Abstract
Proteinase-activated receptor 2 (PAR-2) is a G protein–coupled receptor activated by both trypsin and a specific agonist peptide, SLIGKV-NH2. It has been linked to various pathologies, including pain and inflammation. Several peptide and peptidomimetic agonizts for PAR-2 have been developed exhibiting high potency and efficacy. However, the number of PAR-2 antagonists is smaller. We screened the Food and Drug Administration library of approved compounds to retrieve novel antagonists for repositioning in the PAR-2 structure. The most efficacious compound bicalutamide bound to the PAR-2 binding groove near the extracellular domain as observed in the in silico studies. Further, it showed reduced Ca2+ release in trypsin activated cells in a dose-dependent manner. Hence, bicalutamide is a novel and potent PAR-2 antagonist which could be therapeutically useful in blocking multiple pathways diverging from PAR-2 signaling. Further, the novel scaffold of bicalutamide represents a new molecular structure for PAR-2 antagonism and can serve as a basis for further drug development.
Original language | English (US) |
---|---|
Pages (from-to) | 1522-1526 |
Number of pages | 5 |
Journal | Journal of Cellular Biochemistry |
Volume | 120 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2019 |
Keywords
- antagonist
- drug repositioning
- inflammation
- proteinase-activated receptor 2
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology