title: Computational identification of uncharacterized cruzain binding sites.
abstract: 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.
authors.affiliation: Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Durrant
authors.forename: Henrik
authors.initials: H
authors.lastname: Keränen
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Wilson
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000981:Antiprotozoal Agents / Q000378:metabolism; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D003546:Cysteine Endopeptidases / Q000235:genetics*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000378:metabolism; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D000981:Antiprotozoal Agents; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi