Determination of Allosteric Solvent Effects Between Acetylcholinesterase and Mosquito Selective Carbamates: Implications for High Throughput Screening of Insecticides

Simple item page
dc.contributor.authorSwale, Daniel Roberten
dc.contributor.committeechairBloomquist, Jeffrey R.en
dc.contributor.committeememberMullins, Donald E.en
dc.contributor.committeememberPaulson, Sally L.en
dc.contributor.departmentEntomologyen
dc.date.accessioned2014-03-14T20:50:06Zen
dc.date.adate2010-01-07en
dc.date.available2014-03-14T20:50:06Zen
dc.date.issued2009-12-04en
dc.date.rdate2011-09-06en
dc.date.sdate2009-12-16en
dc.description.abstractMalaria 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.en
dc.description.degreeMaster of Science in Life Sciencesen
dc.identifier.otheretd-12162009-141701en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-12162009-141701/en
dc.identifier.urihttp://hdl.handle.net/10919/36207en
dc.language.isoenen
dc.publisherVirginia Techen
dc.relation.haspartcopyright_permission_maxim.pdfen
dc.relation.haspartSwale_DR_T_2009.pdfen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectMosquito Vector Controlen
dc.subjectHigh-Throughput Screeningen
dc.subjectDMSOen
dc.subjectInsecticidesen
dc.titleDetermination of Allosteric Solvent Effects Between Acetylcholinesterase and Mosquito Selective Carbamates: Implications for High Throughput Screening of Insecticidesen
dc.typeThesisen
thesis.degree.disciplineEntomologyen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Science in Life Sciencesen

Files

Original bundle
Now showing 1 - 2 of 2
Thumbnail Image
Name:
Swale_DR_T_2009.pdf
Size:
3.53 MB
Format:
Adobe Portable Document Format
Download
Thumbnail Image
Name:
copyright_permission_maxim.pdf
Size:
37.81 KB
Format:
Adobe Portable Document Format
Download

Collections

Masters Theses