Molecular modeling on kappa opioid receptor and its interaction with nonpeptide kappa opioid agonists.
OBJECTIVE
To study the interaction between kappa-opioid receptor and its nonpeptide agonists.


METHODS
The "conservation patterns" for G-protein coupled receptors (GPCR) were used to determine 7 transmembrane (TM) regions. Taking the crystallographic coordinates of bacteriorhodopsin (BR) as the template, the 3D structural model was constructed for 7 TM of kappa-opioid subtype with molecular mechanics (MM) method. Five highly active nonpeptide kappa-opioid agonists were docked into the 7 helices of kappa-opioid receptor to study the ligand-receptor interaction.


RESULTS
Four important interactions between U-50488-like agonists and kappa-opioid receptors were drawn according to our modeling study: (1) the protonated pyrrolidine nitrogen of the ligands formed a hydrogen-bond with the carboxyl of Asp138; (2) the carbonyl oxygen of ligands forms a hydrogen bond to the hydroxyl of Ser187; (3) the aryl groups connected to acylamide of the agonists inserted into a hydrophobic cavity enclosed by residues Val239, Val236, Phe235, Val232, Leu186, and Trp183; (4) the pyrrolidine of the ligands in the complexes was surrounded by Ile290, Asp138, Ile194, Ile135, and Cys131.


CONCLUSIONS
The proposed interaction mechanism is helpful for further mutant experiments and designing novel potent kappa-opioid agonists.
Liu
D X
DX
Shanghai Institutes of Materia Medica, Chinese Academy of Sciences, China.
Jiang
H L
HL
Shen
J S
JS
Zhu
W L
WL
Zhao
L
L
Chen
K X
KX
Ji
R Y
RY
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000737:chemistry*; D000700:Analgesics / Q000737:chemistry*; D001436:Bacteriorhodopsins / Q000737:chemistry; D015195:Drug Design; D004347:Drug Interactions; D005136:Eye Proteins / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D009294:Narcotics / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000737:chemistry*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D000700:Analgesics; D005136:Eye Proteins; C089754:G protein-coupled receptor RGR; D009294:Narcotics; D011759:Pyrrolidines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D017473:Receptors, Opioid, kappa; C058467:ICI 197067; D001436:Bacteriorhodopsins; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer