Study on mechanism of interaction of nociceptin and opioids binding with opioid receptor-like 1 receptor.
OBJECTIVE
To study the mechanism of interaction of nociceptin and opioids with ORL1 receptor.


METHODS
Molecular dynamics study was carried out before nociceptin was manually docked into the binding site of ORL1 receptor; DOCK4.0 program was applied to dock four stereoisomers of lofentanyl and etorphine into the binding pocket of ORL1 receptor; Binding energies were calculated, the relationship between binding energy and binding affinity was studied.


RESULTS
Nociceptin fits well into the binding pocket, the N-terminal FGGF tetrapeptide is located in the inner region of the binding cavity, the nociceptin (5-7) interacts with the conservatively variable residues near the other end of binding pocket, and maybe determines selectivity of ORL1 receptor over dynorphin A, the positively charged core of nociceptin (8-13) binds predominantly with negatively charged EL-2 loop, which is thought to be able to mediate receptor activation. The shortest fully active analogue of nociceptin (1-13) is also discussed. The main difference between these two opioids and nociceptin exists in the kinds and the number of conserved and variable residues in the binding pocket and thereafter in the strength of their interaction. Prediction for binding affinities of four stereoisomers of lofentanyl has been performed based on their binding energies, the similar pharmacophore of lofentanyl and other fentanyl analogs, and the good correlation between binding energies and their experimental binding affinities (-log Ki values).


CONCLUSIONS
Ligand docking results from this study are helpful in clarifying experimental observations of ligands interaction with opioid receptors, thus furthering biological investigations.
Huang
X Q
XQ
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China.
Jiang
H L
HL
Luo
X M
XM
Chen
K X
KX
Zhu
Y C
YC
Ji
R Y
RY
Cao
Y
Y
D001665:Binding Sites; D004347:Drug Interactions; D005048:Etorphine / Q000737:chemistry; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D018847:Opioid Peptides / Q000737:chemistry* / Q000378:metabolism; D011957:Receptors, Opioid / Q000737:chemistry* / Q000378:metabolism; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D005048:Etorphine; D005283:Fentanyl; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C034846:lofentanil