Molecular modeling and 3D-QSAR studies of indolomorphinan derivatives as kappa opioid antagonists Original Research Article

Molecular modeling and 3D-QSAR studies were performed on 31 indolomorphinan derivatives to evaluate their antagonistic behaviors on κ opioid receptor and provide information for further modification of this kind of compounds. Best predictions were obtained with CoMFA standard model (q2 = 0.693, N = 4, r2 = 0.900) and CoMSIA combined model (q2 = 0.617, N = 4, r2 = 0.904). Both models were further validated by an external test set of eight compounds with satisfactory predictions: r2 = 0.607 for CoMFA and r2 = 0.701 for CoMSIA. In addition, the 3D structure of human κ opioid receptor was constructed based on the crystal structure of bovine rhodopsin, and the CoMSIA contour plots were then mapped into the structural model of κ opioid receptor–GNTI complex to identify key residues, which might account for κ antagonist potency and selectivity. The roles of nonconserved Glu297 and conserved Lys227 of human κ opioid receptor were then discussed.