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Water-mediated binding of agents that target the DNA minor groove.

Authors
  • Liu, Yang
  • Kumar, Arvind
  • Depauw, Sabine
  • Nhili, Raja
  • David-Cordonnier, Marie-Hélène
  • Lee, Michael P
  • Ismail, Mohamed A
  • Farahat, Abdelbasset A
  • Say, Martial
  • Chackal-Catoen, Sarah
  • Batista-Parra, Adalgisa
  • Neidle, Stephen
  • Boykin, David W
  • Wilson, W David
Type
Published Article
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society
Publication Date
Jul 06, 2011
Volume
133
Issue
26
Pages
10171–10183
Identifiers
DOI: 10.1021/ja202006u
PMID: 21627167
Source
Medline
License
Unknown

Abstract

Small molecule complexes with DNA that incorporate linking water molecules are rare, and the DB921-DNA complex has provided a unique and well-defined system for analysis of water-mediated binding in the context of a DNA complex. DB921 has a benzimidazole-biphenyl system with terminal amidines that results in a linear conformation that does not possess the appropriate radius of curvature to match the minor groove shape and represents a new paradigm that does not fit the classical model of minor groove interactions. To better understand the role of the bound water molecule observed in the X-ray crystal structure of the DB921 complex, synthetic modifications have been made in the DB921 structure, and the interactions of the new compounds with DNA AT sites have been evaluated with an array of methods, including DNase I footprinting, biosensor-surface plasmon resonance, isothermal titration microcalorimetry, and circular dichroism. The interaction of a key compound, which has the amidine at the phenyl shifted from the para position in DB921 to the meta position, has also been examined by X-ray crystallography. The detailed structural, thermodynamic, and kinetic results provide valuable new information for incorporation of water molecules in the design of new lead scaffolds for targeting DNA in chemical biology and therapeutic applications.

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