Discovery of Selective Inhibitors Targeting Acetylcholinesterase 1 from Disease-Transmitting Mosquitoes.
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.
Department of Chemistry, Umeå University , SE-901 87 Umeå, Sweden.
Cecilia
C
Engdahl
Department of Chemistry, Umeå University , SE-901 87 Umeå, Sweden.
Sofie
S
Knutsson
Swedish Defense Research Agency , CBRN Defense and Security, SE-906 21 Umeå, Sweden.
Fredrik
F
Ekström
Department of Chemistry, Umeå University , SE-901 87 Umeå, Sweden.
Anna
A
Linusson
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000330:Aedes / Q000187:drug effects* / Q000201:enzymology; D000818:Animals; D000852:Anopheles / Q000187:drug effects* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D007303:Insect Vectors / Q000187:drug effects* / Q000201:enzymology*; D007306:Insecticides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D000110:Acetylcholinesterase