Superimposition-based protocol as a tool for determining bioactive conformations. I. Application to ligands of the glycinergic receptor (GlyR).

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.