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Updated: Jul 30, 2026
Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
Superimposition-based protocol as a tool for determining bioactive conformations. I. Application to ligands of the
E Gálvez-Ruano1, I Iriepa, A Morreale
1Departamento de Química Orgánica, Universidad de Alcalá de Henares, Ctra. Madrid-Barcelona Km. 33,600, Alcalá de Henares, 28871 Madrid, Spain. enrique.galvez@uah.es
Abstract:
The natural templates (NT) approach, which is a superimposition-based protocol that has been successfully employed in several studies, is here applied to ligands of the glycine ligand-gated ion channel receptor. Bioactive conformations for glycine and its analogs were obtained using strychnine (a natural and specific competitive antagonist) as template. Experimental evidence was used to guide the superimposition protocol. Three essential regions have been defined in strychnine's structure that serve as a pharmacophore for agonist and antagonist activities. Reasonable alignments of known ligands were found in the majority of the cases. Molecular mechanics (i.e., conformational searches for the relatively flexible ligands) and molecular dynamics (for relatively rigid ligands such as strychnine and 5,6,7,8-tetrahydro-4H-isoxazolo[3,4-d]azepin-3-ol) were used to assess the energetic accessibility of the proposed bioactive conformations.
