Structure-based design of insecticidal molecules - an opportunity to control resistant mosquitoes

SNIC 2018/3-309


SNAC Medium

Principal Investigator:

Anna Linusson


UmeƄ universitet

Start Date:


End Date:


Primary Classification:

10405: Organic Chemistry

Secondary Classification:

30103: Medicinal Chemistry




Acetylcholinesterase (AChE) is an essential serine protease in mammals and insects that terminates synaptic transmission by hydrolysis of the neurotransmitter acetylcholine. Blockage by this enzyme by small molecules lead to paralysis and lethality of the organism. This mechanism is used by many of the current insecticides targeting mosquito AChE1 (mqAChE1). The use of insecticides such as organophosphates and carbamates has proved to be the most efficient to reduce infections by disease-transmitting mosquitoes [1], but the widespread use of these insecticides has raised toxicity concern in non-target organisms like honey bee and humans. Furthermore, resistance to both organophosphates and carbamates has emerged among the mosquito populations and, therefore, new selective inhibitors are urgently needed to combat disease-transmitting mosquitoes. In a recent study by the Linusson group, selective non-covalent inhibitors have been identified for mosquitoes using differential high throughput screening [2]. In addition, the structure modeling of mqAChE1 suggested that the selectivity of both covalent and non-covalent inhibitors are related to the differences in two loops at in the structure of AChE. These studies are based on a single static structural model. However, proteins are dynamical in nature and amino acid sequence variations are known to be responsible for substrate selectivity. Therefore, comparative molecular dynamics (MD) simulations and advanced modeling techniques would be crucial to understand molecular mechanism of insecticide specificity in AChE from different species. In the present study, MD simulations of AChE from different mosquito and vertebrate species will be performed. The simulations will further analyzed to identify dynamics variations in the regions near to the active site gorge along with the interaction network both in free form and in presence of inhibitors identified by the Linusson group. The binding interactions between candidate insecticides and AChE1 will be studied in detail using quantum mechanical calculations. Based on these studies, novel selective non-covalent insecticides candidates with enhanced potency will be designed using both computational and experimental approach targeting mqAChE1 and a mutated for causing resistance. The research will result in substantially new fundamental knowledge and in-depth understanding of protein-ligand binding, which will have an impact on drug discovery and medicinal chemistry in general.