The enzyme 3-hydroxykynurenine transaminase as potential target for 1,2,4-oxadiazoles with larvicide activity against the dengue vector Aedes aegypti

The mosquito Aedes aegypti is the vector agent responsible for the transmission of yellow fever and dengue fever viruses to over 80million people in tropical and subtropical regions of the world. Exhaustive efforts have lead to a vaccine candidate with only 30% effectiveness against the dengue virus...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2013-11, Vol.21 (22), p.6996-7003
Main Authors: Oliveira, Vanessa S., Pimenteira, Cecília, da Silva-Alves, Diana C.B., Leal, Laylla L.L., Neves-Filho, Ricardo A.W., Navarro, Daniela M.A.F., Santos, Geanne K.N., Dutra, Kamilla A., dos Anjos, Janaína V., Soares, Thereza A.
Format: Article
Language:English
Subjects:
4-(2-Aminophenyl)-4-oxobutanoic acid
Aedes - drug effects
Aedes - enzymology
Aedes - growth & development
Aedes aegypti
Animals
Binding Sites
Dengue virus
Insecticide
Insecticides
Larva - drug effects
Larva - enzymology
Larvae pigmentation
Malaria vector Anopheles gambiae
Molecular docking calculations
Molecular Docking Simulation
Oxadiazoles - chemical synthesis
Oxadiazoles - chemistry
Oxadiazoles - pharmacology
Protein Structure, Tertiary
Structure-Activity Relationship
Transaminases - antagonists & inhibitors
Transaminases - metabolism
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Summary:The mosquito Aedes aegypti is the vector agent responsible for the transmission of yellow fever and dengue fever viruses to over 80million people in tropical and subtropical regions of the world. Exhaustive efforts have lead to a vaccine candidate with only 30% effectiveness against the dengue virus and failure to protect patients against the serotype 2. Hence, vector control remains the most viable route to dengue fever control programs. We have synthesized a class of 1,2,4-oxadiazole derivatives whose most biologically active compounds exhibit potent activity against Aedes aegypti larvae (ca. of 15ppm) and low toxicity in mammals. Exposure to these larvicides results in larvae pigmentation in a manner correlated with the LC50 measurements. Structural comparisons of the 1,2,4-oxadiazole nucleus against known inhibitors of insect enzymes allowed the identification of 3-hydroxykynurenine transaminase as a potential target for these synthetic larvicides. Molecular docking calculations indicate that 1,2,4-oxadiazole compounds can bind to 3-hydroxykynurenine transaminase with similar conformation and binding energies as its crystallographic inhibitor 4-(2-aminophenyl)-4-oxobutanoic acid.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.09.020