期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 50, 期 11, 页码 2019-2028出版社
AMER CHEMICAL SOC
DOI: 10.1021/ci1002894
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- National Cancer Institute, National Institutes of Health [N01-CO-12400]
- National Institutes of Health [GM53386]
- Division of Cancer Treatment and Diagnosis of the National Cancer Institute
We used synthetic peloruside A for the commercial preparation of [H-3]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 mu M. A less active peloruside A analogue, (11-R)-peloruside A and laulimalide acted as competitive inhibitors of the binding of the [H-3]peloruside A, with apparent K-i values of 9.3 and 0.25 mu M, respectively. Paclitaxel, epothilone B, and discodermolide had essentially no ability to inhibit [H-3]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 beta-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 beta-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.
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