title: Non-peptide ligand binding to the formyl peptide receptor FPR2--A comparison to peptide ligand binding modes.
abstract: Ligands of the FPR2 receptor initiate many signaling pathways including activation of phospholipase C, protein kinase C, the mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/protein kinase B pathway. The possible actions include also calcium flux, superoxide generation, as well as migration and proliferation of monocytes. FPR2 activation may induce a pro- and anti-inflammatory effect depending on the ligand type. It is also found that this receptor is involved in tumor growth. Most of currently known FPR2 ligands are agonists since they were designed based on N-formyl peptides, which are natural agonists of formyl receptors. Since the non-peptide drugs are indispensable for effective treatment strategies, we performed a docking study of such ligands employing a generated dual template homology model of the FPR2 receptor. The study revealed different binding modes of particular classes of these drugs. Based on the obtained docking poses we proposed a detailed location of three hydrophobic pockets in orthosteric binding site of FPR2. Our model emphasizes the importance of aromatic stacking, especially with regard to residues His102(3.29) and Phe257(6.51), for binding of FPR2 ligands. We also identified other residues important for non-peptide ligand binding in the binding site of FPR2.
authors.affiliation: Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, ul. Pasteura 1, 02-093 Warsaw, Poland; Faculty of Horticulture, Biotechnology and Landscape Architecture, Warsaw University of Life Sciences, ul. Nowoursynowska 166, 02-787 Warsaw, Poland.
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Stepniewski
authors.affiliation: Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, ul. Pasteura 1, 02-093 Warsaw, Poland. Electronic address: sfilipek@chem.uw.edu.pl.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Filipek
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010671:Phenylurea Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D047069:Pyrazolones / Q000737:chemistry / Q000378:metabolism; D011724:Pyridazines / Q000737:chemistry / Q000378:metabolism; D052999:Quinazolinones / Q000737:chemistry / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; C105101:FPR2 protein, human; D008024:Ligands; D010671:Phenylurea Compounds; D047069:Pyrazolones; D011724:Pyridazines; D052999:Quinazolinones; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C481578:formyl peptide receptor 2, mouse; C038362:pyrazolone; C062482:pyridazine; C031000:benzimidazole
keywords: FPR2; Formyl peptide receptors; GPCRs; Ligand binding; Non-peptide ligands