Influence of linker length in shape recognition of B∗ DNA by dimeric aminoglycosides

Kumar, Sunil; Spano, Meredith Newby; Arya, Dev P.

doi:10.1016/j.bmc.2015.04.082

Cited by 15 publications

(9 citation statements)

References 23 publications

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“…With the current increase in availability of both gene sequences and the knowledge of their functions in life‐forms ranging from bacteria to humans, there is clearly an unmet need for new, sequence‐specific, small‐molecule DNA probes . Significant variations in the cell‐uptake potential of molecular structures and pharmacokinetic differences will also require discovery and development of a diversity of different molecular systems for DNA recognition that do not currently exist …”

Section: Introductionmentioning

confidence: 99%

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The Thiophene “Sigma‐Hole” as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove

Guo

Kumar

Farahat

et al. 2016

Chemistry A European J

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In spite of its importance in cell function, targeting DNA is under-represented in the design of small molecules. A barrier to progress in this area is the lack of a variety of modules that recognize G•C base pairs (bp) in DNA sequences. To overcome this barrier an entirely new design concept for modules that can bind to mixed GC and AT sequences of DNA is reported. Because of their successes in biological applications, minor-groove-binding heterocyclic cations were selected as the platform for design. Binding to AT sequences requires H-bond donors while recognition of the G-NH2 requires an acceptor. The concept that we report here uses preorganized N-methylbenzimidazole (N-MeBI) thiophene modules for selective binding with mixed bp DNA sequences. The interaction between the thiophene sigma-hole (positive electrostatic potential) and electron donor nitrogen of N-MeBI preorganizes the conformation for accepting an H-bond from G-NH2. The compound-DNA interactions were evaluated with a powerful array of biophysical methods and the results show that N-MeBI-thiophene monomer compounds can strongly and selectively recognize single G•C bp sequences. Replacing the thiophene with other moieties significantly reduces binding affinity and specificity, as predicted by the design concept. These results show that the use of molecular features, such as sigma-hole, can lead to new approaches for small molecules in biomolecular interactions.

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Section: Introductionmentioning

confidence: 99%

“…[7,9,15] Significant variations in the cell-uptake potentialo fm olecular structuresa nd pharmacokinetic differences will also require discoverya nd development of ad iversity of different molecular systems for DNA recognition that do not currently exist. [16][17][18][19]…”

Section: Introductionmentioning

confidence: 99%

The Thiophene “Sigma‐Hole” as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove

Guo

Kumar

Farahat

et al. 2016

Chemistry A European J

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“…Unlike some other ligand screening methods which mandate the presence of a fluorophore in the ligand to be screened, this assay can be used to screen both fluorescent as well as non-fluorescent molecules binding to the nucleic acids. The utility of this assay has been demonstrated by many laboratories which have used both canonical and non-canonical nucleic acid structures of biological interest (Monchaud et al, 2006;Kumar et al, , 2015Kellish et al, 2014). More importantly several applications of this assay have been shown to be useful in discovering G-quadruplex binding ligands (Monchaud et al, 2006).…”

Section: Fluorescence Intercalator Displacement Experimentsmentioning

confidence: 99%

Surface Dependent Dual Recognition of a G-quadruplex DNA With Neomycin-Intercalator Conjugates

et al. 2020

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G-quadruplexes have been characterized as structures of vital importance in the cellular functioning of several life forms. They have subsequently been established to serve as a therapeutic target of several diseases including cancer, HIV, tuberculosis and malaria. In this paper, we report the binding of aminosugar-intercalator conjugates with a well-studied anti-parallel G-quadruplex derived from Oxytricha Nova G-quadruplex DNA. Of the four neomycin-intercalator conjugates studied with varying surface areas, BQQ-neomycin conjugate displayed the best binding to this DNA G-quadruplex structure with an association constant of K a = (1.01 ±0.03) × 10 7 M −1 which is nearly 100-fold higher than the binding of neomycin to this quadruplex. The binding of BQQ-neomycin displays a binding stoichiometry of 1:1 indicating the presence of a single and unique binding site for this G-quadruplex. In contrast, the BQQ-neomycin displays very weak binding to the bacterial A-site rRNA sequence showing that BQQ-does not enhance the neomycin binding to its natural target, the bacterial rRNA A-site. The BQQ-neomycin conjugate is prone to aggregation even at low micromolar concentrations (4 µM) leading to some ambiguities in the analysis of thermal denaturation profiles. Circular dichroism experiments showed that binding of BQQ-neomycin conjugate causes some structural changes in the quadruplex while still maintaining the overall anti-parallel structure. Finally, the molecular docking experiments suggest that molecular surface plays an important role in the recognition of a second site on the G-quadruplex. Overall, these results show that molecules with more than one binding moieties can be made to specifically recognize G-quadruplexes with high affinities. The dual binding molecules comprise of quadruplex groove binding and intercalator units, and the molecular surface of the intercalator plays an important part in enhancing binding interaction to the G-quadruplex structure.

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“…A complete thermodynamic study of neomycin dimer 115 binding to a B-DNA sequence revealed that the first binding event (the high affinity site) is entropically driven and that the ionic strength dependence of the binding is highly dependent on the electrolytic contribution [ 194 ]. The neomycin dimers also displayed length dependent shape recognition of the B-DNA [ 195 ].…”

Section: Reviewmentioning

confidence: 99%

An overview of recent advances in duplex DNA recognition by small molecules

Bhaduri

Ranjan

Arya

2018

Beilstein J. Org. Chem.

111

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As the carrier of genetic information, the DNA double helix interacts with many natural ligands during the cell cycle, and is amenable to such intervention in diseases such as cancer biogenesis. Proteins bind DNA in a site-specific manner, not only distinguishing between the geometry of the major and minor grooves, but also by making close contacts with individual bases within the local helix architecture. Over the last four decades, much research has been reported on the development of small non-natural ligands as therapeutics to either block, or in some cases, mimic a DNA–protein interaction of interest. This review presents the latest findings in the pursuit of novel synthetic DNA binders. This article provides recent coverage of major strategies (such as groove recognition, intercalation and cross-linking) adopted in the duplex DNA recognition by small molecules, with an emphasis on major works of the past few years.

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Influence of linker length in shape recognition of B∗ DNA by dimeric aminoglycosides

Cited by 15 publications

References 23 publications

The Thiophene “Sigma‐Hole” as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove

The Thiophene “Sigma‐Hole” as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove

Surface Dependent Dual Recognition of a G-quadruplex DNA With Neomycin-Intercalator Conjugates

An overview of recent advances in duplex DNA recognition by small molecules

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