Details of Drug Off-Target (DOT)

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

• DOT Name: Beta-nerve growth factor (NGF)
• Synonyms: Beta-NGF
• Gene Name: NGF
• Related Disease:
  Hereditary sensory and autonomic neuropathy
  Hereditary sensory and autonomic neuropathy type 5
• UniProt ID: NGF_HUMAN
• PDB ID: 1SG1; 1WWW; 2IFG; 4EDW; 4EDX; 4ZBN; 5JZ7; 6YW8
• Pfam ID: PF00243
• Sequence:
  MSMLFYTLITAFLIGIQAEPHSESNVPAGHTIPQAHWTKLQHSLDTALRRARSAPAAAIA
  ARVAGQTRNITVDPRLFKKRRLRSPRVLFSTQPPREAADTQDLDFEVGGAAPFNRTHRSK
  RSSSHPIFHRGEFSVCDSVSVWVGDKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCR
  DPNPVDSGCRGIDSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKAVRR
  A
• Function: Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems. Extracellular ligand for the NTRK1 and NGFR receptors, activates cellular signaling cascades to regulate neuronal proliferation, differentiation and survival (Probable). The immature NGF precursor (proNGF) functions as a ligand for the heterodimeric receptor formed by SORCS2 and NGFR, and activates cellular signaling cascades that lead to inactivation of RAC1 and/or RAC2, reorganization of the actin cytoskeleton and neuronal growth cone collapse. In contrast to mature NGF, the precursor form (proNGF) promotes neuronal apoptosis (in vitro). Inhibits metalloproteinase-dependent proteolysis of platelet glycoprotein VI. Binds lysophosphatidylinositol and lysophosphatidylserine between the two chains of the homodimer. The lipid-bound form promotes histamine relase from mast cells, contrary to the lipid-free form.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  Cytokine-cytokine receptor interaction (hsa04060)
  PI3K-Akt sig.ling pathway (hsa04151)
  Apoptosis (hsa04210)
  Neurotrophin sig.ling pathway (hsa04722)
  Inflammatory mediator regulation of TRP channels (hsa04750)
• Reactome Pathway:
  Signalling to RAS (R-HSA-167044)
  NGF processing (R-HSA-167060)
  Frs2-mediated activation (R-HSA-170968)
  ARMS-mediated activation (R-HSA-170984)
  Retrograde neurotrophin signalling (R-HSA-177504)
  TRKA activation by NGF (R-HSA-187042)
  Signalling to p38 via RIT and RIN (R-HSA-187706)
  NRAGE signals death through JNK (R-HSA-193648)
  p75NTR negatively regulates cell cycle via SC1 (R-HSA-193670)
  Ceramide signalling (R-HSA-193681)
  PI3K/AKT activation (R-HSA-198203)
  Signalling to STAT3 (R-HSA-198745)
  NFG and proNGF binds to p75NTR (R-HSA-205017)
  NADE modulates death signalling (R-HSA-205025)
  NRIF signals cell death from the nucleus (R-HSA-205043)
  p75NTR recruits signalling complexes (R-HSA-209543)
  NF-kB is activated and signals survival (R-HSA-209560)
  Axonal growth stimulation (R-HSA-209563)
  PLC-gamma1 signalling (R-HSA-167021)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary sensory and autonomic neuropathy	DIS2VOAM	Strong	Autosomal recessive	[1]
Hereditary sensory and autonomic neuropathy type 5	DISFSWS1	Strong	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Beta-nerve growth factor (NGF).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Beta-nerve growth factor (NGF).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beta-nerve growth factor (NGF).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Beta-nerve growth factor (NGF).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Beta-nerve growth factor (NGF).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Beta-nerve growth factor (NGF).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Beta-nerve growth factor (NGF).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Beta-nerve growth factor (NGF).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Beta-nerve growth factor (NGF).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Beta-nerve growth factor (NGF).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Beta-nerve growth factor (NGF).	[13]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Beta-nerve growth factor (NGF).	[14]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Beta-nerve growth factor (NGF).	[15]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Beta-nerve growth factor (NGF).	[16]
Heroin diacetylmorphine	DMDBWHY	Approved	Heroin diacetylmorphine decreases the expression of Beta-nerve growth factor (NGF).	[16]
Lidocaine	DML4ZOT	Approved	Lidocaine decreases the expression of Beta-nerve growth factor (NGF).	[17]
MCI-186	DM8ZHP1	Approved	MCI-186 increases the expression of Beta-nerve growth factor (NGF).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Beta-nerve growth factor (NGF).	[20]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Beta-nerve growth factor (NGF).	[21]

1 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 Beta-nerve growth factor (NGF).	[19]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
MANGIFERIN	DMWAF5Z	Investigative	MANGIFERIN increases the secretion of Beta-nerve growth factor (NGF).	[22]

References

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• [2] A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet. 2004 Apr 15;13(8):799-805. doi: 10.1093/hmg/ddh096. Epub 2004 Feb 19.
• [3] Exposure to nerve growth factor worsens nephrotoxic effect induced by Cyclosporine A in HK-2 cells. PLoS One. 2013 Nov 7;8(11):e80113. doi: 10.1371/journal.pone.0080113. eCollection 2013.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] 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.
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• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [11] Activation of phosphoinositide 3-kinase/PKB pathway by CB(1) and CB(2) cannabinoid receptors expressed in prostate PC-3 cells. Involvement in Raf-1 stimulation and NGF induction. Cell Signal. 2003 Sep;15(9):851-9. doi: 10.1016/s0898-6568(03)00036-6.
• [12] Dexamethasone and the inflammatory response in explants of human omental adipose tissue. Mol Cell Endocrinol. 2010 Feb 5;315(1-2):292-8.
• [13] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [14] Long term effects of cigarette smoke extract or nicotine on nerve growth factor and its receptors in a bronchial epithelial cell line. Toxicol In Vitro. 2018 Dec;53:29-36. doi: 10.1016/j.tiv.2018.07.020. Epub 2018 Aug 1.
• [15] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [16] Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor. J Psychopharmacol. 2007 Nov;21(8):820-5. doi: 10.1177/0269881107078491. Epub 2007 Aug 22.
• [17] Lidocaine prevents breast cancer growth by targeting neuronatin to inhibit nerve fibers formation. J Toxicol Sci. 2021;46(7):329-339. doi: 10.2131/jts.46.329.
• [18] Edaravone improves the expression of nerve growth factor in human astrocytes subjected to hypoxia/reoxygenation. Neurosci Res. 2010 Mar;66(3):284-9. doi: 10.1016/j.neures.2009.11.011. Epub 2009 Nov 30.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Berberine, a natural antidiabetes drug, attenuates glucose neurotoxicity and promotes Nrf2-related neurite outgrowth. Toxicol Appl Pharmacol. 2013 Nov 1;272(3):787-96. doi: 10.1016/j.taap.2013.08.008. Epub 2013 Aug 15.
• [22] Mangiferin, a naturally occurring glucoxilxanthone improves long-term object recognition memory in rats. Eur J Pharmacol. 2010 Jun 10;635(1-3):124-8. doi: 10.1016/j.ejphar.2010.03.011. Epub 2010 Mar 19.