Nucleic Acids Research Advance Access originally published online on January 9, 2009
Nucleic Acids Research 2009 37(4):1280-1287; doi:10.1093/nar/gkn1043
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Nucleic Acids Research, 2009, Vol. 37, No. 4 1280-1287
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural Biology |
Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform
1James Graham Brown Cancer Center, 2Department of Medicine, 3Department of Biochemistry and Molecular Biology, University of Louisville, 529 S. Jackson Street, Louisville, KY 40202 and 4Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA
*To whom correspondence should be addressed. Tel: +1 502 852 2194; Fax: +1 502 852 4311; Email: john.trent{at}louisville.edu
Received November 21, 2008. Revised December 12, 2008. Accepted December 13, 2008.
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 
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.