title: Receptor-dependent 4D-QSAR analysis of peptidemimetic inhibitors of Trypanosoma cruzi trypanothione reductase with receptor-based alignment.
abstract: Receptor-dependent four-dimensional quantitative structure-activity relationship (RD-4D-QSAR) studies were applied on a series of 21 peptides reversible inhibitors of Trypanosoma cruzi trypanothione reductase (TR) (Amino Acids, 20, 2001, 145). The RD-4D-QSAR (J Chem Inform Comp Sci, 43, 2003, 1591) approach can evaluate multiple conformations from molecular dynamics simulation and several superposition structure alignments inside a box composed by unitary cubic cells. The descriptors are the occupancy frequency of the atoms types inside the grid cells. We could develop 3D-QSAR models that were highly predictive (q(2)  above 0.71). The 3D-QSAR models can be visualized as a spatial map of atom types that are important on the comprehension of the ligand-enzyme interaction mechanism, pointing main pharmacophoric groups and TR subsites described in the literature. We were able also to identify some TR subsites for further development in the drug discovery process against tropical diseases not yet studied.
authors.affiliation: Universidade Federal do Rio de Janeiro, PPGQu, IQ, CT, LabMMol, Rio de Janeiro, RJ, Brazil. samuel.pita@ufba.br
authors.forename: Samuel Silva
authors.initials: SS
authors.lastname: da Rocha Pita
authors.forename: Magaly Girão
authors.initials: MG
authors.lastname: Albuquerque
authors.forename: Carlos Rangel
authors.initials: CR
authors.lastname: Rodrigues
authors.forename: Helena Carla
authors.initials: HC
authors.lastname: Castro
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Hopfinger
mesh_terms: D000977:Antiparasitic Agents / Q000737:chemistry* / Q000494:pharmacology*; D014355:Chagas Disease / Q000188:drug therapy; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000977:Antiparasitic Agents; D008024:Ligands; D057786:Peptidomimetics; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase