WorkSpace and the study of Chagas' disease

Chagas' disease afflicts more than 18 million people throughout South and Central America. Some areas of North America have also seen an increased incidence in recent years. The Trypanosoma cruzi (T. cruzi) parasite, which causes the disease, is most often transmitted by Triatomid bugs living in close proximity to humans. The T. cruzi parasite depends heavily on a small molecule called trypanothione to protect itself against damage from free radicals produced during normal metabolism. The concentration of trypanothione in the cell is carefully maintained by an enzyme called trypanothione reductase (TR). Drugs that inhibit TR should cause the parasite to die. Human cells have a similar enzyme-substrate pair: glutathione and glutathione reductase (GR). Fortunately, the enzyme GR differs electrostatically from TR, so there is hope of developing a drug that will be safe for human cells. The molecular structures of both TR and GR are known from ongoing X-ray crystallography studies. Both enzymes are dimers, that is, they consist of two equivalent domains, each having its own active site (the place where glutathione or trypanothione binds). One surprising feature of this system is a long tunnel passing through the center of the dimer and connecting the active sites of the two domains. While this is a naturally interesting feature to explore in a VR environment, the goal of the research is to evaluate the binding ability of particular drugs. For purposes of early testing, we chose chlorpromazine, an antidepressant drug. Large doses of the drug are known to kill the parasite, but are also toxic to the human host. It is possible that minor structural changes to this molecule would improve the selectivity and potency of the drug. For purposes of testing our VR environment, we present only a token calculation on chlorpromazine