Use of the tubulin bound paclitaxel conformation for structure-based rational drug design

Raphaël Geney, Liang Sun, Paula Pera, Ralph J. Bernacki, Shujun Xia, Susan Band Horwitz, Carlos L. Simmerling, Iwao Ojima

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

A new computational docking protocol has been developed and used in combination with conformational information inferred from REDOR-NMR experiments on microtubule bound 2-(p-fluorobenzoyl)paclitaxel to delineate a unique tubulin binding structure of paclitaxel. A conformationally constrained macrocyclic taxoid bearing a linker between the C-14 and C-3′N positions has been designed and synthesized to enforce this "REDOR-taxol" conformation. The novel taxoid SB-T-2053 inhibits the growth of MCF-7 and LCC-6 human breast cancer cells (wild-type and drug resistant) on the same order of magnitude as paclitaxel. Moreover, SB-T-2053 induces in vitro tubulin polymerization at least as well as paclitaxel, which directly validates our drug design process. These results open a new avenue for drug design of next generation taxoids and other microtubule-stabilizing agents based on the refined structural information of drug-tubulin complexes, in accordance with typical enzyme-inhibitor medicinal chemistry precepts.

Original languageEnglish (US)
Pages (from-to)339-348
Number of pages10
JournalChemistry and Biology
Volume12
Issue number3
DOIs
StatePublished - Mar 2005

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Drug Design
Tubulin
Paclitaxel
Conformations
Taxoids
Pharmaceutical Preparations
Microtubules
Bearings (structural)
Pharmaceutical Chemistry
Excipients
Enzyme Inhibitors
Polymerization
Cells
Nuclear magnetic resonance
Breast Neoplasms
Growth
Experiments

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Use of the tubulin bound paclitaxel conformation for structure-based rational drug design. / Geney, Raphaël; Sun, Liang; Pera, Paula; Bernacki, Ralph J.; Xia, Shujun; Band Horwitz, Susan; Simmerling, Carlos L.; Ojima, Iwao.

In: Chemistry and Biology, Vol. 12, No. 3, 03.2005, p. 339-348.

Research output: Contribution to journalArticle

Geney, R, Sun, L, Pera, P, Bernacki, RJ, Xia, S, Band Horwitz, S, Simmerling, CL & Ojima, I 2005, 'Use of the tubulin bound paclitaxel conformation for structure-based rational drug design', Chemistry and Biology, vol. 12, no. 3, pp. 339-348. https://doi.org/10.1016/j.chembiol.2005.01.004
Geney, Raphaël ; Sun, Liang ; Pera, Paula ; Bernacki, Ralph J. ; Xia, Shujun ; Band Horwitz, Susan ; Simmerling, Carlos L. ; Ojima, Iwao. / Use of the tubulin bound paclitaxel conformation for structure-based rational drug design. In: Chemistry and Biology. 2005 ; Vol. 12, No. 3. pp. 339-348.
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