期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 16, 期 5, 页码 2235-2242出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2007.11.076
关键词
antitubulin; cytotoxicity; HINT; molecular docking; pyrroles
资金
- NCI NIH HHS [CA067236, R15 CA067236] Funding Source: Medline
- NIGMS NIH HHS [R01 GM071894, R01 GM071894-03, GM071894] Funding Source: Medline
Compounds that bind at the colchicine site of tubulin have drawn considerable attention with studies indicating that these agents suppress microtubule dynamics and inhibit tubulin polymerization. Data for 18 polysubstituted pyrrole compounds are reported, including antiproliferative activity against human MDA-MB-435 cells and calculated free energies of binding following docking the compounds into models of alpha beta-tubulin. These docking calculations coupled with HINT interaction analyses are able to represent the complex structures and the binding modes of inhibitors such that calculated and measured free energies of binding correlate with an r(2) of 0.76. Structural analysis of the binding pocket identifies important intermolecular contacts that mediate binding. As seen experimentally, the complex with JG-03-14 (3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester) is the most stable. These results illuminate the binding process and should be valuable in the design of new pyrrole-based colchicine site inhibitors as these compounds have very accessible syntheses. (C) 2007 Elsevier Ltd. All rights reserved.
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