Details of Drug Off-Target (DOT)

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

• DOT Name: Neuroligin-1 (NLGN1)
• Gene Name: NLGN1
• Related Disease:
  Alzheimer disease
  Amyloidosis
  Autism
  Autism spectrum disorder
  Bipolar disorder
  Hirschsprung disease
  Motion sickness
  Non-insulin dependent diabetes
  Pervasive developmental disorder
  Post-traumatic stress disorder
  Acute myelogenous leukaemia
  Attention deficit hyperactivity disorder
  Autism, susceptibility to, 20
  Schizophrenia
  Intellectual disability
  Nervous system disease
  Status epilepticus seizure
• UniProt ID: NLGN1_HUMAN
• PDB ID: 5OJ6; 5OJK
• Pfam ID: PF00135
• Sequence:
  MALPRCTWPNYVWRAVMACLVHRGLGAPLTLCMLGCLLQAGHVLSQKLDDVDPLVATNFG
  KIRGIKKELNNEILGPVIQFLGVPYAAPPTGERRFQPPEPPSPWSDIRNATQFAPVCPQN
  IIDGRLPEVMLPVWFTNNLDVVSSYVQDQSEDCLYLNIYVPTEDVKRISKECARKPGKKI
  CRKGGPLTKKQTDDLGDNDGAEDEDIRDSGGPKPVMVYIHGGSYMEGTGNLYDGSVLASY
  GNVIVITVNYRLGVLGFLSTGDQAAKGNYGLLDLIQALRWTSENIGFFGGDPLRITVFGS
  GAGGSCVNLLTLSHYSEGNRWSNSTKGLFQRAIAQSGTALSSWAVSFQPAKYARMLATKV
  GCNVSDTVELVECLQKKPYKELVDQDIQPARYHIAFGPVIDGDVIPDDPQILMEQGEFLN
  YDIMLGVNQGEGLKFVENIVDSDDGISASDFDFAVSNFVDNLYGYPEGKDVLRETIKFMY
  TDWADRHNPETRRKTLLALFTDHQWVAPAVATADLHSNFGSPTYFYAFYHHCQTDQVPAW
  ADAAHGDEVPYVLGIPMIGPTELFPCNFSKNDVMLSAVVMTYWTNFAKTGDPNQPVPQDT
  KFIHTKPNRFEEVAWTRYSQKDQLYLHIGLKPRVKEHYRANKVNLWLELVPHLHNLNDIS
  QYTSTTTKVPSTDITFRPTRKNSVPVTSAFPTAKQDDPKQQPSPFSVDQRDYSTELSVTI
  AVGASLLFLNILAFAALYYKKDKRRHDVHRRCSPQRTTTNDLTHAQEEEIMSLQMKHTDL
  DHECESIHPHEVVLRTACPPDYTLAMRRSPDDVPLMTPNTITMIPNTIPGIQPLHTFNTF
  TGGQNNTLPHPHPHPHSHSTTRV
• Function: Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members. Plays a role in synapse function and synaptic signal transmission, and probably mediates its effects by recruiting and clustering other synaptic proteins. May promote the initial formation of synapses, but is not essential for this. In vitro, triggers the de novo formation of presynaptic structures. May be involved in specification of excitatory synapses. Required to maintain wakefulness quality and normal synchrony of cerebral cortex activity during wakefulness and sleep. The protein is involved in nervous system development.
• Tissue Specificity: Expressed in the blood vessel walls (at protein level). Highly expressed in brain through prenatal stages, and at lower levels in pancreas islet beta cells.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Posttranslational Modification	[1]
Amyloidosis	DISHTAI2	Strong	Altered Expression	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[4]
Hirschsprung disease	DISUUSM1	Strong	Altered Expression	[5]
Motion sickness	DISZ2WZW	Strong	Genetic Variation	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[7]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[3]
Post-traumatic stress disorder	DISHL1EY	Strong	Biomarker	[8]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[9]
Attention deficit hyperactivity disorder	DISL8MX9	moderate	Genetic Variation	[4]
Autism, susceptibility to, 20	DIS826RH	Moderate	Autosomal dominant	[10]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[11]
Intellectual disability	DISMBNXP	Limited	Biomarker	[12]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[13]
Status epilepticus seizure	DISY3BIC	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Neuroligin-1 (NLGN1).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Neuroligin-1 (NLGN1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neuroligin-1 (NLGN1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neuroligin-1 (NLGN1).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Neuroligin-1 (NLGN1).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Neuroligin-1 (NLGN1).	[21]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Neuroligin-1 (NLGN1).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Neuroligin-1 (NLGN1).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Neuroligin-1 (NLGN1).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Neuroligin-1 (NLGN1).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Neuroligin-1 (NLGN1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Neuroligin-1 (NLGN1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Neuroligin-1 (NLGN1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Neuroligin-1 (NLGN1).	[26]

References

• [1] Epigenetic mechanisms underlying the effects of triptolide and tripchlorolide on the expression of neuroligin-1 in the hippocampus of APP/PS1 transgenic mice.Pharm Biol. 2019 Dec;57(1):453-459. doi: 10.1080/13880209.2019.1629463.
• [2] Correction: Functional significance of rare neuroligin 1 variants found in autism.PLoS Genet. 2017 Oct 3;13(10):e1007035. doi: 10.1371/journal.pgen.1007035. eCollection 2017 Oct.
• [3] Polymorphisms of Ionotropic Glutamate Receptor-Related Genes and the Risk of Autism Spectrum Disorder in a Chinese Population.Psychiatry Investig. 2019 May;16(5):379-385. doi: 10.30773/pi.2019.02.26.3. Epub 2019 May 23.
• [4] Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis.Biol Psychiatry. 2017 Nov 1;82(9):634-641. doi: 10.1016/j.biopsych.2016.08.040. Epub 2016 Oct 18.
• [5] Down-regulation of fibronectin and the correlated expression of neuroligin in hirschsprung disease.Neurogastroenterol Motil. 2017 Dec;29(12). doi: 10.1111/nmo.13134. Epub 2017 Jun 28.
• [6] Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis.Hum Mol Genet. 2015 May 1;24(9):2700-8. doi: 10.1093/hmg/ddv028. Epub 2015 Jan 26.
• [7] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [8] Identification of Key Genes and Pathways in Post-traumatic Stress Disorder Using Microarray Analysis.Front Psychol. 2019 Feb 27;10:302. doi: 10.3389/fpsyg.2019.00302. eCollection 2019.
• [9] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [10] 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.
• [11] Evidence for Association of Cell Adhesion Molecules Pathway and NLGN1 Polymorphisms with Schizophrenia in Chinese Han Population.PLoS One. 2015 Dec 16;10(12):e0144719. doi: 10.1371/journal.pone.0144719. eCollection 2015.
• [12] Novel case of dup(3q) syndrome due to a de novo interstitial duplication 3q24-q26.31 with minimal overlap to the dup(3q) critical region.Am J Med Genet A. 2005 Jan 1;132A(1):84-9. doi: 10.1002/ajmg.a.30384.
• [13] Chromosomal loss of 3q26.3-3q26.32, involving a partial neuroligin 1 deletion, identified by genomic microarray in a child with microcephaly, seizure disorder, and severe intellectual disability.Am J Med Genet A. 2012 Jan;158A(1):159-65. doi: 10.1002/ajmg.a.34349. Epub 2011 Nov 21.
• [14] Altered synaptic properties during integration of adult-born hippocampal neurons following a seizure insult.PLoS One. 2012;7(4):e35557. doi: 10.1371/journal.pone.0035557. Epub 2012 Apr 23.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [17] 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.
• [18] 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.
• [19] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [20] 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.
• [21] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [22] 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.
• [23] 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.
• [24] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [25] 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.
• [26] 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.
• [27] 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.