Finding and characterizing the complexes of drug like molecules with quadruplex DNA: combined use of an enhanced hydroxyl radical cleavage protocol and NMR

Structural information on the complexes of drug like molecules with quadruplex DNAs can aid the development of therapeutics and research tools that selectively target specific quadruplex DNAs. Screening can identify candidate molecules that require additional evaluation. An enhanced hydroxyl radical...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2014-04, Vol.9 (4), p.e96218
Main Authors: Ranpura, Harikrushan, Bialonska, Dobroslawa, Bolton, Philip H
Format: Article
Language:English
Subjects:
Analysis
Aptamers
Aptamers, Nucleotide - chemistry
Biochemistry
Biology and life sciences
Chemical bonds
Chemical properties
Chemistry
Cleavage
Crystallography
Deoxyribonucleic acid
DNA
Drug Design
Drug development
Footprinting
G-Quadruplexes
Gene expression
High-Throughput Screening Assays - methods
Hydrogen
Hydrogen bonding
Hydroxides
Hydroxyl Radical - chemistry
Hydroxyl radicals
Magnetic Resonance Spectroscopy
Molecular biology
NMR
Nuclear magnetic resonance
Porphyrins - chemistry
Protein Binding
Protocol
Quinolinium Compounds - chemistry
Screening
Selective binding
Thrombin
Thrombin - chemistry
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Structural information on the complexes of drug like molecules with quadruplex DNAs can aid the development of therapeutics and research tools that selectively target specific quadruplex DNAs. Screening can identify candidate molecules that require additional evaluation. An enhanced hydroxyl radical cleavage protocol is demonstrated that can efficiently provide structural information on the complexes of the candidate molecules with quadruplex DNA. NMR methods have been used to offer additional structural information about the complexes as well as validate the results of the hydroxyl radical approach. This multi-step protocol has been demonstrated on complexes of the chair type quadruplex formed by the thrombin binding aptamer, d(GGTTGGTGTGGTTGG). The hydroxyl radical results indicate that NSC 176319, Cain's quinolinium that was found by screening, exhibits selective binding to the two TT loops. The NMR results are consistent with selective disruption of the hydrogen bonding between T4 and T13 as well as unstacking of these residues from the bottom quartet. Thus, the combination of screening, hydroxyl radical footprinting and NMR can find new molecules that selectively bind to quadruplex DNAs as well as provide structural information about their complexes.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0096218