Determination of Allosteric Solvent Effects Between Acetylcholinesterase and Mosquito Selective Carbamates: Implications for High Throughput Screening of Insecticides
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We have developed several phenyl-substituted N-methylcarbamates producing a high degree of selectivity for Anopheles gambiae acetylcholinesterase (AgAChE) over human AChE. Molecular models suggest alternate conformations (flexibility) of W84 and W431 (Ag numbering) at the hydrophobic subpocket of the AgAChE active site and poor flexibility within human AChE, allowing for the high selectivity of our novel carbamates. Initial selectivity data was obtained through screening of these insecticides while using ethanol as a solvent. Re-screening of these carbamates in the presence of 0.1% DMSO (v/v) resulted in antagonism of inhibition for AgAChE, thus reducing the AgAChE-selectivity by at least 10-fold. However, the presence of 0.1% DMSO did not antagonize the inhibition of human, Drosophila melanogaster, or Musca domestica AChE. Non-selective carbamates also displayed no solvent-dependent antagonism of inhibition in any species studied, including AgAChE.
Molecular models provide an explanation for antagonism of inhibition when DMSO is present. I, and collaborators, propose that W84 and W431 in AgAChE comprise an allosteric pocket that is stabilized by DMSO and is responsible for the solvent-dependent antagonism of inhibition observed with AgAChE.
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