Molecular modeling on kappa opioid receptor and its interaction with nonpeptide kappa opioid agonists

AIM: To study the interaction between rc-opioid receptor and its nonpeptide agonists. METHODS: The "conservation patterns" for G-protein coupled recep tors ( GPCR) were used to determine 7 transmembrane (TM) regions. Taking th e crystallographic coordinates of bacteriorhodopsin (BR) as the template, t he 3D structural model was constructed for 7 TM of kappa-opioid subtype wit h molecular mechanics (MM) method. Five highly active nonpeptide kappa-opio id agonists were docked into the 7 helices of kappa-opioid receptor to stud y the ligand-receptor interaction. RESULTS: Four important interactions bet ween U-50488-like agonists and kappa-opioid receptors were drawn according to our modeling study: (I) the protonated pyrrolidine nitrogen of the ligan ds formed a hydrogen-bond with the carboxyl of Asp138; (2) the carbonyl oxy gen of ligands forms a hydrogen bond to the hydroxyl Of Ser187; (3) the ary l groups connected to acylamide of the agonists inserted into a hydrophobic cavity enclosed by residues Val239, Val236, Phe235, Val232, Leu186, and Tr p183; (4) the pyrrolidine of the ligands in the complexes was surrounded by Ile290, Asp138, Ile194, Ile135, and Cys131. CONCLUSION: The proposed inter action mechanism is helpful for further mutant experiments and designing no vel potent kappa-opioid agonists.