Exploring the structure of opioid receptors with homology modeling based on single and multiple templates and subsequent docking: A comparative study |
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Authors: | Bera Indrani Laskar Aparna Ghoshal Nanda |
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Institution: | (1) Structural Biology and Bioinformatics Division, (A unit of CSIR), Indian Institute of Chemical Biology, Kolkata, 700032, India; |
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Abstract: | Opioid receptors are the principal targets for opioids, which have been used as analgesics for centuries. Opioid receptors
belong to the rhodopsin family of G-protein coupled receptors (GPCRs). In the absence of crystal structures of opioid receptors,
3D homology models have been reported with bovine rhodopsin as a template, though the sequence homology is low. Recently,
it has been reported that use of multiple templates results in a better model for a target having low sequence identity with
a single template. With the objective of carrying out a comparative study on the structural quality of the 3D models based
on single and multiple templates, the homology models for opioid receptors (mu, delta and kappa) were generated using bovine
rhodopsin as single template and the recently deposited crystal structures of squid rhodopsin, turkey β-1 and human β-2 adrenoreceptors
along with bovine rhodopsin as multiple templates. In this paper we report the results of comparison between the refined 3D
models based on multiple sequence alignment (MSA) and models built with bovine rhodopsin as template, using validation programs
PROCHECK, PROSA, Verify 3D, Molprobity and docking studies. The results indicate that homology models of mu and kappa with
multiple templates are better than those built with only bovine rhodopsin as template, whereas, in many aspects, the homology
model of delta opioid receptor with single template is better with respect to the model based on multiple templates. Three
nonselective ligands were docked to both the models of mu, delta and kappa opioid receptors using GOLD 3.1. The results of
docking complied well with the pharamacophore, reported for nonspecific opioid ligands. The comparison of docking results
for models with multiple templates and those with single template have been discussed in detail. Three selective ligands for
each receptor were also docked. As the crystallographic structures are not yet known, this comparison will help in choosing
better homology models of opioid receptors for studying ligand receptor interactions to design new potent opioid antagonists. |
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