Evaluation of the Influence of Compound Structure on Stacked-Dimer Formation in the DNA Minor Groove

Wang, L; Carrasco, Carolina; Kumar, Arvind; Ce, Stephens; Bailly, Christian; Dw, Boykin; Wilson, W. David

doi:10.1021/bi002301r

Cited by 65 publications

(90 citation statements)

References 23 publications

(49 reference statements)

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“…It has been shown previously that a benzimidazolecontaining dicationic compound (without amide bond linkage) can form a dimer in the DNA minor groove [12,13]. Our results provide evidence of the ¢rst dicationic polyamide that is capable of dimerizing in the minor groove.…”

Section: Conformational Changes May Occur Upon Gl020924^dnasupporting

confidence: 62%

A novel dicationic polyamide ligand binds in the DNA minor groove as a dimer

Zhang¹,

Dai²,

Schmitz³

et al. 2001

FEBS Letters

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We have investigated DNA binding properties of a dicationic polyamide molecule (GL020924) that has exhibited unique protein displacement and gene regulation activities. Fluorescence, thermal melting and electrospray ionization mass spectrometry experiments showed that the binding stoichiometry of GL020924 is 2:1 to various DNA oligomers with 8^11 contiguous A/T bp. In accordance with those findings, circular dichroism experiments showed GL020924 binds as a partially staggered side-by-side dimer spanning 10^12 bp. These observations and molecular modeling studies demonstrate that the 2:1 GL020924^DNA complex may exhibit a novel form of stacking orientation involving at least partially parallel peptide groups. ß

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Section: Conformational Changes May Occur Upon Gl020924^dnasupporting

confidence: 62%

A novel dicationic polyamide ligand binds in the DNA minor groove as a dimer

Zhang¹,

Dai²,

Schmitz³

et al. 2001

FEBS Letters

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“…Diamidines that recognize DNA sequences that contain GC base pairs, including majority GC sequences, have now been described [76][77][78][79][80]. In addition we realize that the curved shape of diamidines is one option for binding but is not a requirement.…”

Section: Discussionmentioning

confidence: 99%

Antiparasitic compounds that target DNA

et al. 2008

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Designed, synthetic heterocyclic diamidines have excellent activity against eukaryotic parasites that cause diseases such as sleeping sickness and leishmania and adversely affect millions of people each year. The most active compounds bind specifically and strongly in the DNA minor groove at AT sequences. The compounds enter parasite cells rapidly and appear first in the kinetoplast that contains the mitochondrial DNA of the parasite. With time the compounds are also generally seen in the cell nucleus but are not significantly observed in the cytoplasm. The kinetoplast decays over time and disappears from the mitochondria of treated cells. At this point the compounds begin to be observed in other regions of the cell, such as the acidocalcisomes. The cells typically die in 24-48 hours after treatment. Active compounds appear to selectively target extended AT sequences and induce changes in kinetoplast DNA minicircles that cause a synergistic destruction of the catenated kinetoplast DNA network and cell death.

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“…This is indicative of an interaction with very strong positive cooperativity, as can be seen by the characteristic curvature for positive cooperativity in the plot ( Figure 4A). 28,41,42 The strong, cooperative binding of DB1242 creates a dimer structure that can block DNaseI digestion and can account for the unexpected interaction and strong footprint of DB1242 in the -GCTCG-sequence. It should be noted that results for all of the compounds in Figure 1 could only be obtained in SPR experiments up to approximately 4 μM due to erratic results for subtraction of the blank flow cell signal above the 4 μM concentration range.…”

Section: Biosensor -Spr: Affinity Stoichiometry Cooperativitymentioning

confidence: 99%

Design of DNA Minor Groove Binding Diamidines That Recognize GC Base Pair Sequences: A Dimeric-Hinge Interaction Motif

et al. 2007

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The classical model of DNA minor groove binding compounds is that they should have a crescent shape that closely fits the helical twist of the groove. Several compounds with relatively linear shape and large dihedral twist, however, have been found recently to bind strongly to the minor groove. These observations raise the question of how far the curvature requirement could be relaxed. As an initial step in experimental analysis of this question, a linear triphenyl diamidine, DB1111 and a series of nitrogen tricyclic analogues were prepared. The goal with the heterocycles is to design GC binding selectivity into heterocyclic compounds that can get into cells and exert biological effects. The compounds have a zero radius of curvature from amidine carbon to amidine carbon but a significant dihedral twist across the tricyclic and amidine-ring junctions. They would not be expected to bind well to the DNA minor groove by shape-matching criteria. Detailed DNaseI footprinting studies of the sequence specificity of this set of diamidines indicated that a pyrimidine heterocyclic derivative, DB1242, has remarkable binding specificity for a GC rich sequence, -GCTCG-. It binds to the GC sequence more strongly than to the usual AT recognition sequences for curved minor groove agents. Other similar derivatives did not exhibit the GC specificity. Biosensor-surface plasmon resonance and isothermal titration calorimetry experiments indicate that DB1242 binds to the GC sequence as a highly cooperative stacked dimer. Circular dichroism results indicate that the compound binds in the minor groove. Molecular modeling studies support a minor groove complex and provide an inter-compound and compound-DNA hydrogen bonding rational for the unusual GC binding specificity and the requirement for a pyrimidine heterocycle. This compound represents a new direction in development of DNA sequence specific agents and it is the first non-polyamide, synthetic compound to specifically recognize a DNA sequence with a majority of GC base pairs.

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Evaluation of the Influence of Compound Structure on Stacked-Dimer Formation in the DNA Minor Groove

Cited by 65 publications

References 23 publications

A novel dicationic polyamide ligand binds in the DNA minor groove as a dimer

A novel dicationic polyamide ligand binds in the DNA minor groove as a dimer

Antiparasitic compounds that target DNA

Design of DNA Minor Groove Binding Diamidines That Recognize GC Base Pair Sequences: A Dimeric-Hinge Interaction Motif

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