In recent years there has been a dramatic
In recent years there has been a dramatic increase in identification and optimization of potent CRTh2 antagonists which may not only inhibit the recruitment and activation of Th2 cells but also accelerate apoptosis and clearance of these cells from inflamed tissue, thereby promoting the resolution of allergic inflammation . It has been suggested that low molecular weight CRTh2 antagonists were expected to counteract pathophysiological effects of PGD2 and display controlling effects on allergic inflammation . CRTh2 antagonist have a variety of fused 6–5 membered ring chemotypes as core structure and has strong preference for carboxylic Luciferase Reporter Assay Kit moiety which is important in binding , , . Docking study suggests that key interaction is made by carboxylic acid group of antagonists with a lysine on transmembrane helixV of CRTh2 . Ramatroban, a drug marketed for allergic rhinitis is a potent CRTh2 antagonist , , , , , . Several companies have taken CRTh2 antagonists into clinical trials and reported positive results in preliminary phase II studies . Furthermore antagonizing selectively CRTh2 receptor could be useful in the treatment of asthma and other inflammatory diseases.
The aim of this study was to identify new potent inhibitors and to investigate important chemical features responsible for inhibition of CRTh2 receptor. Studies have suggested that pharmacophore model is widely used to explore the important chemical features and to find new class of chemical entities , , . Hence in this study, ligand based 3D pharmacophore models were generated and the best hypotheses were selected based on potency validation and Guner-Henry scoring methods. The two hypotheses such as DHNPR and DHNPRR (hydrogen bond donor (D), hydrophobic (H), negatively ionizable group (N), positively ionizable group (P) and aromatic rings group (R)) was employed to screen against ZINC database. The obtained hits were subsequently filtered by fitness score, Lipinski's rule of five and ADME (Absorption, Distribution, Metabolism and Excretion) properties. Virtual screening was found to be successful method especially when combined with molecular docking studies to eliminate the false positive results. Therefore, molecular docking was performed to identify the binding modes and interaction of the hits in the active site of CRTh2. Twenty eight compounds from zinc database were selected and its activity values were calculated using the 3D CoMFA model generated from the known inhibitors. Finally, nine of the identified potential leads were evaluated for inhibitory activity against CRTh2.
Materials and methods
Results and discussion
Conflict of interest
Chemoattractant receptor–homologous molecule expressed on Th2 lymphocytes (CRTH2) has been identified as a G protein-coupled receptor, predominantly expressed on Th2 cells, and plays a key role in allergic diseases, driving the IgE response, eosinophilia, and release of proinflammatory cytokines., , Activation of CRTH2 promotes the release of histamine from basophils and degranulation of eosinophiles., , Thus, CRTH2 is involved in complex inflammatory processes, and a CRTH2 antagonist might have beneficial effects in a variety of inflammatory diseases., , Ramatroban (), a thromboxane A2 receptor (TP) antagonist currently used for the treatment of allergic rhinitis, was shown to be a potent CRTH2 antagonist. Indomethacin (), a well-known analgesic and cyclooxygenase 1 and 2 (COX-1 and COX-2) enzyme inhibitor, was reported to show CRTH2 agonist potency. Since then, a large number of CRTH2 antagonists including several series of indole acids have been reported. These CRTH2 antagonists have a variety of fused 6–5-membered ring chemotypes as a core structure such as indole (),, , , 5-azaindole (), 7-azaindole (), benzimidazole,, indolizine, spiro–indoline; in addition, they have an acetic acid moiety ().