CoMFA validation of the superposition of six classes of compounds which block GABA receptors non-competitively.
Thirty-six compounds, representing six different structural classes of insecticides which are known to act at the gamma-aminobutyric acid receptor/chloride ionophore, have been superimposed by methods which maximise the commonality of steric and electrostatic fields. Maximal steric and electrostatic alignment was derived by pairwise comparisons of the different chemical classes with picrotoxinin. To test the validity of the combined superposition, a Comparative Molecular Field Analysis (CoMFA) was carried out within SYBYL, using recently published in vivo and in vitro binding data for insecticides. The resultant partial least-squares (PLS) analysis of sampled steric and electrostatic fields showed a significant statistical correlation with the published biological data. The predictive model obtained was shown to have a greater than 95% chance of significance.
Calder
J A
JA
Department of Chemistry, Roussel Uclaf Environmental Health, Berkhamsted, U.K.
Wyatt
J A
JA
Frenkel
D A
DA
Casida
J E
JE
D000495:Allosteric Site; D000818:Animals; D018118:Chloride Channels; D004563:Electrochemistry; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D007306:Insecticides / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D010852:Picrotoxin / Q000737:chemistry / Q000494:pharmacology; D012984:Software; D013329:Structure-Activity Relationship
D018118:Chloride Channels; D058787:GABA-A Receptor Antagonists; D007306:Insecticides; D008565:Membrane Proteins; D010852:Picrotoxin