Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4651SI)

• DOT Name: Atrial natriuretic peptide receptor 2 (NPR2)
• Synonyms: EC 4.6.1.2; Atrial natriuretic peptide receptor type B; ANP-B; ANPR-B; NPR-B; Guanylate cyclase B; GC-B
• Gene Name: NPR2
• Related Disease:
  Acromesomelic dysplasia 1, Maroteaux type
  Short stature with nonspecific skeletal abnormalities
  Tall stature-scoliosis-macrodactyly of the great toes syndrome
• UniProt ID: ANPRB_HUMAN
• EC Number: 4.6.1.2
• Pfam ID: PF01094 ; PF00211 ; PF07714
• Sequence:
  MALPSLLLLVAALAGGVRPPGARNLTLAVVLPEHNLSYAWAWPRVGPAVALAVEALGRAL
  PVDLRFVSSELEGACSEYLAPLSAVDLKLYHDPDLLLGPGCVYPAASVARFASHWRLPLL
  TAGAVASGFSAKNDHYRTLVRTGPSAPKLGEFVVTLHGHFNWTARAALLYLDARTDDRPH
  YFTIEGVFEALQGSNLSVQHQVYAREPGGPEQATHFIRANGRIVYICGPLEMLHEILLQA
  QRENLTNGDYVFFYLDVFGESLRAGPTRATGRPWQDNRTREQAQALREAFQTVLVITYRE
  PPNPEYQEFQNRLLIRAREDFGVELGPSLMNLIAGCFYDGILLYAEVLNETIQEGGTRED
  GLRIVEKMQGRRYHGVTGLVVMDKNNDRETDFVLWAMGDLDSGDFQPAAHYSGAEKQIWW
  TGRPIPWVKGAPPSDNPPCAFDLDDPSCDKTPLSTLAIVALGTGITFIMFGVSSFLIFRK
  LMLEKELASMLWRIRWEELQFGNSERYHKGAGSRLTLSLRGSSYGSLMTAHGKYQIFANT
  GHFKGNVVAIKHVNKKRIELTRQVLFELKHMRDVQFNHLTRFIGACIDPPNICIVTEYCP
  RGSLQDILENDSINLDWMFRYSLINDLVKGMAFLHNSIISSHGSLKSSNCVVDSRFVLKI
  TDYGLASFRSTAEPDDSHALYAKKLWTAPELLSGNPLPTTGMQKADVYSFGIILQEIALR
  SGPFYLEGLDLSPKEIVQKVRNGQRPYFRPSIDRTQLNEELVLLMERCWAQDPAERPDFG
  QIKGFIRRFNKEGGTSILDNLLLRMEQYANNLEKLVEERTQAYLEEKRKAEALLYQILPH
  SVAEQLKRGETVQAEAFDSVTIYFSDIVGFTALSAESTPMQVVTLLNDLYTCFDAIIDNF
  DVYKVETIGDAYMVVSGLPGRNGQRHAPEIARMALALLDAVSSFRIRHRPHDQLRLRIGV
  HTGPVCAGVVGLKMPRYCLFGDTVNTASRMESNGQALKIHVSSTTKDALDELGCFQLELR
  GDVEMKGKGKMRTYWLLGERKGPPGLL
• Function: Receptor for the C-type natriuretic peptide NPPC/CNP hormone. Has guanylate cyclase activity upon binding of its ligand. May play a role in the regulation of skeletal growth.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  cGMP-PKG sig.ling pathway (hsa04022)
  Vascular smooth muscle contraction (hsa04270)
  Oxytocin sig.ling pathway (hsa04921)
• Reactome Pathway: Physiological factors (R-HSA-5578768)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acromesomelic dysplasia 1, Maroteaux type	DISGIJPF	Definitive	Autosomal recessive	[1]
Short stature with nonspecific skeletal abnormalities	DISRNBJZ	Strong	Autosomal dominant	[2]
Tall stature-scoliosis-macrodactyly of the great toes syndrome	DISSOGO0	Strong	Autosomal dominant	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Atrial natriuretic peptide receptor 2 (NPR2) decreases the response to substance of Afimoxifene.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Atrial natriuretic peptide receptor 2 (NPR2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Atrial natriuretic peptide receptor 2 (NPR2).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Atrial natriuretic peptide receptor 2 (NPR2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Atrial natriuretic peptide receptor 2 (NPR2).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Atrial natriuretic peptide receptor 2 (NPR2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Atrial natriuretic peptide receptor 2 (NPR2).	[9]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Atrial natriuretic peptide receptor 2 (NPR2).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Atrial natriuretic peptide receptor 2 (NPR2).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Atrial natriuretic peptide receptor 2 (NPR2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Atrial natriuretic peptide receptor 2 (NPR2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Atrial natriuretic peptide receptor 2 (NPR2).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Atrial natriuretic peptide receptor 2 (NPR2).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Atrial natriuretic peptide receptor 2 (NPR2).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Atrial natriuretic peptide receptor 2 (NPR2).	[17]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet. 2004 Jul;75(1):27-34. doi: 10.1086/422013. Epub 2004 May 14.
• [3] An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene. PLoS One. 2012;7(8):e42180. doi: 10.1371/journal.pone.0042180. Epub 2012 Aug 3.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] 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.
• [10] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [15] 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.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [18] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.