Nonbonded bivalence approach to cell-permeable molecules that target DNA sequences

Research output: Contribution to journalArticle

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Abstract

Polyamides such as the natural antibiotic distamycin A can form binary or ternary complexes with B-DNA. The driving forces and advantages for forming the ternary complexes are not fully understood. The computational studies reported herein suggest that three- and four-ring polyamides have a propensity for forming the same dimer conformations in water as those in their ternary complexes. The pre-dimerization of a polyamide in water facilitates the formation of the ternary complex, making the polyamide more selective, and tighter binding to the minor groove whose minimal width is predetermined by the B-DNA sequence. Relative to the dimer tethered with covalent bonds, the smaller, monomeric polyamide available from reversible dimerization in water makes the molecule inherently more cell permeable. A nonbonded bivalence approach that dimerizes molecules by intermolecular interactions is proposed for improving affinity, selectivity, and cell permeability.

Original languageEnglish (US)
Pages (from-to)3063-3068
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number11
DOIs
StatePublished - Jun 1 2004

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Keywords

  • Antibiotics
  • Distamycin A
  • Lexitropsins
  • Polyamides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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