{"id":{"repo_id":"vt","oai_identifier":"oai:vtechworks.lib.vt.edu:10919/36207"},"canonical_url":"https://search.dev.ndltd.org/etd/vt/oai:vtechworks.lib.vt.edu:10919/36207","repository":{"repo_id":"vt","name":"Virginia Tech","base_url":"https://vtechworks.lib.vt.edu/oai/request"},"display":{"title":"Determination of Allosteric Solvent Effects Between Acetylcholinesterase and Mosquito Selective Carbamates: Implications for High Throughput Screening of Insecticides","abstract":"Malaria is vectored by the mosquito Anopheles gambiae (Ag) in Sub-Saharan Africa and infects approximately 500 million people annually. The increasing prevalence of pyrethroid-resistant mosquitoes has amplified the need for development of new, selective mosquitocides for use on insecticide-treated nets. 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.","abstract_html":"Malaria is vectored by the mosquito Anopheles gambiae (Ag) in Sub-Saharan Africa and infects approximately 500 million people annually. The increasing prevalence of pyrethroid-resistant mosquitoes has amplified the need for development of new, selective mosquitocides for use on insecticide-treated nets. 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.","abstract_has_math":false,"creators":["Swale, Daniel Robert"],"institution":"Virginia Tech","degree_name":"Master of Science in Life Sciences","degree_level":"masters","degree_discipline":"Entomology","degree_department":"Entomology","school":null,"contributors":[],"advisors":[],"committee_chairs":["Bloomquist, Jeffrey R."],"committee_members":["Mullins, Donald E.","Paulson, Sally L."],"year":2009,"date_issued":"2009-12-04","date_published":"2009-12-04","updated_at":"2026-07-22T22:18:52Z","subjects":["Mosquito Vector Control","High-Throughput Screening","DMSO","Insecticides"],"languages":["en"],"rights":["In Copyright"],"rights_urls":["http://rightsstatements.org/vocab/InC/1.0/"],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["etd-12162009-141701"],"render_values":[{"text":"etd-12162009-141701","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/10919/36207","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeechair","label":"Committee Chair","values":["Bloomquist, Jeffrey R."]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Mullins, Donald E.","Paulson, Sally L."]},{"key":"dc:contributor.department","label":"Department","values":["Entomology"]},{"key":"dc:creator","label":"Author","values":["Swale, Daniel Robert"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2014-03-14T20:50:06Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2014-03-14T20:50:06Z","2011-09-06"]},{"key":"dc:date.issued","label":"Date","values":["2009-12-04"]},{"key":"dc:publisher","label":"Institution","values":["Virginia Tech"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Entomology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["masters"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Master of Science in Life Sciences"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Virginia Polytechnic Institute and State University"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Mosquito Vector Control","High-Throughput Screening","DMSO","Insecticides"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["In Copyright"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://rightsstatements.org/vocab/InC/1.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["etd-12162009-141701"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/10919/36207"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Malaria is vectored by the mosquito Anopheles gambiae (Ag) in Sub-Saharan Africa and infects approximately 500 million people annually. The increasing prevalence of pyrethroid-resistant mosquitoes has amplified the need for development of new, selective mosquitocides for use on insecticide-treated nets. 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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Master of Science in Life Sciences"]},{"key":"dc:title","label":"Title","values":["Determination of Allosteric Solvent Effects Between Acetylcholinesterase and Mosquito Selective Carbamates: Implications for High Throughput Screening of Insecticides"]}]}],"canonical_facts":{"dc:contributor.committeechair":["Bloomquist, Jeffrey R."],"dc:contributor.committeemember":["Mullins, Donald E.","Paulson, Sally L."],"dc:contributor.department":["Entomology"],"dc:creator":["Swale, Daniel Robert"],"dc:date.accessioned":["2014-03-14T20:50:06Z"],"dc:date.available":["2014-03-14T20:50:06Z","2011-09-06"],"dc:date.issued":["2009-12-04"],"dc:description.abstract":["Malaria is vectored by the mosquito Anopheles gambiae (Ag) in Sub-Saharan Africa and infects approximately 500 million people annually. The increasing prevalence of pyrethroid-resistant mosquitoes has amplified the need for development of new, selective mosquitocides for use on insecticide-treated nets. 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."],"dc:description.degree":["Master of Science in Life Sciences"],"dc:identifier.other":["etd-12162009-141701"],"dc:identifier.uri":["http://hdl.handle.net/10919/36207"],"dc:language.iso":["en"],"dc:publisher":["Virginia Tech"],"dc:rights":["In Copyright"],"dc:rights.uri":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:subject":["Mosquito Vector Control","High-Throughput Screening","DMSO","Insecticides"],"dc:title":["Determination of Allosteric Solvent Effects Between Acetylcholinesterase and Mosquito Selective Carbamates: Implications for High Throughput Screening of Insecticides"],"dc:type":["Thesis"],"thesis:degree_discipline":["Entomology"],"thesis:degree_level":["masters"],"thesis:degree_name":["Master of Science in Life Sciences"],"thesis:institution_name":["Virginia Polytechnic Institute and State University"]},"updated_at":"2026-07-22T22:18:52Z"}