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

No Thumbnail Available
File version
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)
Primary Supervisor
Other Supervisors
Editor(s)
Date
2015
Size
File type(s)
Location
License
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 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.

Journal Title

Journal of Chemical Information and Modeling

Conference Title
Book Title
Edition
Volume

55

Issue

6

Thesis Type
Degree Program
School
Publisher link
Patent number
Funder(s)
Grant identifier(s)
Rights Statement
Rights Statement
Item Access Status
Note
Access the data
Related item(s)
Subject

Medicinal and Biomolecular Chemistry not elsewhere classified

Medicinal and Biomolecular Chemistry

Theoretical and Computational Chemistry

Computation Theory and Mathematics

Persistent link to this record
Citation
Collections