol conformation

J Med Chem. 2006 Apr 20;49(8):2478-88. doi: 10.1021/jm051119r.

Abstract

T-Taxol is a proposal for the bioactive conformation of paclitaxel (PTX) derived from fitting ligand conformations to the electron crystallographic (EC) density. Although confirmed by a number of studies, some structural ambiguities based on the interpretation of two solid-state REDOR (13)C-(19)F distances in a fluorinated PTX derivative remain. An evaluation of the static and dynamic properties of the PTX-tubulin complex shows that small 6-12 degrees variations in calculated torsions and a justifiable increase of the REDOR distance error to > or = +/-0.7 A readily resolves key discrepancies around T-Taxol's service as the bioactive conformation. In addition, conformational analysis reveals a range of (13)C-(19)F separations compatible with the REDOR measurements suggesting that the present PTX REDOR distances may not provide a precise model for bioactive, tubulin-bound bridged taxanes. In addition, we show that New York-Taxol (PTX-NY), a recently proposed alternative to T-Taxol, is incompatible with both the EC density and the activity of a highly active series of bridged taxanes.

MeSH terms

  • Binding Sites
  • Crystallography
  • Docetaxel
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Paclitaxel / chemistry*
  • Paclitaxel / pharmacology
  • Protein Structure, Tertiary
  • Stereoisomerism
  • Structure-Activity Relationship
  • Taxoids / chemistry
  • Taxoids / pharmacology
  • Tubulin / chemistry
  • Tubulin / drug effects

Substances

  • Ligands
  • Taxoids
  • Tubulin
  • nonataxel
  • Docetaxel
  • Paclitaxel