Identification of the three-dimensional pharmacophore of kappa-opioid receptor agonists

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