title: Structural analysis and molecular docking of trypanocidal aryloxy-quinones in trypanothione and glutathione reductases: a comparison with biochemical data.
abstract: A set of aryloxy-quinones, previously synthesized and evaluated against Trypanosoma cruzi epimastigotes cultures, were found more potent and selective than nifurtimox. One of the possible mechanisms of the trypanocidal activity of these quinones could be inhibition of trypanothione reductase (TR). Considering that glutathione reductase (GR) is the equivalent of TR in humans, biochemical, kinetic, and molecular docking studies in TR and GR were envisaged and compared with the trypanocidal and cytotoxic data of a set of aryloxy-quinones. Biochemical assays indicated that three naphthoquinones (Nq-h, Nq-g, and Nq-d) selectively inhibit TR and the TR kinetic analyses indicated that Nq-h inhibit TR in a noncompetitive mechanism. Molecular dockings were performed in TR and GR in the following three putative binding sites: the catalytic site, the dimer interface, and the nicotinamide adenine dinucleotide phosphate-binding site. In TR and GR, the aryloxy-quinones were found to exhibit high affinity for a site near it cognate-binding site in a place in which the noncompetitive kinetics could be justified. Taking as examples the three compounds with TR specificity (TRS) (Nq-h, Nq-g, and Nq-d), the presence of a network of contacts with the quinonic ring sustained by the triad of Lys62, Met400', Ser464' residues, seems to contribute hardly to the TRS. Compound Nq-b, a naphthoquinone with nitrophenoxy substituent, proved to be the best scaffold for the design of trypanocidal compounds with low toxicity. However, the compound displayed only a poor and non-selective effect toward TR indicating that TR inhibition is not the main reason for the antiparasitic activity of the aryloxy-quinones.
authors.affiliation: a Centro de Bioinformática estructural, DETEMA, Facultad de Química , UdelaR , Montevideo , Uruguay.
authors.forename: Brenda
authors.initials: B
authors.lastname: Vera
authors.affiliation: b Facultad de Química , Pontificia Universidad Católica de Chile , Santiago , Chile.|c Campus de Ciencias Agropecuarias, Facultad de Medicina Veterinaria y Zootecnia , Universidad Autónoma de Nuevo León , Nuevo León , Mexico.
authors.forename: Karina
authors.initials: K
authors.lastname: Vázquez
authors.affiliation: d Departamento de Ciencias del Ambiente, Facultad de Química y Biología , Universidad de Santiago, Chile , Santiago , Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Mascayano
authors.affiliation: b Facultad de Química , Pontificia Universidad Católica de Chile , Santiago , Chile.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Tapia
authors.affiliation: e Centro de investigaciones biomédicas y aplicadas, Escuela de Medicina, Facultad de Ciencias Médicas , Universidad de Santiago, Chile , Santiago , Chile.
authors.forename: Victoria
authors.initials: V
authors.lastname: Espinosa
authors.affiliation: f Departamento de Ciencias Químicas, Facultad de Ciencias Exactas , Universidad Andrés Bello , Quillota 980, Viña del Mar , Chile.
authors.forename: Jorge
authors.initials: J
authors.lastname: Soto-Delgado
authors.affiliation: b Facultad de Química , Pontificia Universidad Católica de Chile , Santiago , Chile.
authors.forename: Cristian O
authors.initials: CO
authors.lastname: Salas
authors.affiliation: a Centro de Bioinformática estructural, DETEMA, Facultad de Química , UdelaR , Montevideo , Uruguay.
authors.forename: Margot
authors.initials: M
authors.lastname: Paulino
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D009249:NADP / Q000737:chemistry / Q000378:metabolism; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity; D013816:Thermodynamics; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development
chemical_list: D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D009249:NADP; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005980:Glutathione Reductase
keywords: Chagas disease; aryloxy-quinones; glutathione reductase; molecular docking; trypanothione reductase