3D-pharmacophore identification for kappa-opioid agonists using ligand-based drug-design techniques.

A selective kappa-opioid receptor (KOR) agonist might act as a powerful analgesic without the side effects of micro-opioid receptor-selective drugs such as morphine. The eight classes of known KOR agonists have different chemical structures, making it difficult to construct a pharmacophore model that takes them all into account. Here, we summarize previous efforts to identify the pharmacophore for kappa-opioid agonists and propose a new three-dimensional pharmacophore model that encompasses the kappa-activities of all classes. This utilizes conformational sampling of agonists by high-temperature molecular dynamics and pharmacophore extraction through a series of molecular superpositions.