Conformationally sampled pharmacophore for peptidic delta opioid ligands

Opioids represent the frontline treatment for acute pain, despite their side effects, motivating efforts toward developing novel opioid analgesics. To facilitate these efforts, a novel modeling approach, the conformationally sampled pharmacophore (CSP), has been developed that increases the probability of including the receptor bound form in the model. This method, originally used for developing a nonpeptidic delta opioid efficacy pharmacophore, is extended to peptidic ligands using replica exchange molecular dynamics simulation for conformational sampling. The developed 2D CSP indicates that the spatial relationship of the basic nitrogen and the hydrophobic moiety in the delta opioid ligands differentiates activity. In addition, results indicate that both peptidic and nonpeptidic ligands have the same binding mode with the receptor. Thus, the CSP approach distinguishes both peptidic and nonpeptidic delta opioid agonists and antagonists and is anticipated to be of general utility for the development of pharmacophores for species with multiple rotatable bonds.