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Dr. Sacchettini
http://puffer.tamu.edu/ We study interactions that occur between proteins and their ligands, substrates and inhibitors, using X-ray crystallography, microcalorimetry, and molecular biology. We aim to determine a precise understanding of the molecular details of protein:ligand binding, and apply this understanding to rational drug design. In collaboration with several academic labs, as well as GlaxoSmithKline (GSK) and Astra Zeneca, we work on several enzymes of human pathogens including M. tuberculosis, P. falciparum and Borrellia burgdorferi. Our approach to drug discovery is to combine information from the 3-D structure of target proteins with bound inhibitors usually obtained from high throughput screens. This information is then used to computationally design inhibitors with the goal of improving the affinity to the enzyme's active site. By synthesizing and testing the next generation of inhibitors, we can begin to create a database of new candidate lead compounds ready for in vivo screening. Using these techniques, we have now designed and synthesized several compounds that appear to be potential drug candidates against M. tuberculosis, and are being tested by GSK. We are using protein crystallography to further our understanding of the structural basis of the cellular immune response. This occurs through a concerted effort to determine the 3-D structures of several major histocompatibility complexes with specific antigen peptides bound and T-cell receptors. These studies have permitted many insights into how cells notify the immune system of their infection. We are also continuing our work on antibody structure, with several new antibody:antigen complexes completed. Graduate students are an intricate part of this research, and are trained in X-ray crystallography, molecular biology and some aspects of protein structure function, as well as computational methods in inhibitor design. We are setting up a high throughput inhibitor and COMBI chemistry lab with which CBI students would be involved. |
