The use of insecticides has proved to be the most efficient to reduce infections by disease-transmitting mosquitoes . Common insecticides work by inhibiting the enzyme acetylcholinesterase (AChE), which leads to muscle paralysis and death. Humans and other vertebrates have only one AChE variant while mosquitoes have two variants, mqAChE1 and mqAChE2, the former is an important target for insecticides such as organophosphates and carbamates. Widespread use of these compounds has raised toxicity concern in non-target organisms like honey bee and humans. mqAChE1 is also responsible for AChE-mediated insensitivity to both organophosphates and carbamates resulting in emergence of insecticide resistant mosquitoes. Therefore, new selective inhibitors are urgently needed to combat disease-transmitting mosquitoes.
New ways to inhibit mqAChE have been proposed and designed using sequence and structural comparison between mosquito and vertebrate species . Further, to overcome the carbamate insensitivity conferred by the G119S mutation in mqAChE1, new inhibitors have been developed but they were poorly selective to mqAChE1 over human AChE .
All these newly designed selective inhibitors are covalent inhibitors and therefore design and synthesis of non-covalent inhibitors will be a major step forward in the present scenario. Interestingly, studies by us using cluster analysis of functional descriptors suggests that non-covalent inhibitors are less sensitive to G119S resistance mutation. It is noteworthy that examples of non-covalent inhibitors for mqAChE1 are very sparse. In a recent study by the Linusson group, selective non-covalent inhibitors have been identified for mosquitoes using differential high throughput screening . Also, 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 the entrance of active site gorge 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 two loops and other regions near to active site gorge along with the interaction network both in apo and in presence of inhibitors identified by us. Based on these studies, novel selective non-covalent inhibitors with enhanced potency will be designed using both computational and experimental approach targeting mqAChE1 and G119S mutation. The research will result in substantially new fundamental knowledge and in-depth understanding of protein-ligand binding, which will have an impact on insecticide design and medicinal chemistry in general.
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