Medicinal Chemist
Protein Crystallography
Southern Research Institute
2000 Ninth Avenue South
Birmingham, AL 35205
205- 581-2555
E-mail: li@sri.org
The major goals of the laboratory are to unravel the three-dimensional structures of protein molecules and to exploit the structural insight of targeted proteins for the design of therapeutic agents to treat cancer and infectious diseases. The research group focuses on protein structure analysis and structure-based design of inhibitors to target three major cellular processes — nucleoside metabolic pathway, folate biosynthesis/metabolic pathway and signaling transduction pathways. In collaboration with the laboratories of Bill Parker and Joe Maddry, investigations are under way into the structural biology and molecular mechanisms of key enzymes in the nucleoside metabolic pathway in Mycobacterium tuberculosis.
In particular, crystals of adenosine kinase and X-ray diffraction data for determination of high resolution structure have been obtained. The lab is pursuing studies of enzymes in the folate biosynthesis/metabolic pathway in M. tuberculosis, Francisella tularensis and Bacillus anthracis. From crystals of dihydrofolate reductase from B. anthracis, the structure of dihydrofolate reductase from M. tuberculosis has been determined which leads to the discovery of novel antifolates for TB therapeutic treatment. In collaboration with scientist at The University of Alabama at Birmingham, Southern Research is pursuing the studies of structure and function of protein kinases and other signaling molecules implicated in cancer, including protein kinases C, proline-rich tyrosine kinase 2 and p130-CAS. These studies will provide molecular insights regarding the nature of protein-protein interactions or interactions between proteins and ligands and suggest specific pharmacophore model for the drug design.
The major experimental techniques used in this laboratory include protein overexpression in both prokaryotic and eukaryotic cell systems, protein purification and crystallization, X-ray diffraction, interactive computer graphics and molecular modeling, including de novo ligand design, protein-ligand docking and screening of three-dimensional structural databases of compound libraries.