3-(1H-indol-3-yl)-2-[3-(4-nitrophenyl)ureido]propanamide enantiomers with human formyl-peptide receptor agonist activity

Molecular modeling of chiral recognition by FPR2

Igor A. Schepetkin, Liliya N. Kirpotina, Andrey Ivanovich Khlebnikov, Marcello Leopoldo, Ermelinda Lucente, Enza Lacivita, Paola De Giorgio, Mark T. Quinn

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

N-formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. Recent studies indicated that FPRs have stereo-selective preference for chiral ligands. Here, we investigated the structure-activity relationship of 24 chiral ureidopropanamides, including previously reported compounds PD168368/PD176252 and their close analogs, and used molecular modeling to define chiral recognition by FPR2. Unlike previously reported 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones, whose R-forms preferentially activated FPR1/FPR2, we found that four S-enantiomers in the seven ureidopropanamide pairs tested preferentially activated intracellular Ca 2+ flux in FPR2-transfected cells, while the R-counterpart was more active in two enantiomer pairs. Thus, active enantiomers of FPR2 agonists can be in either R- or S-configurations, depending on the molecular scaffold and specific substituents at the chiral center. Using molecular modeling approaches, including field point methodology, homology modeling, and docking studies, we propose a model that can explain stereoselective activity of chiral FPR2 agonists. Importantly, our docking studies of FPR2 chiral agonists correlated well with the FPR2 pharmacophore model derived previously. We conclude that the ability of FPR2 to discriminate between the enantiomers is the consequence of the arrangement of the three asymmetric hydrophobic subpockets at the main orthosteric FPR2 binding site with specific orientation of charged regions in the subpockets.

Original languageEnglish
Pages (from-to)404-416
Number of pages13
JournalBiochemical Pharmacology
Volume85
Issue number3
DOIs
Publication statusPublished - 1 Feb 2013
Externally publishedYes

Fingerprint

Formyl Peptide Receptor
Molecular modeling
Enantiomers
Structure-Activity Relationship
G-Protein-Coupled Receptors
Binding Sites
Scaffolds
Ligands
Fluxes
4-nitrophenyl

Keywords

  • Agonist
  • Chiral recognition
  • Enantiomer
  • G protein-coupled receptor
  • N-formyl peptide receptor

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

3-(1H-indol-3-yl)-2-[3-(4-nitrophenyl)ureido]propanamide enantiomers with human formyl-peptide receptor agonist activity : Molecular modeling of chiral recognition by FPR2. / Schepetkin, Igor A.; Kirpotina, Liliya N.; Khlebnikov, Andrey Ivanovich; Leopoldo, Marcello; Lucente, Ermelinda; Lacivita, Enza; De Giorgio, Paola; Quinn, Mark T.

In: Biochemical Pharmacology, Vol. 85, No. 3, 01.02.2013, p. 404-416.

Research output: Contribution to journalArticle

Schepetkin, Igor A. ; Kirpotina, Liliya N. ; Khlebnikov, Andrey Ivanovich ; Leopoldo, Marcello ; Lucente, Ermelinda ; Lacivita, Enza ; De Giorgio, Paola ; Quinn, Mark T. / 3-(1H-indol-3-yl)-2-[3-(4-nitrophenyl)ureido]propanamide enantiomers with human formyl-peptide receptor agonist activity : Molecular modeling of chiral recognition by FPR2. In: Biochemical Pharmacology. 2013 ; Vol. 85, No. 3. pp. 404-416.
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abstract = "N-formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. Recent studies indicated that FPRs have stereo-selective preference for chiral ligands. Here, we investigated the structure-activity relationship of 24 chiral ureidopropanamides, including previously reported compounds PD168368/PD176252 and their close analogs, and used molecular modeling to define chiral recognition by FPR2. Unlike previously reported 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones, whose R-forms preferentially activated FPR1/FPR2, we found that four S-enantiomers in the seven ureidopropanamide pairs tested preferentially activated intracellular Ca 2+ flux in FPR2-transfected cells, while the R-counterpart was more active in two enantiomer pairs. Thus, active enantiomers of FPR2 agonists can be in either R- or S-configurations, depending on the molecular scaffold and specific substituents at the chiral center. Using molecular modeling approaches, including field point methodology, homology modeling, and docking studies, we propose a model that can explain stereoselective activity of chiral FPR2 agonists. Importantly, our docking studies of FPR2 chiral agonists correlated well with the FPR2 pharmacophore model derived previously. We conclude that the ability of FPR2 to discriminate between the enantiomers is the consequence of the arrangement of the three asymmetric hydrophobic subpockets at the main orthosteric FPR2 binding site with specific orientation of charged regions in the subpockets.",
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AU - Schepetkin, Igor A.

AU - Kirpotina, Liliya N.

AU - Khlebnikov, Andrey Ivanovich

AU - Leopoldo, Marcello

AU - Lucente, Ermelinda

AU - Lacivita, Enza

AU - De Giorgio, Paola

AU - Quinn, Mark T.

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Y1 - 2013/2/1

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KW - N-formyl peptide receptor

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