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The assembly-inducing laulimalide/peloruside a binding site on tubulin: molecular modeling and biochemical studies with [³H]peloruside A.
Nguyen, Tam Luong; Xu, Xiaoming; Gussio, Rick; Ghosh, Arun K; Hamel, Ernest.
Afiliação
  • Nguyen TL; Target Structure-Based Drug Discovery Group, SAIC-Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
J Chem Inf Model ; 50(11): 2019-28, 2010 Nov 22.
Article em En | MEDLINE | ID: mdl-21028850
We used synthetic peloruside A for the commercial preparation of [³H]peloruside A. The radiolabeled compound bound to preformed tubulin polymer in amounts stoichiometric with the polymer's tubulin content, with an apparent K(d) value of 0.35 µM. A less active peloruside A analogue, (11-R)-peloruside A and laulimalide acted as competitive inhibitors of the binding of the [³H]peloruside A, with apparent K(i) values of 9.3 and 0.25 µM, respectively. Paclitaxel, epothilone B, and discodermolide had essentially no ability to inhibit [³H]peloruside A binding, confirming that these compounds bind to a different site on tubulin polymer. We modeled both laulimalide and peloruside A into the binding site on ß-tubulin that was identified by Huzil et al. (J. Mol. Biol. 2008, 378, 1016-1030), but our model provides a more reasonable structural basis for the protein-ligand interaction. There is a more complete desolvation of the peloruside A ligand and a greater array of favorable hydrophobic and electrostatic interactions exhibited by peloruside A at its ß-tubulin binding site. In addition, the protein architecture in our peloruside A binding model was suitable for binding laulimalide. With the generation of both laulimalide and peloruside A binding models, it was possible to delineate the structural basis for the greater activity of laulimalide relative to peloruside A and to rationalize the known structure-activity relationship data for both compounds.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trítio / Tubulina (Proteína) / Modelos Moleculares / Macrolídeos / Compostos Bicíclicos Heterocíclicos com Pontes / Multimerização Proteica / Lactonas Limite: Animals Idioma: En Revista: J Chem Inf Model Assunto da revista: INFORMATICA MEDICA / QUIMICA Ano de publicação: 2010 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trítio / Tubulina (Proteína) / Modelos Moleculares / Macrolídeos / Compostos Bicíclicos Heterocíclicos com Pontes / Multimerização Proteica / Lactonas Limite: Animals Idioma: En Revista: J Chem Inf Model Assunto da revista: INFORMATICA MEDICA / QUIMICA Ano de publicação: 2010 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos