Development of a common 3D pharmacophore for delta-opioid recognition from peptides and non-peptides using a novel computer program

A unified three-dimensional (3D) pharmacophore for recognition of the delta-opioid receptor by families of structurally diverse delta-opioid ligands, including peptides and non-peptides, has been determined. An additional structural feature required for delta-selectivity was also characterized using a subset of these ligands that are highly selective for the delta-opioid receptor. To obtain these pharmacophores, we have used a recently developed computer program that performs systematic and automated comparisons of molecules to determine whether any common 3D relationships exist among candidate recognition moieties in high-affinity analogs. All the low-energy conformations of each ligand are included in these comparisons. The program developed should be applicable in general to molecular superimposition problems in rational drug design and to develop both 3D recognition and activation pharmacophores for any receptor for which high- and low-affinity analogs and agonists and antagonists have been identified.