Use of the tubulin bound paclitaxel conformation for structure-based rational drug design.
Chem Biol
; 12(3): 339-48, 2005 Mar.
Article
em En
| MEDLINE
| ID: mdl-15797218
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.
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Base de dados:
MEDLINE
Assunto principal:
Tubulina (Proteína)
/
Desenho de Fármacos
/
Paclitaxel
Limite:
Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article