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 B. Horwitz, Carlos L. Simmerling, Iwao Ojima

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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
Issue number3
StatePublished - Mar 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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