title: Superimposition-based protocol as a tool for determining bioactive conformations. II. Application to the GABA(A) receptor.
abstract: The natural templates (NT) superimposition method is used to determine the pharmacophoric requirements of the A subtype of the gamma-aminobutyric acid (GABA) receptor. Bioactive conformations for antagonists and agonists are found by superimposing them on a relatively rigid alkaloid bicuculline, which itself is a competitive antagonist at this ligand-gated ion channel receptor. As has been usual in the application of this modeling method, consideration of available experimental data is the cornerstone for obtaining realistic models. The identification of two substructural fragments of bicuculline permitted classification of the ligands. Analysis of the antagonists and agonists with respect to the two substructural fragments revealed two bioactive conformations of the highly flexible GABA molecule, one of which is extended with the nonhydrogenic atoms roughly coplanar torsional angles of -37 and -179 degrees at N-C-C-C and C-C-C-C (carboxyl), respectively. The second bioactive compound is clearly non planar (torsional angles of -81 and -109 degrees at N-C-C-C and C-C-C-C (carboxyl), respectively).
authors.affiliation: Departamento de Química Orgánica, Universidad de Alcalá de Henares, Madrid, Spain. enrique.galvez@uah.es
authors.forename: E
authors.initials: E
authors.lastname: Gálvez-Ruano
authors.forename: I
authors.initials: I
authors.lastname: Iriepa
authors.forename: A
authors.initials: A
authors.lastname: Morreale
authors.forename: D B
authors.initials: DB
authors.lastname: Boyd
mesh_terms: D001640:Bicuculline / Q000737:chemistry; D001667:Binding, Competitive; D003198:Computer Simulation; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D011963:Receptors, GABA-A / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008024:Ligands; D011963:Receptors, GABA-A; D001640:Bicuculline