Molecular modeling and 3D-QSAR studies of indolomorphinan derivatives as kappa opioid antagonists
Bioorg. Med. Chem. 14(2006)601-610，-0001，（）：
Molecular modeling and 3D-QSAR studies were performed on 31 indolomorphinan derivatives to evaluate their antagonistic behaviors on jopioid 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 j 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 j opioid receptor-GNTI complex to identify key residues, which might account for jantagonist potency and selectivity. The roles of nonconserved Glu297 and conserved Lys227 of human jopioid receptor were then discussed.