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Small-molecule G-quadruplex interactions: Systematic exploration of conformational space using multiple molecular dynamics

Husby, Jarmila, Todd, Alan K., Platts, James Alexis and Neidle, Stephen 2013. Small-molecule G-quadruplex interactions: Systematic exploration of conformational space using multiple molecular dynamics. Biopolymers 99 (12) , pp. 989-1005. 10.1002/bip.22340

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Abstract

G-quadruplexes are higher-order four-stranded structures formed from repetitive guanine-containing tracts in nucleic acids. They comprise a core of stacked guanine-quartets linked by loops of length and sequence that vary with the context in which the quadruplex sequence occurs. Such sequences can be found in a number of genomic environments; at the telomeric ends of eukaryotic chromosomes, in promoter regions, in untranslated sequences and in open reading frames. Quadruplex formation can inhibit telomere maintenance, transcription and translation, especially when enhanced by quadruplex-binding small molecules, and quadruplex targeting is currently of considerable interest. The available experimental structural data shows that quadruplexes can have high conformational flexibility, especially in loop regions, which has hampered attempts to use high-throughput docking to find quadruplex-binding small-molecules with new scaffolds or to optimize existing ones with structure-based design methods. An approach to overcome the challenge of quadruplex conformational flexibility is presented here, which uses a combined multiple molecular dynamics and sampling approach. Two test small molecules have been used, RHPS4 and pyridostatin, which themselves have contrasting degrees of conformational flexibility.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Uncontrolled Keywords: quadruplex; dna; drug
Additional Information: Special Issue: 50th Anniversary Special Issue on Nucleic Acids
Publisher: Wiley-Blackwell
ISSN: 0006-3525
Last Modified: 04 Jun 2017 06:12
URI: http://orca-mwe.cf.ac.uk/id/eprint/57296

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