Development of Small Molecule Non-peptide Formyl Peptide Receptor (FPR) Ligands and Molecular Modeling of Their Recognition
I.A. Schepetkin, A.I. Khlebnikov, M.P. Giovannoni, L.N. Kirpotina, A. Cilibrizzi and M.T. Quinn
Affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT 59717, USA.
Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) expressed on a variety of cell types.
These receptors play an important role in the regulation of inflammatory reactions and sensing cellular damage. They have
also been implicated in the pathogenesis of various diseases, including neurodegenerative diseases, cataract formation,
and atherogenesis. Thus, FPR ligands, both agonists and antagonists, may represent novel therapeutics for modulating
host defense and innate immunity. A variety of molecules have been identified as receptor subtype-selective and mixed
FPR agonists with potential therapeutic value during last decade. This review describes our efforts along with recent advances
in the identification, optimization, biological evaluation, and structure–activity relationship (SAR) analysis of
small molecule non-peptide FPR agonists and antagonists, including chiral molecules. Questions regarding the interaction
at the molecular level of benzimidazoles, pyrazolones, pyridazin-3(2H)-ones, N-phenylureas and other derivatives with
FPR1 and FPR2 are discussed. Application of computational models for virtual screening and design of FPR ligands is
Keywords: Agonist, Ca2+ mobilization, chiral recognition, formyl peptide receptor, G protein-coupled receptor, neutrophil,
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