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  • Three Homology Models of PAR2 Derived from Different Templates: Application to Antagonist Discovery

    Author(s)
    Perry, Samuel R.
    Xu, Weijun
    Wirija, Anna
    Lim, Junxian
    Yau, Mei-Kwan
    Stoermer, Martin J.
    Lucke, Andrew J.
    Fairlie, David P.
    Griffith University Author(s)
    Perry, Samuel
    Year published
    2015
    Metadata
    Show full item record
    Abstract
    Protease activated receptor 2 (PAR2) is an unusual G-protein coupled receptor (GPCR) involved in inflammation and metabolism. It is activated through cleavage of its N-terminus by proteases. The new N-terminus functions as a tethered ligand that folds back and intramolecularly activates PAR2, initiating multiple downstream signaling pathways. The only compounds reported to date to inhibit PAR2 activation are of moderate potency. Three structural models for PAR2 have been constructed based on sequence homology with known crystal structures for bovine rhodopsin, human ORL-1 (also called nociceptin/orphanin FQ receptor), and ...
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    Protease activated receptor 2 (PAR2) is an unusual G-protein coupled receptor (GPCR) involved in inflammation and metabolism. It is activated through cleavage of its N-terminus by proteases. The new N-terminus functions as a tethered ligand that folds back and intramolecularly activates PAR2, initiating multiple downstream signaling pathways. The only compounds reported to date to inhibit PAR2 activation are of moderate potency. Three structural models for PAR2 have been constructed based on sequence homology with known crystal structures for bovine rhodopsin, human ORL-1 (also called nociceptin/orphanin FQ receptor), and human PAR1. The three PAR2 model structures were compared and used to predict potential interactions with ligands. Virtual screening for ligands using the Chembridge database, and either ORL-1 or PAR1 derived PAR2 models led to identification of eight new small molecule PAR2 antagonists (IC50 10–100 μM). Notably, the most potent compound 1 (IC50 11 μM) was derived from the less homologous template protein, human ORL-1. The results suggest that virtual screening against multiple homology models of the same GPCR can produce structurally diverse antagonists and that this may be desirable even when some models have less sequence homology with the target protein.
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    Journal Title
    Journal of Chemical Information and Modeling
    Volume
    55
    Issue
    6
    DOI
    https://doi.org/10.1021/acs.jcim.5b00087
    Subject
    Medicinal and Biomolecular Chemistry not elsewhere classified
    Medicinal and Biomolecular Chemistry
    Theoretical and Computational Chemistry
    Computation Theory and Mathematics
    Publication URI
    http://hdl.handle.net/10072/370486
    Collection
    • Journal articles

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