Molecular modeling of mu opioid receptor and receptor-ligand interaction
Abstract
AIM: To construct the 3D structural model of mu opioid receptor (mu OR) and study
the interaction between mu OR and fentanyl derivatives.
METHODS: The 3D structure of mu OR was modeled using the bacteriorhodopsin (bRh)
as a template, in which the alignments of transmembrane (TM) of bRh and mu OR
were achieved by scoring the alignment between the amino acid sequence of mu OR
and the structure of bRh. The fentanyl derivatives were docked into the 7 helices
of mu OR and the binding energies were calculated.
RESULTS: (1) The receptor-ligand interaction models were obtained for fentanyl
derivatives. (2) In these models, the fundamental binding sites were possibly
Asp147 and His297. The negatively charged oxygen of Asp147 and the positively
charged ammonium group of ligand formed the potent electrostatic and
hydrogen-binding interactions. Whereas the interactions between the positively
charged nitrogen of His297 and the carbonyl oxygen of ligand were weak. In
addition, there were some pi-pi interactions between the receptor and the ligand.
(3) The binding energies of the receptor-ligand complexes had a good correlation
with the analgesic activities (-lg ED50) of the fentanyl derivatives.
CONCLUSION: This model is helpful for understanding the receptor-ligand
interaction and for designing novel mu OR selective ligands.
Keywords:
the interaction between mu OR and fentanyl derivatives.
METHODS: The 3D structure of mu OR was modeled using the bacteriorhodopsin (bRh)
as a template, in which the alignments of transmembrane (TM) of bRh and mu OR
were achieved by scoring the alignment between the amino acid sequence of mu OR
and the structure of bRh. The fentanyl derivatives were docked into the 7 helices
of mu OR and the binding energies were calculated.
RESULTS: (1) The receptor-ligand interaction models were obtained for fentanyl
derivatives. (2) In these models, the fundamental binding sites were possibly
Asp147 and His297. The negatively charged oxygen of Asp147 and the positively
charged ammonium group of ligand formed the potent electrostatic and
hydrogen-binding interactions. Whereas the interactions between the positively
charged nitrogen of His297 and the carbonyl oxygen of ligand were weak. In
addition, there were some pi-pi interactions between the receptor and the ligand.
(3) The binding energies of the receptor-ligand complexes had a good correlation
with the analgesic activities (-lg ED50) of the fentanyl derivatives.
CONCLUSION: This model is helpful for understanding the receptor-ligand
interaction and for designing novel mu OR selective ligands.