High-throughput, high-resolution strategy for the rapid structural elucidation of site-selective DNA binding agents

BIOL 122

Mark A. Lewis, malewis@iupui.edu1, Kristie D. Goodwin, kdgoodwin@iupui.edu2, Millie M. Georgiadis2, and Eric C. Long1. (1) Department of Chemistry & Chemical Biology, Purdue School of Science, Indiana University-Purdue University Indianapolis (IUPUI), 402 North Blackford Street, Indianapolis, IN 46202, (2) Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indiana University-Purdue University Indianapolis (IUPUI), 635 Barnhill Drive, Indianapolis, IN 46202
A general strategy for the rapid structural analysis of DNA binding ligands is described. By combining a high-throughput fluorescent intercalator displacement (HT-FID) assay and a high-resolution (HR) host-guest crystallographic technique, a system was produced that is capable of determining detailed structural information pertaining to DNA-ligand interactions within ~ 3 days. This “HT-HR” strategy can quickly reveal the binding site preferences for even an unstudied DNA-interacting ligand and, subsequently, oligonucleotides can be designed and the host-guest crystallographic method used to generate diffraction quality crystals, at times, overnight. Using the HT-HR strategy, we have examined the DNA interactions of: (1) RT-29, a new benzimidazole-diamidine compound that displays anti-trypanosomal activity; (2) netropsin; and (3) combinatorial libraries of minor groove binding compounds. Our analyses suggest that the HT-HR strategy can expedite the screening of novel DNA binding and damaging agents, including libraries of potential DNA-interacting compounds.
 

Chemistry and Metabolism
4:30 PM-6:30 PM, Tuesday, 12 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Biological Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006