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 language | English (US) |
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Pages (from-to) | 3063-3068 |
Number of pages | 6 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 12 |
Issue number | 11 |
DOIs | |
State | Published - Jun 1 2004 |
Keywords
- Antibiotics
- Distamycin A
- Lexitropsins
- Polyamides
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry