Targeting Trypanothione Reductase of Leishmanial major to Fight Against Cutaneous Leishmaniasis.
Leishmania major
cutaneous
homology modeling
leishmaniasi
macrophages
trypanothione reductase
virtual screening.
Journal
Infectious disorders drug targets
ISSN: 2212-3989
Titre abrégé: Infect Disord Drug Targets
Pays: United Arab Emirates
ID NLM: 101269158
Informations de publication
Date de publication:
2019
2019
Historique:
received:
29
01
2018
revised:
13
03
2018
accepted:
27
04
2018
pubmed:
8
5
2018
medline:
13
5
2020
entrez:
8
5
2018
Statut:
ppublish
Résumé
1.2-2.0 million cases of leishmaniasis occur annually throughout the world. The available drugs like Amphotericin B, antimonials and miltefosine are unable to fulfill the need due to less effectiveness, high toxicity, resistance, high cost and complex route of administration. Leishmania survives inside the macrophages through different evasion mechanisms; one of that is activation of its trypanothione reductase enzyme which neutralizes the reactive oxygen species generated inside the macrophages to kill the parasites. This enzyme is unique and absent in human, therefore in this study I targeted it for screening of new inhibitors to fight against leishmaniasis. Homology modeling of Leishmania major trypanothione reductase was performed using Phyre2 server. The homology based modelled protein was validated with PROCHECK analysis. Ligplot analysis was performed to predict the active residues inside the binding pocket. Further, virtual screening of ligand library containing 113 ligands from PubChem Bioassay was performed against the target using AutoDock Vina Tool. Top five ligands showed best binding affinity. The molecule having PubChem CID: 10553746 showed highest binding affinity of -11.3 kcal/mol. Over all this molecule showed highest binding affinity and moderate number of hydrogen bonds. Hopefully, this molecule will be able to block the activity of target enzyme, trypanothione reductase of Leishmania major effectively and may work as new molecules to fight against cutaneous leishmanaisis. This study will help the researchers to identify the new molecules which can block the activity of leishmanial-trypanothione reductase, a novel enzyme of trypanosomatids. These screened inhibitors may also be effective not only in leishmaniasis but also other trypanosomatid-mediated infectious diseases.
Sections du résumé
BACKGROUND
BACKGROUND
1.2-2.0 million cases of leishmaniasis occur annually throughout the world. The available drugs like Amphotericin B, antimonials and miltefosine are unable to fulfill the need due to less effectiveness, high toxicity, resistance, high cost and complex route of administration. Leishmania survives inside the macrophages through different evasion mechanisms; one of that is activation of its trypanothione reductase enzyme which neutralizes the reactive oxygen species generated inside the macrophages to kill the parasites. This enzyme is unique and absent in human, therefore in this study I targeted it for screening of new inhibitors to fight against leishmaniasis.
METHODS
METHODS
Homology modeling of Leishmania major trypanothione reductase was performed using Phyre2 server. The homology based modelled protein was validated with PROCHECK analysis. Ligplot analysis was performed to predict the active residues inside the binding pocket. Further, virtual screening of ligand library containing 113 ligands from PubChem Bioassay was performed against the target using AutoDock Vina Tool.
RESULTS
RESULTS
Top five ligands showed best binding affinity. The molecule having PubChem CID: 10553746 showed highest binding affinity of -11.3 kcal/mol. Over all this molecule showed highest binding affinity and moderate number of hydrogen bonds. Hopefully, this molecule will be able to block the activity of target enzyme, trypanothione reductase of Leishmania major effectively and may work as new molecules to fight against cutaneous leishmanaisis.
CONCLUSION
CONCLUSIONS
This study will help the researchers to identify the new molecules which can block the activity of leishmanial-trypanothione reductase, a novel enzyme of trypanosomatids. These screened inhibitors may also be effective not only in leishmaniasis but also other trypanosomatid-mediated infectious diseases.
Identifiants
pubmed: 29732996
pii: IDDT-EPUB-90162
doi: 10.2174/1871526518666180502141849
doi:
Substances chimiques
Antiprotozoal Agents
0
Ligands
0
NADH, NADPH Oxidoreductases
EC 1.6.-
trypanothione reductase
EC 1.8.1.12
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
388-393Informations de copyright
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