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Dual-target drugs against Leishmania donovani for potential novel therapeutics

Antioxidant defense mechanisms are important for a parasite to overcome oxidative stress and survive within host macrophage cells. Mitochondrial iron superoxide dismutase A (FeSODA) and trypanothione reductase (TR) are critical enzymes in the antioxidant defense mechanism of Leishmania donovani. FeS...

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Autores principales: Bora, Kushal, Sarma, Manash, Kanaujia, Shankar Prasad, Dubey, Vikash Kumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603092/
https://www.ncbi.nlm.nih.gov/pubmed/37884555
http://dx.doi.org/10.1038/s41598-023-45448-x
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author Bora, Kushal
Sarma, Manash
Kanaujia, Shankar Prasad
Dubey, Vikash Kumar
author_facet Bora, Kushal
Sarma, Manash
Kanaujia, Shankar Prasad
Dubey, Vikash Kumar
author_sort Bora, Kushal
collection PubMed
description Antioxidant defense mechanisms are important for a parasite to overcome oxidative stress and survive within host macrophage cells. Mitochondrial iron superoxide dismutase A (FeSODA) and trypanothione reductase (TR) are critical enzymes in the antioxidant defense mechanism of Leishmania donovani. FeSODA is responsible for neutralizing reactive oxygen species in mitochondria, while TR is responsible for reducing trypanothione, the molecules that help the parasite fight oxidative stress in Leishmania. In this study, we used multitarget ligands to inhibit both the FeSODA and TR enzymes. We combined structure-based drug design using virtual screening approach to find inhibitors against both the targets. The ZINC15 database of biogenic compounds was utilized to extract drugs-like molecules against leishmaniasis. The compounds were screened by standard precision (SP) and extra precision (XP) docking methods. Two compounds, ZINC000008876351 and ZINC000253403245, were selected based on molecular docking based on the binding affinity for both the targets. The screened molecules ZINC000008876351 and ZINC000253403245 showed strong hydrogen bonding with the target proteins according to the Molecular mechanics with generalised Born and surface area solvation (MM-GBSA) techniques. These two compounds were also experimentally investigated on promastigotes stage of L. donovani. Under in vitro condition, the compounds show inhibitory effects on L. donovani promastigotes with IC(50) values of 24.82 ± 0.61 µM for ZINC000008876351 and 7.52 ± 0.17 µM for ZINC000253403245. Thus, the screened compounds seem to have good potential as therapeutic candidates for leishmaniasis.
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spelling pubmed-106030922023-10-28 Dual-target drugs against Leishmania donovani for potential novel therapeutics Bora, Kushal Sarma, Manash Kanaujia, Shankar Prasad Dubey, Vikash Kumar Sci Rep Article Antioxidant defense mechanisms are important for a parasite to overcome oxidative stress and survive within host macrophage cells. Mitochondrial iron superoxide dismutase A (FeSODA) and trypanothione reductase (TR) are critical enzymes in the antioxidant defense mechanism of Leishmania donovani. FeSODA is responsible for neutralizing reactive oxygen species in mitochondria, while TR is responsible for reducing trypanothione, the molecules that help the parasite fight oxidative stress in Leishmania. In this study, we used multitarget ligands to inhibit both the FeSODA and TR enzymes. We combined structure-based drug design using virtual screening approach to find inhibitors against both the targets. The ZINC15 database of biogenic compounds was utilized to extract drugs-like molecules against leishmaniasis. The compounds were screened by standard precision (SP) and extra precision (XP) docking methods. Two compounds, ZINC000008876351 and ZINC000253403245, were selected based on molecular docking based on the binding affinity for both the targets. The screened molecules ZINC000008876351 and ZINC000253403245 showed strong hydrogen bonding with the target proteins according to the Molecular mechanics with generalised Born and surface area solvation (MM-GBSA) techniques. These two compounds were also experimentally investigated on promastigotes stage of L. donovani. Under in vitro condition, the compounds show inhibitory effects on L. donovani promastigotes with IC(50) values of 24.82 ± 0.61 µM for ZINC000008876351 and 7.52 ± 0.17 µM for ZINC000253403245. Thus, the screened compounds seem to have good potential as therapeutic candidates for leishmaniasis. Nature Publishing Group UK 2023-10-26 /pmc/articles/PMC10603092/ /pubmed/37884555 http://dx.doi.org/10.1038/s41598-023-45448-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Bora, Kushal
Sarma, Manash
Kanaujia, Shankar Prasad
Dubey, Vikash Kumar
Dual-target drugs against Leishmania donovani for potential novel therapeutics
title Dual-target drugs against Leishmania donovani for potential novel therapeutics
title_full Dual-target drugs against Leishmania donovani for potential novel therapeutics
title_fullStr Dual-target drugs against Leishmania donovani for potential novel therapeutics
title_full_unstemmed Dual-target drugs against Leishmania donovani for potential novel therapeutics
title_short Dual-target drugs against Leishmania donovani for potential novel therapeutics
title_sort dual-target drugs against leishmania donovani for potential novel therapeutics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603092/
https://www.ncbi.nlm.nih.gov/pubmed/37884555
http://dx.doi.org/10.1038/s41598-023-45448-x
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