title: Structure-activity relationships for a class of selective inhibitors of the major cysteine protease from Trypanosoma cruzi.
abstract: Chagas' disease is a parasitic infection widely distributed throughout Latin America, with devastating consequences in terms of human morbidity and mortality. Cruzain, the major cysteine protease from Trypanosoma cruzi, is an attractive target for antitrypanosomal chemotherapy. In the present work, classical two-dimensional quantitative structure-activity relationships (2D QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 45 thiosemicarbazone and semicarbazone derivatives as inhibitors of T. cruzi cruzain. Significant statistical models (HQSAR, q(2) = 0.75 and r(2) = 0.96; classical QSAR, q(2) = 0.72 and r(2) = 0.83) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 10 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, r(2)(pred) = 0.95; classical QSAR, r(2)(pred) = 0.91), indicating the existence of complementary between the two ligand-based drug design techniques.
authors.affiliation: Laboratório de Química Medicinal e Computacional, Centro de Biotecnologia Molecular Estrutural, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos-SP, Brazil.
authors.forename: Rafael V C
authors.initials: RV
authors.lastname: Guido
authors.forename: Gustavo H G
authors.initials: GH
authors.lastname: Trossini
authors.forename: Marcelo S
authors.initials: MS
authors.lastname: Castilho
authors.forename: Glaucius
authors.initials: G
authors.lastname: Oliva
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Ferreira
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D003546:Cysteine Endopeptidases