Engdahl_2016_J.Med.Chem_59_9409

Reference

Title : Discovery of Selective Inhibitors Targeting Acetylcholinesterase 1 from Disease-Transmitting Mosquitoes - Engdahl_2016_J.Med.Chem_59_9409
Author(s) : Engdahl C , Knutsson S , Ekstrom F , Linusson A
Ref : Journal of Medicinal Chemistry , 59 :9409 , 2016
Abstract :

Vector control of disease-transmitting mosquitoes is increasingly important due to the re-emergence and spread of infections such as malaria and dengue. We have conducted a high throughput screen (HTS) of 17,500 compounds for inhibition of the essential AChE1 enzymes from the mosquitoes Anopheles gambiae and Aedes aegypti. In a differential HTS analysis including the human AChE, several structurally diverse, potent, and selective noncovalent AChE1 inhibitors were discovered. For example, a phenoxyacetamide-based inhibitor was identified with a 100-fold selectivity for the mosquito over the human enzyme. The compound also inhibited a resistance conferring mutant of AChE1. Structure-selectivity relationships could be proposed based on the enzymes' 3D structures; the hits' selectivity profiles appear to be linked to differences in two loops that affect the structure of the entire active site. Noncovalent inhibitors of AChE1, such as the ones presented here, provide valuable starting points toward insecticides and are complementary to existing and new covalent inhibitors.

PubMedSearch : Engdahl_2016_J.Med.Chem_59_9409
PubMedID: 27598521
Gene_locus related to this paper: anoga-ACHE1 , mouse-ACHE

Related information

Mutation G119S_anoga-ACHE1
Inhibitor G119S_anoga-ACHE1    STK133938
Gene_locus G119S_anoga-ACHE1    STK133938    anoga-ACHE1    mouse-ACHE
Structure G119S_anoga-ACHE1    STK133938    anoga-ACHE1    mouse-ACHE    5FUM

Citations formats

Engdahl C, Knutsson S, Ekstrom F, Linusson A (2016)
Discovery of Selective Inhibitors Targeting Acetylcholinesterase 1 from Disease-Transmitting Mosquitoes
Journal of Medicinal Chemistry 59 :9409

Engdahl C, Knutsson S, Ekstrom F, Linusson A (2016)
Journal of Medicinal Chemistry 59 :9409