Molecular docking of 2-(benzimidazol-2-ylthio)-N-phenylacetamide-derived small-molecule agonists of human formyl peptide receptor 1

Khlebnikov, Аndrei I.; Schepetkin, Igor A.; Kirpotina, Liliya N.; Brive, Lars; Dahlgren, Cláes; Jutila, Mark A.; Quinn, Mark T.

doi:10.1007/s00894-011-1307-x

Cited by 17 publications

(38 citation statements)

References 35 publications

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“…Several subpockets of the FPR1 binding site, including two channels ( A and C ), two cavities ( B and E ), and the bottom ( D ) were recently described for this model [43], and the same designation of the subpockets ( A-D ) is used here for comparison (Figure 6B). To determine if these subpockets could accommodate the FPR1 antagonist pharmacophore, receptor-docking poses of compound 10 were determined.…”

Section: Resultsmentioning

confidence: 99%

“…According to our docking study, the pharmacophore area I with hydrophobic area III are located near the bottom D of the FPR1 binding site, the protrusion is fitted in cavity B , and area II is located in cavity E with the long hexyl chain positioned in channel C (Figure 6B). FPR1 residues corresponding to these areas of the binding pocket were enumerated previously [43]. …”

Section: Resultsmentioning

confidence: 99%

“…Structure of compound 10 was pre-optimized by the semi-empirical PM3 method using HyperChem software, saved in Tripos MOL2 format, imported into the Molegro Virtual Docker (MVD) program (MVD 2010.4.2, MolegroApS), and docked as reported previously [43]. …”

Section: Methodsmentioning

confidence: 99%

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Antagonism of human formyl peptide receptor 1 (FPR1) by chromones and related isoflavones

Schepetkin

Kirpotina

Khlebnikov

et al. 2014

Biochemical Pharmacology

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Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) expressed on a variety of cell types. Because FPRs play an important role in the regulation of inflammatory reactions implicated in disease pathogenesis, FPR antagonists may represent novel therapeutics for modulating innate immunity. Previously, 4H-chromones were reported to be potent and competitive FPR1 antagonists. In the present studies, 96 additional chromone analogs, including related synthetic and natural isoflavones were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited fMLF-induced intracellular Ca2+ mobilization in FPR1-HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-HL60 and FPR1-RBL cells. Compound 10 (6-hexyl-2-methyl-3-(1-methyl-1H-benzimidazol-2-yl)-4-oxo-4H-chromen-7-yl acetate) was found to be the most potent FPR1-specific antagonist, with binding affinity Ki~100 nM. These chromones inhibited Ca2+ flux and chemotaxis in human neutrophils with nanomolar-micromolar IC50 values. In addition, the most potent novel FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPR1-RBL cells. These antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca2+ mobilization in FPR2-HL60 cells, FPR3-HL60 cells, RBL cells transfected with murine Fpr1, or interleukin 8-induced Ca2+ flux in human neutrophils and RBL cells transfected with CXC chemokine receptor 1 (CXCR1). Moreover, pharmacophore modeling showed that the active chromones had a significantly higher degree of similarity with the pharmacophore template as compared to inactive analogs. Thus, the chromone/isoflavone scaffold represents a relevant backbone for development of novel FPR1 antagonists.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Antagonism of human formyl peptide receptor 1 (FPR1) by chromones and related isoflavones

Schepetkin

Kirpotina

Khlebnikov

et al. 2014

Biochemical Pharmacology

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“…Previous mutagenesis and ligand-docking studies of FPR (Fujita et al 2011;Khlebnikov et al 2012;Mills et al 2000) have revealed that the amino acid residues constituting the ligand-binding pocket form two cavities located inside the transmembrane domains. There were 10 amino acid residues proposed as the sites critical for ligand binding in the FPR1: F102, V105, D106, L109, R205, F206, W254, Y257, S287, and F291 (Fujita et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Adaptive Evolution of Formyl Peptide Receptors in Mammals

et al. 2015

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The formyl peptide receptors (FPRs) are a family of chemoattractant receptors with important roles in host defense and the regulation of inflammatory reactions. In humans, three FPR paralogs have been identified (FPR1, FPR2, and FPR3) and may have functionally diversified by gene duplication and adaptive evolution. However, the evolutionary mechanisms operating in the diversification of FPR family genes and the changes in selection pressures have not been characterized to date. Here, we have made a comprehensive evolutionary analysis of FPR genes from mammalian species. Phylogenetic analysis showed that an early duplication was responsible for FPR1 and FPR2/FPR3 splitting, and FPR3 originated from the latest duplication event near the origin of primates. Codon-based tests of positive selection reveal interesting patterns in FPR1 and FPR2 versus FPR3, with the first two genes showing clear evidence of positive selection at some sites while the majority of them evolve under strong negative selection. In contrast, our results suggest that the selective pressure may be relaxed in the FPR3 lineage. Of the six amino acid sites inferred to evolve under positive selection in FPR1 and FPR2, four sites were located in extracellular loops of the protein. The electrostatic potential of the extracellular surface of FPR might be affected more frequently with amino acid substitutions in positively selected sites. Thus, positive selection of FPRs among mammals may reflect a link between changes in the sequence and surface structure of the proteins and is likely to be important in the host's defense against invading pathogens.

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“…Additionally, there are examples of what appear to be small structural modifications that change a ligand from a target-selective functionality to a nonselective functionality against FPR1 and FPR2. For instance, Khlebnikov et al (2012) report that by modifying the p-COOCH 3 group on their benzimidazole selective FPR1 agonist (AG-11/05) to a m-COCH 3 group, they obtained the dual FPR1/FPR2 agonist (AG-11/06). In a similar manner, we observed that the modification of the phenol portion of the R 2 functionality of the FPR2 selective antagonist (1754-20) to a methyl group yielded the dual FPR1/FPR2 antagonist (1754-26) ( Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Selective Agonists and Antagonists of Formylpeptide Receptors: Duplex Flow Cytometry and Mixture-Based Positional Scanning Libraries

et al. 2013

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The formylpeptide receptor (FPR1) and formylpeptide-like 1 receptor (FPR2) are G protein-coupled receptors that are linked to acute inflammatory responses, malignant glioma stem cell metastasis, and chronic inflammation. Although several Nformyl peptides are known to bind to these receptors, more selective small-molecule, high-affinity ligands are needed for a better understanding of the physiologic roles played by these receptors. High-throughput assays using mixture-based combinatorial libraries represent a unique, highly efficient approach for rapid data acquisition and ligand identification. We report the superiority of this approach in the context of the simultaneous screening of a diverse set of mixture-based small-molecule libraries. We used a single cross-reactive peptide ligand for a duplex flow cytometric screen of FPR1 and FPR2 in colorcoded cell lines. Screening 37 different mixture-based combinatorial libraries totaling more than five million small molecules (contained in 5,261 mixture samples) resulted in seven libraries that significantly inhibited activity at the receptors. Using positional scanning deconvolution, selective high-affinity (low nM K i ) individual compounds were identified from two separate libraries, namely, pyrrolidine bis-diketopiperazine and polyphenyl urea. The most active individual compounds were characterized for their functional activities as agonists or antagonists with the most potent FPR1 agonist and FPR2 antagonist identified to date with an EC 50 of 131 nM (4 nM K i ) and an IC 50 of 81 nM (1 nM K i ), respectively, in intracellular Ca 21 response determinations. Comparative analyses of other previous screening approaches clearly illustrate the efficiency of identifying receptor selective, individual compounds from mixture-based combinatorial libraries.

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Molecular docking of 2-(benzimidazol-2-ylthio)-N-phenylacetamide-derived small-molecule agonists of human formyl peptide receptor 1

Cited by 17 publications

References 35 publications

Antagonism of human formyl peptide receptor 1 (FPR1) by chromones and related isoflavones

Antagonism of human formyl peptide receptor 1 (FPR1) by chromones and related isoflavones

Adaptive Evolution of Formyl Peptide Receptors in Mammals

Selective Agonists and Antagonists of Formylpeptide Receptors: Duplex Flow Cytometry and Mixture-Based Positional Scanning Libraries

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