Ten major pathogenic protozoa form a serious threat to the well-being of humankind and cause a global disease burden to hundreds of millions of people. Four of these protozoa are considered agents of bioterrorism. There is a desperate need for new medicines for treating infected patients and for use as prophylaxis. Current drugs have major side effects and are increasingly becoming ineffective due to drug resistance. In this bleak situation, the genome sequences for these parasites, which are becoming available just now, function as new resources for developing novel medicines in the battle against these diseases.

1. analyzing the genomes sequences from the ten protozoa for medically relevant protein targets; the targets will primarily consist of proteins that are essential to parasite biology and are potential targets of small molecule ligands with suitable pharmacological properties;
2. expressing, crystallizing and determining three-dimensional structures of the selected crucial proteins to identify the characteristics of key functional sites in these essential proteins;
3. determining three-dimensional structures of target proteins in complex with small molecule ligands;
4. discovering in solution small molecule ligands binding to target proteins;
5. applying computational processes to these structures to predict ligands targeting such key sites;
6. using these ligand-bound structures to establish outside collarorations for the development of new leads and drug candidates.

   In addition to the drug development potential, small molecule ligands are useful probes to test the significance of biological function. Inhibitors of enzymes have illuminated the metabolic and cellular processes for decades. With the same technology as searching for drug-leads, one can develop small molecules to probe cellular function, and this will be invaluable in hypothesis testing for various functions of proteins as well as validating potential drug targets before serious lead selection is begun.

   Protein targets of medical relevance will be selected from the following pathogenic protozoa: Plasmodium falciparum, Plasmodium vivax, Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, Leishmania infantum, Toxoplasma gondii, Entamoeba histolytica, Giardia lamblia and Cryptosporidium parvum. The last four organisms are biodefense agents. All of these organisms are the subject of ongoing or completed Genome Sequencing projects.