College of Pharmacy
These researchers study the interactions in small molecule-macromolecular complexes of therapeutically important protein targets for use in structure-based drug/ligand design. Their primary experimental technique is X-ray crystallography, which requires significant computational resources. They are using MSI laboratories to assist in processing and analyzing multi-gigabyte data sets from diffraction data; they then use the processed data to determine the protein/complex structure. The structure is then finalized by iterative cycles of model fitting using graphic workstations and refinement. Experimental analyses are followed with the application of a variety of computational and visualization techniques to provide insights into the structural basis for ligand binding that can be applied to compound optimization and proposals for chemical synthesis. Completed structures will be prepared for deposition in the Research Collaboratory for Structural Bioinformatics database and for publication. Currently active projects include two involving the development of antibacterial agents, one where the focus is on discovery of small molecule mediators of cell motility with anticancer and antiinflammatory applications, and one project in which inhibitors of a proeolytic enzyme (caspase-2) are being sought for potential therapeutic application in neurodegenerative diseases.
The Finzel laboratory is also committed to making structural data more readily available for use in structure-based design by providing novel web-based tools for protein structure superposition and comparative visualization. A database application that pulls together computational services for protein superposition based on substructure conformational matching and comprehensive substructure searching is being created. These tools support teaching and data management in structure-based drug design.