title: Novel aryl β-aminocarbonyl derivatives as inhibitors of Trypanosoma cruzi trypanothione reductase: binding mode revised by docking and GRIND2-based 3D-QSAR procedures.
abstract: Trypanothione reductase has long been investigated as a promising target for chemotherapeutic intervention in Chagas disease, since it is an enzyme of a unique metabolic pathway that is exclusively present in the pathogen but not in the human host, which has the analog Glutathione reductase. In spite of the present data-set includes a small number of compounds, a combined use of flexible docking, pharmacophore perception, ligand binding site prediction, and Grid-Independent Descriptors GRIND2-based 3D-Quantitative Structure-Activity Relationships (QSAR) procedures allowed us to rationalize the different biological activities of a series of 11 aryl β-aminocarbonyl derivatives, which are inhibitors of Trypanosoma cruzi trypanothione reductase (TcTR). Three QSAR models were built and validated using different alignments, which are based on docking with the TcTR crystal structure, pharmacophore, and molecular interaction fields. The high statistical significance of the models thus obtained assures the robustness of this second generation of GRIND descriptors here used, which were able to detect the most important residues of such enzyme for binding the aryl β-aminocarbonyl derivatives, besides to rationalize distances among them. Finally, a revised binding mode has been proposed for our inhibitors and independently supported by the different methodologies here used, allowing further optimization of the lead compounds with such combined structure- and ligand-based approaches in the fight against the Chagas disease.
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Ribeirão Preto, SP, Brazil. tomich@fcfrp.usp.br
authors.forename: Carlos Henrique Tomich
authors.initials: CH
authors.lastname: de Paula da Silva
authors.forename: Lílian Sibelle Campos
authors.initials: LS
authors.lastname: Bernardes
authors.forename: Vinícius Barreto
authors.initials: VB
authors.lastname: da Silva
authors.forename: Carlos Leomar
authors.initials: CL
authors.lastname: Zani
authors.forename: Ivone
authors.initials: I
authors.lastname: Carvalho
mesh_terms: D001665:Binding Sites; D002090:Butyrophenones / Q000737:chemistry*; D014355:Chagas Disease / Q000188:drug therapy; D008024:Ligands; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D002090:Butyrophenones; D008024:Ligands; D015800:Protozoan Proteins; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase