Drug repositioning as an effective therapy for protease-activated receptor 2 inhibition |
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Authors: | Uzma Saqib Rajkumar Savai DongFang Liu Sreeparna Banerjee Mirza S. Baig |
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Affiliation: | 1. Discipline of Chemistry, Indian Institute of Technology Indore (IITI), Indore, India;2. Department of Lung Development and Remodeling, Member of the German Center for Lung Research (DZL), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;3. Center for Inflammation & Epigenetics, Houston Methodist Research Institute, Houston, Texas;4. Department of Biological Sciences, Orta Doğu Teknik Üniversitesi (ODTU/METU), Ankara, Turkey;5. Discipline of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India |
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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. |
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Keywords: | antagonist drug repositioning inflammation proteinase-activated receptor 2 |
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