Comparative modeling of human kappa opioid receptor and docking analysis with the peptide YFa

The kappa opioid receptor belongs to the super family of G protein – coupled receptors that are of utmost significance in the development of potent analgesic drugs for the treatment of severe pain. An accurate evaluation of the ligand binding pathways into this receptor at molecular level may play a key role in the design of new molecules with more desirable properties and reduced side effects. In this study, homology model of the human kappa opioid receptor was developed by MODELLER using the X-ray crystal structure of bovine rhodopsin as template. Initial structure of the receptor was refined computationally with energy minimization and molecular dynamics simulation at 300 K in a pre-equilibrated phospholipid bilayer by GROMACS. The Met-enkaphalin-Arg-Phe based opioid peptide YFa (YGGFMKKKFMRF) designed and characterized by our laboratory was docked into the optimized model and the critical amino acids responsible for binding were identified. A number of low energy binding poses of YFa with the receptor were assessed after the molecular docking in which the peptide was observed to interact with the receptor's extracellular amino acids through hydrogen bonds. The human kappa opioid receptor model optimized in a phospholipid bilayer should provide a good starting point for further characterization of the binding modes of other opioid ligands. Furthermore, the biologically favorable molecular interactions between YFa and human kappa opioid receptor observed by our study might be able to justify the specificity of this peptide.

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► We constructed the homology model of HKOR and optimized it in a complete membrane water environment.
► An in house designed peptide, YFa was docked into the active site of HKOR defined by the three ELs of the receptor.
► The peptide, YFa interacted with the HKOR in a common binding pocket similar to endogenous peptide DynA.
► The residues conserved between the DynA and YFa (YGGF) interacted with residues of EL2.
► Common interactions with Asn25, Ser26, Arg202, Pro215, Glu297 and Ser311 of HKOR were preserved in the both the peptides.