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Drug repositioning as an effective therapy for protease-activated receptor 2 inhibition.

Uzma SaqibSoni Savai PullamsettiDongfang LiuSreeparna BanerjeeMirza S Baig
Published in: Journal of cellular biochemistry (2018)
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.
Keyphrases
  • chronic pain
  • emergency department
  • risk assessment
  • climate change
  • cell proliferation
  • neuropathic pain
  • molecular dynamics simulations
  • protein kinase
  • dna binding
  • pi k akt