<i>Leishmania mexicana</i> Trypanothione Reductase Inhibitors: Computational and Biological Studies
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. <i>Leishmania mexicana</i> trypanothione reductase (LmTR), a NADPH-depende...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2019-09-01
|
Series: | Molecules |
Subjects: | |
Online Access: | https://www.mdpi.com/1420-3049/24/18/3216 |
id |
doaj-50f736332d504d28a4ccddbd55946140 |
---|---|
record_format |
Article |
spelling |
doaj-50f736332d504d28a4ccddbd559461402020-11-25T02:42:11ZengMDPI AGMolecules1420-30492019-09-012418321610.3390/molecules24183216molecules24183216<i>Leishmania mexicana</i> Trypanothione Reductase Inhibitors: Computational and Biological StudiesFélix Matadamas-Martínez0Alicia Hernández-Campos1Alfredo Téllez-Valencia2Alejandra Vázquez-Raygoza3Sandra Comparán-Alarcón4Lilián Yépez-Mulia5Rafael Castillo6Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, MexicoDepartamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, MexicoFacultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango Av. Universidad y Fanny Anitúa S/N, Durango 34000, MexicoFacultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango Av. Universidad y Fanny Anitúa S/N, Durango 34000, MexicoUnidad 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, MexicoUnidad 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, MexicoDepartamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, MexicoLeishmanicidal 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. <i>Leishmania mexicana</i> 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-<i>Leishmania</i> 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 <i>L. mexicana</i> 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 µM) and showed the highest leishmanicidal activity (IC<sub>50</sub> = 58 µM) of all the selected compounds. It was more active than glucantime, and although its half-maximal cytotoxicity concentration (CC<sub>50</sub> = 53 µM) 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-<i>Leishmania</i> drugs that are more potent and less cytotoxic.https://www.mdpi.com/1420-3049/24/18/3216trypanothione reductasemolecular dockingenzyme inhibitorsleishmanicidal activity |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Félix Matadamas-Martínez Alicia Hernández-Campos Alfredo Téllez-Valencia Alejandra Vázquez-Raygoza Sandra Comparán-Alarcón Lilián Yépez-Mulia Rafael Castillo |
spellingShingle |
Félix Matadamas-Martínez Alicia Hernández-Campos Alfredo Téllez-Valencia Alejandra Vázquez-Raygoza Sandra Comparán-Alarcón Lilián Yépez-Mulia Rafael Castillo <i>Leishmania mexicana</i> Trypanothione Reductase Inhibitors: Computational and Biological Studies Molecules trypanothione reductase molecular docking enzyme inhibitors leishmanicidal activity |
author_facet |
Félix Matadamas-Martínez Alicia Hernández-Campos Alfredo Téllez-Valencia Alejandra Vázquez-Raygoza Sandra Comparán-Alarcón Lilián Yépez-Mulia Rafael Castillo |
author_sort |
Félix Matadamas-Martínez |
title |
<i>Leishmania mexicana</i> Trypanothione Reductase Inhibitors: Computational and Biological Studies |
title_short |
<i>Leishmania mexicana</i> Trypanothione Reductase Inhibitors: Computational and Biological Studies |
title_full |
<i>Leishmania mexicana</i> Trypanothione Reductase Inhibitors: Computational and Biological Studies |
title_fullStr |
<i>Leishmania mexicana</i> Trypanothione Reductase Inhibitors: Computational and Biological Studies |
title_full_unstemmed |
<i>Leishmania mexicana</i> Trypanothione Reductase Inhibitors: Computational and Biological Studies |
title_sort |
<i>leishmania mexicana</i> trypanothione reductase inhibitors: computational and biological studies |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2019-09-01 |
description |
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. <i>Leishmania mexicana</i> 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-<i>Leishmania</i> 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 <i>L. mexicana</i> 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 µM) and showed the highest leishmanicidal activity (IC<sub>50</sub> = 58 µM) of all the selected compounds. It was more active than glucantime, and although its half-maximal cytotoxicity concentration (CC<sub>50</sub> = 53 µM) 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-<i>Leishmania</i> drugs that are more potent and less cytotoxic. |
topic |
trypanothione reductase molecular docking enzyme inhibitors leishmanicidal activity |
url |
https://www.mdpi.com/1420-3049/24/18/3216 |
work_keys_str_mv |
AT felixmatadamasmartinez ileishmaniamexicanaitrypanothionereductaseinhibitorscomputationalandbiologicalstudies AT aliciahernandezcampos ileishmaniamexicanaitrypanothionereductaseinhibitorscomputationalandbiologicalstudies AT alfredotellezvalencia ileishmaniamexicanaitrypanothionereductaseinhibitorscomputationalandbiologicalstudies AT alejandravazquezraygoza ileishmaniamexicanaitrypanothionereductaseinhibitorscomputationalandbiologicalstudies AT sandracomparanalarcon ileishmaniamexicanaitrypanothionereductaseinhibitorscomputationalandbiologicalstudies AT lilianyepezmulia ileishmaniamexicanaitrypanothionereductaseinhibitorscomputationalandbiologicalstudies AT rafaelcastillo ileishmaniamexicanaitrypanothionereductaseinhibitorscomputationalandbiologicalstudies |
_version_ |
1724774773623357440 |