People - [ Faculty ]
Currently we are developing a better understanding of the structure, stability, and drug binding properties of G-quadruplex and i-Motif DNA's. Sequences capable of forming these unique intra-molecular-folded DNA structures are located in the regulatory regions of more than 40% of all human genes. The oncogenes c-MYC, Bcl-2, K-ras, and several others, are known to have P-1 promoter region sequences that can form single-stranded or looped-out G-quadruplex and i-Motif structures. Drugs that bind to and stabilize these structures may be able to turn off the expression of these oncogenes, providing a new approach to the treatment of cancer. By measuring the energetics of these specific DNA -binding interactions, we hope to provide the information needed to develop drugs that are more selective for cancer- specific targets and therefore, more effective in the treatment of cancer.
Our lab is generally interested in the characterization of specific high affinity interactions that take place between small molecules and biopolymers, e.g. drug binding to nucleic acids and/or proteins. In these studies we use a variety of microcalorimetry (ITC and DSC), light scattering (static and dynamic) and spectroscopic techniques (CD, Fluorescence, UV-vis, and NMR). We also use computational methods and molecular dynamics to model these interactions. The defining focus of our lab is the use of energetic or thermodynamic data in rational drug design.
Vangala, K., Ameer, F., Salomons, G., Le, V., Lewis, E.A., Liu, D., Yu, L., Zhang, D. (2012). “Studying Protein and Gold Nanoparticle Interaction Using Organothiols as Molecular Probes”, Journal of Physical Chemistry C., 116(5), 3645-3652.
Henderson, K.L., Le, V.H., Lewis, E.A., Emerson, J.P. (2012) “Exploring substrate binding in homoprotocatechuate 2,3-dioxygenase using isothermal titration calorimetry”, JBIC, 17(7), 991-994.
Song, H., Wilson, D.L., Farquhar, E.R., Lewis, E.A., Emerson , J.P. (2012) “Revisiting Zinc Coordination in Human Carbonic Anhydrase II”, Inorganic Chemistry, Online publication October 3, 2012, DOI: 10.1021/ic301645j.
Emerson, J.P., Le, V., Lewis, E.A., (2012) “Calorimetry”, eLS, John Wiley and Sons Ltd, DOI: 10.1002/9780470015902.a0003010.pub3.
Le, V., Lewis, E.A., (2012) “Modeling Complex Equilibria in ITC Experiments: Thermodynamic Parameters Estimation for a Three Binding Site Model”, Analytical Biochemistry, DOI:10.1016/j.ab.2012.11.030.
Dettler, J.M., Buscaglia, R., Le, V., Lewis, E.A. (2011) "DSC Deconvolution of the Structural Complexity of c-MYC P1 Promoter G-Quadruplexes" Biophysical Journal, 100(6),1517-1525.
Lewis, E.A., Munde, M., Wang, S., Rettig, M. Le, V, Machha, V., Wilson, W.D. (2011) “Complexity in the binding of minor groove agents: netropsin has two thermodynamically different DNA binding modes at a single site”, Nucleic Acids Research, doi: 101093/nar/gkr699, published online: September 3, 2011.
Dettler, J.M., Lewis, E.A. (2011) Biophysical Studies of the Structure, Stability and Ligand Properties of G-Quadruplex DNA: Thoughts and Comparisons of the K-ras, c-MYC, and Bcl-2 Oncogene promoter Sequence Quadruplexes”, Chapter 3, pp 33-50 in ACS Symposium Series, v 1082, Frontiers in Nucleic Acids, R.W. Sheardy and S.A. Winkle, eds. Doi:10.1021/bk-2011-1082.ch003, published online October 25, 2011.