V. Jo Davisson, Ph.D. Professor of Medicinal Chemistry and Molecular Pharmacology Phone: (765) 494-5238 Fax: (765) 494-1414 E-mail: davisson@purdue.edu Full directory listing

Specialization: Natural Product Drugs, Chemical Biology, Bionanotechnology

Education

Research: Natural Product Drugs, Chemical Biology, Bionanotechnology

A central theme for the studies in the laboratory is the discovery of the molecular basis for specificity in biological systems and the use of this information in drug discovery and development. Aligned with all of the projects are strategies for developing and implementing new methods and technologies to measure and quantify the dynamics of biological systems. These tools are deployed in approaches to define markers of disease, to understand drug mechanism(s) of action and to discover new drugs. We use chemical agents and/or drugs to define these "pharmacological systems" from the scale of protein-ligand interactions to the level of the cellular networks dictating the phenotypic and behavioral changes that they effect. The experimental approaches are diversified and rely on a variety of analytical, chemical, genetic, and biophysical methodologies allowing students and postdoctoral associates to cross the boundaries of traditional disciplines and to engage in a highly collaborative research enterprise. Examples include:

• Genetic and protoemic analyses to reveal details of cellular pharmacology
• Chemical design and synthesis of biochemical and pharmacological probes
• Kinetic measurements using optical spectroscopy, imaging or mass spectrometry to unravel the mechanism and dynamics of protein-ligand interactions
• Molecular modeling and protein x-ray crystallography for three-dimensional structures of molecular targets.
• Synthesis of solid supports for affinity selection, chemical tags for proteomic identification and quantification using mass spectrometry, optical properties and/or plasmonic materials

The recent establishment of the high throughput biology research efforts in the Bindley Bioscience Center of Purdue's Discovery Park offers a new critical pathway for the full pursuit of many of the studies of biological systems and the associated technology development. Numerous opportunities for collaborative projects exist with the research staff and facilities in Discovery Park.

Medicinal Chemistry and Cellular Pharmacology of Natural Product Drugs

Drugs from nature still offer the most diverse platforms for understanding how chemicals can be engineered to modulate cellular function. Evolution of these chemicals has created a natural pharmacological tool-kit for revealing a diverse array of targets, pathways and their associated networks through which drugs may elicit actions on living systems. However, only those drugs that can selectively alter cellular signaling or metabolism will have the most potential for utility in future pharmacotherapy or chemoprevention strategies. The information available from single protein target screens or from global cellular toxicities are not rich enough sources to enable decisions regarding the selectivity of drug effects. An overall focus of the research is the development and validation of medium to high throughput pharmacoproteomic, metabolomic, and cytomic approaches based upon molecular and phenotypic markers to discover global cellular effects of potential therapeutic agents.

Chemical, Nanoscale, and Microscale Tools for Analysis of Biological Systems

Many of the critical questions regarding biological systems under investigation in the laboratory are limited by the available technologies and tools, and this shortcoming provides inspiration for innovative developments. The challenges of identification and quantification of drug effects in cellular systems persist despite the availability of new biochemical methodologies. Current proteomic systems lack the accuracy, multiplexing capabilities, and dynamic range to fully enable a quantitative analysis of drug effects at the proteomic and cellular level. To meet these challenges, we are pursuing several collaborative projects that involve chemical development at the molecular scale, nanoscale, and microscale for both ex vivo and in vivo cellular analyses.

Azole Nucleobases as Chemical Tools for DNA/RNA Technologies

Using the concept of degenerate recognition, we are currently exploring in vitro methods to create artificial DNA molecules that are replicated with reduced fidelity. This research in collaboration with the laboratory of Professor Don Bergstrom uses these artificial nucleobases to probe the fidelity of a broad range of DNA and RNA polymerases. The unique properties of these nucleosides/nucleotides with degenerate recognition features are being exploited as tools for revealing the chemical basis for selectivity of DNA and RNA polymerases and to create novel random mutagenesis technologies. The potential for the pharmacological relevance of these analogs in their use as alternative substrates or inhibitors for viral RNA dependent RNA polymerases is currently under investigation.

Protein-Ligand and Protein-Protein Dynamics

At the heart of cellular signaling machinery are the protein-protein interactions. The laboratory has a long-standing interest and expertise in the analysis of both the chemistry and biology of allosteric effects and regulation of protein function. The application and integration of new methods and technologies are aligned with two major areas of global relevance to drug discovery and drug design. The first area is to selectively modulate the functional networks of heat shock proteins. The second area of interest is the investigation of existing therapeutic agents and their impact on mitochondrial function by activation of pro-apoptotic pathways.

Representative Publications

Anadu, N. O., Hollingshead, M., Davisson, V. J., Cushman, M. (2006) "Synthesis and anticancer activity of brefeldin A ester derivatives" Journal of Medicinal Chemistry 49, 3897-3905.

Amaro, R. E., Myers, R. S., Davisson, V. J., Luthey-Schulten, Z. A. (2007) "A network of conserved interactions regulates the allosteric signal in a glutamine amidotransferase" Biochemistry 46, 2156 - 2173.

Schweitzer, D., Zhu, J., Jarori, G. Kane, J. J., Tanaka, J., Higa, T., Davisson, V. J. Helquist, P. (2007) "Synthesis of carbamate derivatives of iejimalides. Retention of normal antiproliferative activity and localization of binding in cancer cells" Bioorganic and Medicinal Chemistry 15, 3208-3216.

Loethen, Y. L., Knudsen, G. M., Davis, B., Gudihal, R., Davisson, V. J., Ben-Amotz, D. (2008) "Protein Quantitation in 2-D Gels using Fluorescence with Water Raman as an Internal Standard" Journal of Proteome Research 7, 1341-1345.

Rozhkov, R., Davisson, V. J., Bergstrom, D. E. (2008) "Fluorogenic Transformations Based on Formation of C-C Bonds Catalyzed by Palladium: An Efficient Approach for High Throughput Optimizations and Kinetic Studies" Advanced Synthesis and Catalysis 350, 71-75.

Deb, S. K., Davis, B., Knudsen, G. M., Gudihal, R., Ben-Amotz, D. Davisson, V. J. (2008) "Detection and Relative Quantification of Proteins by Surface Enhanced Raman Using Isotopic Labels" Journal of the American Chemical Society 30 9624-9625.

Liu, F., Hindupur, J., Nguyen, J. L., Ruf, K. J., Zhu, J., Schieler, J. L., Bonham, C. C., Wood, K. V., Davisson, V. J., Rochet, J.-L. (2008) "Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults" Free Radical Biology & Medicine 45 242-255.

Deb, S. K., Davis, B., Ben-Amotz, D., Davisson, V. J. (2008) "Accurate Concentration Measurements Using Surface-Enhanced Raman and Deuterium Exchanged Dye Pairs" Applied Spectroscopy 62, 1001-1007.

Knudsen, Gi., Davis, B., Deb, S., Loethen, Y., Gudihal, R., Perera, P., Ben Amotz, D., Davisson, V. J. (2008) "Quantification of Isotope Encoded Proteins in 2-D Gels Using Surface Enhanced Resonance Raman" Bioconjugate Chemistry 19, 2212-2220.