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Chagas disease, caused by the unicellular parasite Trypanosoma cruzi, claims 50,000 lives annually and is the leading cause of infectious myocarditis in the world. As current antichagastic therapies like nifurtimox and benznidazole are highly toxic, ineffective at parasite eradication, and subject to increasing resistance, novel therapeutics are urgently needed. Cruzain, the major cysteine protease of Trypanosoma cruzi, is one attractive drug target. In the current work, molecular dynamics simulations and a sequence alignment of a non-redundant, unbiased set of peptidase C1 family members are used to identify uncharacterized cruzain binding sites. The two sites identified may serve as targets for future pharmacological intervention. Author Summary: Chagas disease, an infection that afflicts millions of people in Central and South America, is caused by the unicellular parasite Trypanosoma cruzi. In the chronic stage of the disease, patients' hearts are adversely affected. Chagas is the leading cause of infectious heart disease in the world. The current drugs used to treat Chagas disease are highly toxic, unable to eradiate the parasite, and subject to increasing drug resistance. Consequently, researchers are actively looking for new treatments. One attractive drug target is a Chagas protein called cruzain, which is required for the parasite's survival. Drugs that can inhibit the correct functioning of cruzain within the parasite may one day serve as powerful treatments in the fight against this devastating tropical disease. To design drugs that will be effective against cruzain, we need to know what portions of the protein are crucial for its functionality. For example, portions of the protein that bind to other proteins or to small molecules are likely to be critical. These regions are called "binding sites." In the current work, we identify two uncharacterized cruzain binding sites. With this knowledge in hand, future researchers may be able to design drugs that target these sites. [ABSTRACT FROM AUTHOR]