Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVI4Q85)

• DOT Name: Neuropeptide FF receptor 2 (NPFFR2)
• Synonyms: G-protein coupled receptor 74; G-protein coupled receptor HLWAR77; Neuropeptide G-protein coupled receptor
• Gene Name: NPFFR2
• UniProt ID: NPFF2_HUMAN
• Pfam ID: PF00001
• Sequence:
  MNSFFGTPAASWCLLESDVSSAPDKEAGRERRALSVQQRGGPAWSGSLEWSRQSAGDRRR
  LGLSRQTAKSSWSRSRDRTCCCRRAWWILVPAADRARRERFIMNEKWDTNSSENWHPIWN
  VNDTKHHLYSDINITYVNYYLHQPQVAAIFIISYFLIFFLCMMGNTVVCFIVMRNKHMHT
  VTNLFILNLAISDLLVGIFCMPITLLDNIIAGWPFGNTMCKISGLVQGISVAASVFTLVA
  IAVDRFQCVVYPFKPKLTIKTAFVIIMIIWVLAITIMSPSAVMLHVQEEKYYRVRLNSQN
  KTSPVYWCREDWPNQEMRKIYTTVLFANIYLAPLSLIVIMYGRIGISLFRAAVPHTGRKN
  QEQWHVVSRKKQKIIKMLLIVALLFILSWLPLWTLMMLSDYADLSPNELQIINIYIYPFA
  HWLAFGNSSVNPIIYGFFNENFRRGFQEAFQLQLCQKRAKPMEAYALKAKSHVLINTSNQ
  LVQESTFQNPHGETLLYRKSAEKPQQELVMEELKETTNSSEI
• Function: Receptor for NPAF (A-18-F-amide) and NPFF (F-8-F-amide) neuropeptides, also known as morphine-modulating peptides. Can also be activated by a variety of naturally occurring or synthetic FMRF-amide like ligands. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
• Tissue Specificity: Isoform 1 is abundant in placenta. Relatively highly expressed in thymus, testis, and small intestine. Expressed at low levels in several tissues including spleen, prostate, brain, heart, ovary, colon, kidney, lung, liver and pancreas and not expressed in skeletal muscle and leukocytes. Isoform 2 expression is highest in placenta (but at relatively low level compared to isoform 1). Very low level of expression in numerous tissues including adipose tissue and many brain regions. Isoform 3 is expressed in brain and heart and, at lower levels, in kidney, liver, lung and pancreas.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Orexin and neuropeptides FF and QRFP bind to their respective receptors (R-HSA-389397)

Molecular Interaction Atlas (MIA) of This DOT

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Neuropeptide FF receptor 2 (NPFFR2).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neuropeptide FF receptor 2 (NPFFR2).	[2]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Neuropeptide FF receptor 2 (NPFFR2).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Neuropeptide FF receptor 2 (NPFFR2).	[4]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Neuropeptide FF receptor 2 (NPFFR2).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neuropeptide FF receptor 2 (NPFFR2).	[5]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Neuropeptide FF receptor 2 (NPFFR2).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neuropeptide FF receptor 2 (NPFFR2).	[8]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Neuropeptide FF receptor 2 (NPFFR2).	[9]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neuropeptide FF receptor 2 (NPFFR2).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Neuropeptide FF receptor 2 (NPFFR2).	[7]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [5] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [6] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [7] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [8] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [9] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.