DNA remains an underrepresented target for small molecule therapeutic agents. There is mounting evidence to indicate that non-B DNA structures play prominent roles in gene expression and in the function of telomeres. Targeting these structural elements is an attractive and innovative strategy for the development of new therapeutic agents. The use of small molecules in such an antigene strategy is promising for many reasons. Targeting the gene before its amplification to produce multiple mRNA and protein molecules is advantageous because there are fewer targets to hit. In addition, is easier to manipulate small molecules (rather than therapeutic DNA or RNA molecules) chemically to optimize binding and pharmacological properties. We seek renewal for our innovative and highly productive program to develop an integrated virtual and actual screening platform for the discovery of new lead compounds that bind selectively to unique DNA structures of biological significance. Progress during the initial funding period was outstanding, and we achieved most of the specific aims proposed in our initial proposal. We have discovered several compounds that bind selectively to particular quadruplex structures, a target of intense current interest. We propose studies that will continue to develop and optimize the integrated screening platform. During the next funding period, we will focus on the discovery of lead compounds that bind selectively to biologically important quadruplex and DNA-RNA hybrid structures. In order to do this, we will develop structural models for complex quadruplex structures using a novel approach that integrates molecular dynamics simulations with rigorous experimental validation. We will characterize the biophysical and functional properties of the novel quadruplex binders we have discovered during the initial funding period.
Specific aims i nclude: 1. Development and refinement of the virtual screening platform. 2. Development of higher-throughput assays for ligand binding. 3. Discovery of lead compounds that bind to functionally important nucleic acid structures. 4. Biophysical and biological characterization of novel G-quadruplex binding agents discovered during the initial funding period. The proposed studies will deliver an improved integrated platform for the discovery of novel lead compounds and a thorough characterization of several newly-discovered quadruplex binders with unique chemical scaffolds.
This project will develop an integrated computational and experimental screening platform for the discovery of new drugs that target specific structures of functional importance within the genome. The initial funding period for this project was successful and productive, and we will continue our efforts. Several novel lead compounds were discovered that bind to functionally important quadruplex structures. We will characterize the biophysical and biological properties of these novel agents.
|Le, Huy T; Dean, William L; Buscaglia, Robert et al. (2014) An investigation of G-quadruplex structural polymorphism in the human telomere using a combined approach of hydrodynamic bead modeling and molecular dynamics simulation. J Phys Chem B 118:5390-405|
|Gray, Robert D; Trent, John O; Chaires, Jonathan B (2014) Folding and unfolding pathways of the human telomeric G-quadruplex. J Mol Biol 426:1629-50|
|Buscaglia, Robert; Miller, M Clarke; Dean, William L et al. (2013) Polyethylene glycol binding alters human telomere G-quadruplex structure by conformational selection. Nucleic Acids Res 41:7934-46|
|Garbett, Nichola C; Chaires, Jonathan B (2012) Thermodynamic studies for drug design and screening. Expert Opin Drug Discov 7:299-314|
|Petraccone, Luigi; Spink, Charles; Trent, John O et al. (2011) Structure and stability of higher-order human telomeric quadruplexes. J Am Chem Soc 133:20951-61|
|Holt, Patrick A; Buscaglia, Robert; Trent, John O et al. (2011) A Discovery Funnel for Nucleic Acid Binding Drug Candidates. Drug Dev Res 72:178-186|
|Gray, Robert D; Chaires, Jonathan B (2011) Linkage of cation binding and folding in human telomeric quadruplex DNA. Biophys Chem 159:205-9|
|Gray, Robert D; Petraccone, Luigi; Trent, John O et al. (2010) Characterization of a K+-induced conformational switch in a human telomeric DNA oligonucleotide using 2-aminopurine fluorescence. Biochemistry 49:179-94|
|Petraccone, Luigi; Garbett, Nichola C; Chaires, Jonathan B et al. (2010) An integrated molecular dynamics (MD) and experimental study of higher order human telomeric quadruplexes. Biopolymers 93:533-48|
|Chaires, Jonathan B (2010) Human telomeric G-quadruplex: thermodynamic and kinetic studies of telomeric quadruplex stability. FEBS J 277:1098-106|
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