Enzyme Dynamics\nDetermine the Potency and Selectivity\nof Inhibitors Targeting Disease-Transmitting Mosquitoes

Vector control of mosquitoes with insecticides is an\nimportant\ntool for preventing the spread of mosquito-borne diseases including\nmalaria, dengue, chikungunya, and Zika. Development of active ingredients\nfor insecticides are urgently needed because existing agents exhibit\noff-target toxicity and are subject to increasing resistance. We therefore\nseek to develop noncovalent inhibitors of the validated insecticidal\ntarget acetylcholinesterase 1 (AChE1) from mosquitoes. Here we use\nmolecular dynamics simulations to identify structural properties essential\nfor the potency of reversible inhibitors targeting AChE1 from Anopheles gambiae (<i>Ag</i>AChE1), the\nmalaria-transmitting mosquito, and for selectivity relative to the\nvertebrate Mus musculus AChE (<i>m</i>AChE). We show that the collective motions of apo <i>Ag</i>AChE1 and <i>m</i>AChE differ, with <i>Ag</i>AChE1 exhibiting less dynamic movement. Opening and closing\nof the gorge, which regulates access to the catalytic triad, is enabled\nby different mechanisms in the two species, which could be linked\nto their differing amino acid sequences. Inhibitor binding reduced\nthe overall magnitude of dynamics of AChE. In particular, more potent\ninhibitors reduced the flexibility of the Ω loop at the entrance\nof the gorge. The selectivity of inhibitors for <i>Ag</i>AChE1 over <i>m</i>AChE derives from the positioning of\nthe α-helix lining the binding gorge. Our findings emphasize\nthe need to consider dynamics when developing inhibitors targeting\nthis enzyme and highlight factors needed to create potent and selective <i>Ag</i>AChE1 inhibitors that could serve as active ingredients\nto combat disease-transmitting mosquitoes.