Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform
Holt, A, Ragazzon, PA, Strekowski, L, Chaires, J and Trent, J 2009, 'Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform' , Nucleic Acids Research, 37 (4) , pp. 1280-1287.
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Virtual Screening is an increasingly attractive way to discover new small molecules with potential medicinal value. We introduce a novel strategy that integrates use of the molecular docking software Surflex with experimental validation by the method of competition dialysis. This integrated approach was used to identify ligands that selectively bind to the triplex DNA poly(dA)-[poly(dT)](2). A library containing approximately 2 million ligands was virtually screened to identify compounds with chemical and structural similarity to a known triplex intercalator, the napthylquinoline MHQ-12. Further molecular docking studies using compounds with high structural similarity resulted in two compounds that were then demonstrated by competition dialysis to have a superior affinity and selectivity for the triplex nucleic acid than MHQ-12. One of the compounds has a different chemical backbone than MHQ-12, which demonstrates the ability of this strategy to 'scaffold hop' and to identify small molecules with novel binding properties. Biophysical characterization of these compounds by circular dichroism and thermal denaturation studies confirmed their binding mode and selectivity. These studies provide a proof-of-principle for our integrated screening strategy, and suggest that this platform may be extended to discover new compounds that target therapeutically relevant nucleic acid morphologies.
|Themes:||Health and Wellbeing|
|Schools:||Schools > School of Environment and Life Sciences > Biomedical Research Centre|
|Journal or Publication Title:||Nucleic Acids Research|
|Publisher:||Oxford University Press|
|Funders:||National Institutes of Health, James Graham Brown Foundation, National Institutes of Health|
|Depositing User:||PA Ragazzon|
|Date Deposited:||26 Jan 2015 13:46|
|Last Modified:||26 Jan 2015 13:46|
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