Target Information

Target General Information

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Target ID

T87831 (Former ID: TTDR00011)

Target Name

N-formyl peptide receptor (FPR1)

Synonyms

N-formylpeptide chemoattractant receptor; FPR1; FPR

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Gene Name

FPR1

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Peptic ulcer [ICD-11: DA61]

Function

High affinity receptor for N-formyl-methionyl peptides (fMLP), which are powerful neutrophil chemotactic factors (PubMed:2161213, PubMed:2176894, PubMed:10514456, PubMed:15153520). Binding of fMLP to the receptor stimulates intracellular calcium mobilization and superoxide anion release (PubMed:2161213, PubMed:1712023, PubMed:15153520). This response is mediated via a G-protein that activates a phosphatidylinositol- calcium second messenger system(PubMed:1712023, PubMed:10514456).

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BioChemical Class

GPCR rhodopsin

UniProt ID

FPR1_HUMAN

Sequence

METNSSLPTNISGGTPAVSAGYLFLDIITYLVFAVTFVLGVLGNGLVIWVAGFRMTHTVT
TISYLNLAVADFCFTSTLPFFMVRKAMGGHWPFGWFLCKFVFTIVDINLFGSVFLIALIA
LDRCVCVLHPVWTQNHRTVSLAKKVIIGPWVMALLLTLPVIIRVTTVPGKTGTVACTFNF
SPWTNDPKERINVAVAMLTVRGIIRFIIGFSAPMSIVAVSYGLIATKIHKQGLIKSSRPL
RVLSFVAAAFFLCWSPYQVVALIATVRIRELLQGMYKEIGIAVDVTSALAFFNSCLNPML
YVFMGQDFRERLIHALPASLERALTEDSTQTSDTATNSTLPSAEVELQAK

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3D Structure

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AlphaFold

HIT2.0 ID

T71XEF

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

Rebamipide

Drug Info

Phase 3

Peptic ulcer

[2], [3]

Mode of Action

[+] 2 Modes of Action

Antagonist

[+] 6 Antagonist drugs

Rebamipide

Drug Info

[1]

3570-0208

Drug Info

[4]

BVT173187

Drug Info

[8]

diamide 7

Drug Info

[10]

group E 1682-2106

Drug Info

[12]

methionine benzimidazole 6

Drug Info

[10]

Agonist

[+] 6 Agonist drugs

AG-09/1

Drug Info

[5]

AG-11/03

Drug Info

[6]

AG-14

Drug Info

[7]

CGEN-855

Drug Info

[9]

fMet-Leu-Phe

Drug Info

[11]

PMID22607879CR-(-)-5f

Drug Info

[13]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Cholesterol

Ligand Info

Structure Description

The structure of Formyl Peptide Receptor 1 in complex with Gi and peptide agonist fMIFL

PDB:7VFX

Method

Electron microscopy

Resolution

2.80 Å

Mutation

[14]

PDB Sequence

YLFLDIITYL

³¹

VFAVTFVLGV

⁴¹

LGNGLVIWVA

⁵¹

GFRMTHTVTT

⁶¹

ISYLNLAVAD

⁷¹

FCFTSTLPFF

⁸¹

MVRKAMGGHW

⁹¹

PFGWFLCKFV

¹⁰¹

FTIVDINLFG

¹¹¹

SVFLIALIAL

¹²¹

DRCVCVLHPV

¹³¹

WTQNHRTVSL

¹⁴¹

AKKVIIGPWV

¹⁵¹

MALLLTLPVI

¹⁶¹

IRVTTVPGKT

¹⁷¹

GTVACTFNFS

¹⁸¹

PWTNDPKERI

¹⁹¹

NVAVAMLTVR

²⁰¹

GIIRFIIGFS

²¹¹

APMSIVAVSY

²²¹

GLIATKIHKQ

²³¹

GLIKSSRPLR

²⁴¹

VLSFVAAAFF

²⁵¹

LCWSPYQVVA

²⁶¹

LIATVRIREL

²⁷¹

LQGMYKEIGI

²⁸¹

AVDVTSALAF

²⁹¹

FNSCLNPMLY

³⁰¹

VFMGQDFRER

³¹¹

LIHAL

Residue

Distance (Å)

ILE48

4.273

GLY52

3.607

PHE53

3.980

HIS57

3.562

ILE62

3.773

LEU65

3.657

ASN66

3.535

VAL69

3.655

PHE72

4.044

CYS73

3.809

SER76

4.083

ILE104

4.052

ILE107

4.106

ASN108

4.739

PHE114

3.830

ALA117

3.885

Residue

Distance (Å)

LEU118

3.648

LEU121

4.927

LEU141

4.312

LYS143

3.055

LYS144

4.135

VAL145

3.581

ILE146

3.681

ILE147

4.549

GLY148

3.819

PRO149

3.990

TRP150

3.667

MET152

3.804

ALA212

4.085

PRO213

3.885

ILE216

3.973

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Ligand Name: N-formylmethionine

Ligand Info

Structure Description

The structure of Formyl Peptide Receptor 1 in complex with Gi and peptide agonist fMIFL

PDB:7VFX

Method

Electron microscopy

Resolution

2.80 Å

Mutation

[14]

PDB Sequence

YLFLDIITYL

³¹

VFAVTFVLGV

⁴¹

LGNGLVIWVA

⁵¹

GFRMTHTVTT

⁶¹

ISYLNLAVAD

⁷¹

FCFTSTLPFF

⁸¹

MVRKAMGGHW

⁹¹

PFGWFLCKFV

¹⁰¹

FTIVDINLFG

¹¹¹

SVFLIALIAL

¹²¹

DRCVCVLHPV

¹³¹

WTQNHRTVSL

¹⁴¹

AKKVIIGPWV

¹⁵¹

MALLLTLPVI

¹⁶¹

IRVTTVPGKT

¹⁷¹

GTVACTFNFS

¹⁸¹

PWTNDPKERI

¹⁹¹

NVAVAMLTVR

²⁰¹

GIIRFIIGFS

²¹¹

APMSIVAVSY

²²¹

GLIATKIHKQ

²³¹

GLIKSSRPLR

²⁴¹

VLSFVAAAFF

²⁵¹

LCWSPYQVVA

²⁶¹

LIATVRIREL

²⁷¹

LQGMYKEIGI

²⁸¹

AVDVTSALAF

²⁹¹

FNSCLNPMLY

³⁰¹

VFMGQDFRER

³¹¹

LIHAL

Residue

Distance (Å)

ASP106

2.720

LEU109

3.978

PHE110

3.504

VAL113

4.042

LEU156

4.734

ARG201

2.894

Residue

Distance (Å)

ARG205

3.071

GLY209

3.939

TRP254

4.163

TYR257

3.082

GLN258

4.429

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Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Mas-related G-protein coupled receptor MRG (MAS1L)		22.936 (75/327)	5.25E-07
Mas-related G-protein coupled receptor member G (MRGPRG)		33.945 (37/109)	1.34E-06
Mas-related G-protein coupled receptor member F (MRGPRF)		27.703 (41/148)	2.23E-05
Olfactory receptor 10J3 (OR10J3)	PF13853	26.047 (56/215)	3.88E-05
Olfactory receptor 10V1 (OR10V1)	PF13853	22.697 (69/304)	4.88E-05
Olfactory receptor 1C1 (OR1C1)	PF13853	24.272 (50/206)	5.77E-05
Olfactory receptor 5M9 (OR5M9)	PF13853	20.579 (64/311)	1.06E-04
Putative olfactory receptor 1F12P (OR1F12P)	PF13853	23.182 (51/220)	1.44E-04
Olfactory receptor 10Q1 (OR10Q1)	PF13853	23.793 (69/290)	8.96E-04
Olfactory receptor 1F1 (OR1F1)	PF13853	30.827 (41/133)	4.00E-03
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KEGG Pathway	Pathway ID	Affiliated Target
Rap1 signaling pathway	hsa04015	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Neutrophil extracellular trap formation	hsa04613	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	5	Degree centrality	5.37E-04	Betweenness centrality	4.13E-04
Closeness centrality	2.08E-01	Radiality	1.36E+01	Clustering coefficient	3.00E-01
Neighborhood connectivity	1.48E+01	Topological coefficient	2.31E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Rap1 signaling pathway

Neuroactive ligand-receptor interaction

Staphylococcus aureus infection

NetPath Pathway

[+] 1 NetPath Pathways

Leptin Signaling Pathway

Panther Pathway

[+] 1 Panther Pathways

Inflammation mediated by chemokine and cytokine signaling pathway

PID Pathway

[+] 1 PID Pathways

Urokinase-type plasminogen activator (uPA) and uPAR-mediated signaling

Reactome

[+] 1 Reactome Pathways

G alpha (i) signalling events

WikiPathways

[+] 5 WikiPathways

GPCRs, Class A Rhodopsin-like

Human Complement System

Peptide GPCRs

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Rebamipide suppresses formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide production by inhibiting fMLP-receptor binding in human neutrophils. J Pharmacol Exp Ther. 2001 Apr;297(1):388-94.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 871).

REF 3

The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E2 in rat stomach. Aliment Pharmacol Ther. 2000 Apr;14 Suppl 1:116-24.

REF 4

Discovery of selective probes and antagonists for G-protein-coupled receptors FPR/FPRL1 and GPR30. Curr Top Med Chem. 2009;9(13):1227-36.

REF 5

Identification of novel small-molecule agonists for human formyl peptide receptors and pharmacophore models of their recognition. Mol Pharmacol. 2010 Feb;77(2):159-70.

REF 6

Molecular docking of 2-(benzimidazol-2-ylthio)-N-phenylacetamide-derived small-molecule agonists of human formyl peptide receptor 1. J Mol Model. 2012 Jun;18(6):2831-43.

REF 7

High-throughput screening for small-molecule activators of neutrophils: identification of novel N-formyl peptide receptor agonists. Mol Pharmacol. 2007 Apr;71(4):1061-74.

REF 8

A non-peptide receptor inhibitor with selectivity for one of the neutrophil formyl peptide receptors, FPR 1. Biochem Pharmacol. 2012 Jun 15;83(12):1655-62.

REF 9

REF 10

Discovery of small molecule human FPR1 receptor antagonists. Bioorg Med Chem Lett. 2011 May 15;21(10):2991-7.

REF 11

Further studies on the structural requirements for synthetic peptide chemoattractants. Biochemistry. 1980 May 27;19(11):2404-10.

REF 12

Integration of virtual screening with high-throughput flow cytometry to identify novel small molecule formylpeptide receptor antagonists. Mol Pharmacol. 2005 Nov;68(5):1301-10.

REF 13

Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists. Bioorg Med Chem. 2012 Jun 15;20(12):3781-92.

REF 14

Structural basis for recognition of N-formyl peptides as pathogen-associated molecular patterns. Nat Commun. 2022 Sep 5;13(1):5232.

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