Leishmania mexicana Trypanothione Reductase Inhibitors: Computational and Biological Studies
Por:
Matadamas-Martinez, Felix, Hernandez-Campos, Alicia, Tellez-Valencia, Alfredo, Vazquez-Raygoza, Alejandra, Comparan-Alarcon, Sandra, Yepez-Mulia, Lilian, Castillo, Rafael
Publicada:
1 sep 2019
Resumen:
Leishmanicidal drugs have many side effects, and drug resistance to all
of them has been documented. Therefore, the development of new drugs and
the identification of novel therapeutic targets are urgently needed.
Leishmania mexicana trypanothione reductase (LmTR), a NADPH-dependent
flavoprotein oxidoreductase important to thiol metabolism, is essential
for parasite viability. Its absence in the mammalian host makes this
enzyme an attractive target for the development of new anti-Leishmania
drugs. Herein, a tridimensional model of LmTR was constructed and the
molecular docking of 20 molecules from a ZINC database was performed.
Five compounds (ZINC04684558, ZINC09642432, ZINC12151998, ZINC14970552,
and ZINC11841871) were selected (docking scores -10.27 kcal/mol to -5.29
kcal/mol and structurally different) and evaluated against recombinant
LmTR (rLmTR) and L. mexicana promastigote. Additionally, molecular
dynamics simulation of LmTR-selected compound complexes was achieved.
The five selected compounds inhibited rLmTR activity in the range of
32.9% to 40.1%. The binding of selected compounds to LmTR involving
different hydrogen bonds with distinct residues of the molecule monomers
A and B is described. Compound ZINC12151998 (docking score -10.27
kcal/mol) inhibited 32.9% the enzyme activity (100 mu M) and showed the
highest leishmanicidal activity (IC50 = 58 mu M) of all the selected
compounds. It was more active than glucantime, and although its
half-maximal cytotoxicity concentration (CC50 = 53 mu M) was higher than
that of the other four compounds, it was less cytotoxic than
amphotericin B. Therefore, compound ZINC12151998 provides a promising
starting point for a hit-to-lead process in our search for new
anti-Leishmania drugs that are more potent and less cytotoxic.
Filiaciones:
Matadamas-Martinez, Felix:
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Unidad Médica de Alta Especialidad-Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, 06720, Mexico
Univ Nacl Autonoma Mexico, Fac Quim, Dept Farm, Mexico City 04510, DF, Mexico
Hernandez-Campos, Alicia:
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Univ Nacl Autonoma Mexico, Fac Quim, Dept Farm, Mexico City 04510, DF, Mexico
Tellez-Valencia, Alfredo:
Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Av. Universidad y Fanny Anitúa S/N, Durango, 34000, Mexico
Univ Juarez Estado Durango, Fac Med & Nutr, Ave Univ& Fanny Anitua S-N, Durango 34000, CO, Mexico
Vazquez-Raygoza, Alejandra:
Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Av. Universidad y Fanny Anitúa S/N, Durango, 34000, Mexico
Univ Juarez Estado Durango, Fac Med & Nutr, Ave Univ& Fanny Anitua S-N, Durango 34000, CO, Mexico
Comparan-Alarcon, Sandra:
Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Unidad Médica de Alta Especialidad-Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, 06720, Mexico
Inst Mexicano Seguro Social, Ctr Med Nacl Siglo XXI, Unidad Med Alta Especialidad Hosp Pediat, Unidad Invest Med Enfermedades Infecciosas & Para, Mexico City 06720, DF, Mexico
Yepez-Mulia, Lilian:
Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Unidad Médica de Alta Especialidad-Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, 06720, Mexico
Inst Mexicano Seguro Social, Ctr Med Nacl Siglo XXI, Unidad Med Alta Especialidad Hosp Pediat, Unidad Invest Med Enfermedades Infecciosas & Para, Mexico City 06720, DF, Mexico
Castillo, Rafael:
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Univ Nacl Autonoma Mexico, Fac Quim, Dept Farm, Mexico City 04510, DF, Mexico
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