To develop human kappa opioid receptor (hOPRK) ligands, we have predicted a 3D theoretical model of the OPRK and the binding mode of OPRK selective antagonist buprenorphine by using the GEnSeMBLE (GPCR Ensemble of Structures in Membrane BiLayer Environment) and the DarwinDock Monte Carlo protocol. Docking revealed several polar interactions at D3.32, K5.39, E6.58, S211EC2, and Q213EC2 consistent with mutagenesis studies. We also find that several tyrosine residues provide additional hydrophobic interactions at Y3.33, Y7.35, Y7.36, and Y7.43. The predictive ability of the model was evaluated by docking a set of known hOPRK antagonists into the binding site of this model. We performed a virtual screening to identify novel molecular scaffolds as potential leads for the hOPRK. This approach will lead to the generation of novel selective hOPRK ligands with reduced side effects that are clinically useful for the treatment of pain through peripheral mechanisms.

Prediction of 3D structure for the kappa opioid receptor and novel kappa opioid receptor selective ligands

243rd National Meeting (2012)

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