Structural requirements for ligands of the δ-opioid receptor

Abstract

The δ-opioid receptor is sensitive to ligand geometry. In order to assist the synthesis of new δ-selective opioid ligands, the structure elements of δ-selective opioid ligands necessary for their effective binding were investigated. The automated docking procedure with a flexible ligand was used to simulate the binding of 17 δ-selective ligands to the δ-receptor. It was found that voluminous N-alkyl groups reduce the binding potency of naltrindole derivatives by preventing the ligands from adopting the preferred conformation in the receptor. This was confirmed by enantiospecific binding of chiral compounds where only one enantiomer adopts the naltrindole-like preferred conformation in the binding pocket. Voluminous groups replacing the hydroxyl group in the 3-hydroxybenzyl fragment of naltrindole analogs reduce the binding potency due to unfavorable steric interactions with the receptor. The two diastereoisomers of the potent δ-opioid ligand SNC80 confirmed the preferred binding conformation and the major receptor-ligand interactions.

Keywords

• molecular modeling
• δ-opioid receptor
• ligand-receptor interactions
• docking simulation