Target Information

Target General Information

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Target ID

T27944 (Former ID: TTDC00043)

Target Name

Neuropeptide Y receptor type 4 (NPY4R)

Synonyms

Pancreatic polypeptide receptor 1; PPYR1; NPY4R; NPY4-R

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Gene Name

NPY4R

Target Type

Clinical trial target

[1]

Disease

[+] 3 Target-related Diseases

Obesity [ICD-11: 5B80-5B81]

Schizophrenia [ICD-11: 6A20]

Acute diabete complication [ICD-11: 5A2Y]

Function

Receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is PP, PP (2-36) and [Ile-31, Gln-34] PP > [Pro-34] PYY > PYY and [Leu-31, Pro-34] NPY > NPY > PYY (3-36) and NPY (2-36) > PP (13- 36) > PP (31-36) > NPY free acid.

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BioChemical Class

GPCR rhodopsin

UniProt ID

NPY4R_HUMAN

Sequence

MNTSHLLALLLPKSPQGENRSKPLGTPYNFSEHCQDSVDVMVFIVTSYSIETVVGVLGNL
CLMCVTVRQKEKANVTNLLIANLAFSDFLMCLLCQPLTAVYTIMDYWIFGETLCKMSAFI
QCMSVTVSILSLVLVALERHQLIINPTGWKPSISQAYLGIVLIWVIACVLSLPFLANSIL
ENVFHKNHSKALEFLADKVVCTESWPLAHHRTIYTTFLLLFQYCLPLGFILVCYARIYRR
LQRQGRVFHKGTYSLRAGHMKQVNVVLVVMVVAFAVLWLPLHVFNSLEDWHHEAIPICHG
NLIFLVCHLLAMASTCVNPFIYGFLNTNFKKEIKALVLTCQQSAPLEESEHLPLSTVHTE
VSKGSLRLSGRSNPI

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Discontinued Drug(s)

[+] 2 Discontinued Drugs

TM30338

Drug Info

Discontinued in Phase 2

Obesity

[2]

TM30339

Drug Info

Discontinued in Phase 2

Schizophrenia

[3]

Mode of Action

[+] 3 Modes of Action

Modulator

[+] 1 Modulator drugs

TM30338

Drug Info

[4]

Agonist

[+] 3 Agonist drugs

TM30339

Drug Info

[1]

PD-4074

Drug Info

[6]

[125I]GR231118

Drug Info

[7]

Inhibitor

[+] 7 Inhibitor drugs

Adp[-Trp-Arg-Nva-Arg-Tyr-NH2]2

Drug Info

[5]

H-[Trp-Arg-Nva-Arg-Tyr]2-NH2

Drug Info

[5]

H-[Trp-Arg-Nva-Arg-Tyr]3-NH2

Drug Info

[5]

Pim[-Trp-Arg-Nva-Arg-Tyr-NH2]2

Drug Info

[5]

Sub[-Trp-Arg-Nva-Arg-Tyr-NH2]2

Drug Info

[5]

Sub[-Tyr-Arg-Leu-Arg-Tyr-NH2]2

Drug Info

[5]

[Cys-Trp-Arg-Nva-Arg-Tyr-NH2]2

Drug Info

[5]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

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). Human Similarity Proteins Human Pathway Affiliation

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).

Human Similarity Proteins

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Olfactory receptor 5D16 (OR5D16)	PF13853	22.899 (79/345)	5.00E-03

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy

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 Affiliated Biological Pathways

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KEGG Pathway

[+] 1 KEGG Pathways

Neuroactive ligand-receptor interaction

Reactome

[+] 2 Reactome Pathways

Peptide ligand-binding receptors

G alpha (i) signalling events

WikiPathways

[+] 4 WikiPathways

GPCRs, Class A Rhodopsin-like

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

Neuropeptide y receptor selective ligands in the treatment of obesity. Endocr Rev. 2007 Oct;28(6):664-84.

REF 2

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800023122)

REF 3

ClinicalTrials.gov (NCT00746824) A Study to Determine the Effects of TM30339 on Weight Loss in Obese Individuals.. U.S. National Institutes of Health.

REF 4

Anti-Obesity Drug Discovery and Development, Atta-ur- Rahman, page(108)

REF 5

Neuropeptide Y (NPY) Y4 receptor selective agonists based on NPY(32-36): development of an anorectic Y4 receptor selective agonist with picomolar a... J Med Chem. 2006 Apr 20;49(8):2661-5.

REF 6

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. (Target id: 307).

REF 7

[(125)I]-GR231118: a high affinity radioligand to investigate neuropeptide Y Y(1) and Y(4) receptors. Br J Pharmacol. 2000 Jan;129(1):37-46.

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