Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ2MO6B)

• DOT Name: Pro-interleukin-16 (IL16)
• Gene Name: IL16
• UniProt ID: IL16_HUMAN
• PDB ID: 1I16; 1X6D; 5FB8
• Pfam ID: PF00595
• Sequence:
  MESHSRAGKSRKSAKFRSISRSLMLCNAKTSDDGSSPDEKYPDPFEISLAQGKEGIFHSS
  VQLADTSEAGPSSVPDLALASEAAQLQAAGNDRGKTCRRIFFMKESSTASSREKPGKLEA
  QSSNFLFPKACHQRARSNSTSVNPYCTREIDFPMTKKSAAPTDRQPYSLCSNRKSLSQQL
  DCPAGKAAGTSRPTRSLSTAQLVQPSGGLQASVISNIVLMKGQAKGLGFSIVGGKDSIYG
  PIGIYVKTIFAGGAAAADGRLQEGDEILELNGESMAGLTHQDALQKFKQAKKGLLTLTVR
  TRLTAPPSLCSHLSPPLCRSLSSSTCITKDSSSFALESPSAPISTAKPNYRIMVEVSLQK
  EAGVGLGIGLCSVPYFQCISGIFVHTLSPGSVAHLDGRLRCGDEIVEISDSPVHCLTLNE
  VYTILSHCDPGPVPIIVSRHPDPQVSEQQLKEAVAQAVENTKFGKERHQWSLEGVKRLES
  SWHGRPTLEKEREKNSAPPHRRAQKVMIRSSSDSSYMSGSPGGSPGSGSAEKPSSDVDIS
  THSPSLPLAREPVVLSIASSRLPQESPPLPESRDSHPPLRLKKSFEILVRKPMSSKPKPP
  PRKYFKSDSDPQKSLEERENSSCSSGHTPPTCGQEARELLPLLLPQEDTAGRSPSASAGC
  PGPGIGPQTKSSTEGEPGWRRASPVTQTSPIKHPLLKRQARMDYSFDTTAEDPWVRISDC
  IKNLFSPIMSENHGHMPLQPNASLNEEEGTQGHPDGTPPKLDTANGTPKVYKSADSSTVK
  KGPPVAPKPAWFRQSLKGLRNRASDPRGLPDPALSTQPAPASREHLGSHIRASSSSSSIR
  QRISSFETFGSSQLPDKGAQRLSLQPSSGEAAKPLGKHEEGRFSGLLGRGAAPTLVPQQP
  EQVLSSGSPAASEARDPGVSESPPPGRQPNQKTLPPGPDPLLRLLSTQAEESQGPVLKMP
  SQRARSFPLTRSQSCETKLLDEKTSKLYSISSQVSSAVMKSLLCLPSSISCAQTPCIPKE
  GASPTSSSNEDSAANGSAETSALDTGFSLNLSELREYTEGLTEAKEDDDGDHSSLQSGQS
  VISLLSSEELKKLIEEVKVLDEATLKQLDGIHVTILHKEEGAGLGFSLAGGADLENKVIT
  VHRVFPNGLASQEGTIQKGNEVLSINGKSLKGTTHHDALAILRQAREPRQAVIVTRKLTP
  EAMPDLNSSTDSAASASAASDVSVESTAEATVCTVTLEKMSAGLGFSLEGGKGSLHGDKP
  LTINRIFKGAASEQSETVQPGDEILQLGGTAMQGLTRFEAWNIIKALPDGPVTIVIRRKS
  LQSKETTAAGDS
• Function: Interleukin-16 stimulates a migratory response in CD4+ lymphocytes, monocytes, and eosinophils. Primes CD4+ T-cells for IL-2 and IL-15 responsiveness. Also induces T-lymphocyte expression of interleukin 2 receptor. Ligand for CD4.; [Isoform 1]: May act as a scaffolding protein that anchors ion channels in the membrane.; Isoform 3 is involved in cell cycle progression in T-cells. Appears to be involved in transcriptional regulation of SKP2 and is probably part of a transcriptional repression complex on the core promoter of the SKP2 gene. May act as a scaffold for GABPB1 (the DNA-binding subunit the GABP transcription factor complex) and HDAC3 thus maintaining transcriptional repression and blocking cell cycle progression in resting T-cells.
• Tissue Specificity: .Expressed in hemopoietic tissues, such as resting T-cells, but undetectable during active T-cell proliferation.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)
• Reactome Pathway: Other interleukin signaling (R-HSA-449836)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Pro-interleukin-16 (IL16).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Pro-interleukin-16 (IL16).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Pro-interleukin-16 (IL16).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Pro-interleukin-16 (IL16).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Pro-interleukin-16 (IL16).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Pro-interleukin-16 (IL16).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Pro-interleukin-16 (IL16).	[5]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Pro-interleukin-16 (IL16).	[6]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Pro-interleukin-16 (IL16).	[8]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Pro-interleukin-16 (IL16).	[9]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Pro-interleukin-16 (IL16).	[10]
Ergotidine	DM78IME	Approved	Ergotidine increases the expression of Pro-interleukin-16 (IL16).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Pro-interleukin-16 (IL16).	[12]
Clobenpropit	DM537OH	Investigative	Clobenpropit increases the expression of Pro-interleukin-16 (IL16).	[11]
Dimaprit	DMA4NI2	Investigative	Dimaprit increases the expression of Pro-interleukin-16 (IL16).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the secretion of Pro-interleukin-16 (IL16).	[7]
Eugenol	DM7US1H	Patented	Eugenol increases the secretion of Pro-interleukin-16 (IL16).	[7]
geraniol	DMS3CBD	Investigative	geraniol increases the secretion of Pro-interleukin-16 (IL16).	[7]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the secretion of Pro-interleukin-16 (IL16).	[7]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol increases the secretion of Pro-interleukin-16 (IL16).	[7]
Farnesol	DMV2X1B	Investigative	Farnesol increases the secretion of Pro-interleukin-16 (IL16).	[7]

References

• [1] 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.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [4] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [5] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [6] Alcohol and Cannabinoids Differentially Affect HIV Infection and Function of Human Monocyte-Derived Dendritic Cells (MDDC). Front Microbiol. 2015 Dec 22;6:1452. doi: 10.3389/fmicb.2015.01452. eCollection 2015.
• [7] The THP-1 cell toolbox: a new concept integrating the key events of skin sensitization. Arch Toxicol. 2019 Apr;93(4):941-951.
• [8] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [9] Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma. Br J Cancer. 2010 Jun 29;103(1):52-60.
• [10] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [11] Histamine h(4) and h(2) receptors control histamine-induced interleukin-16 release from human CD8(+) T cells. J Pharmacol Exp Ther. 2002 Oct;303(1):300-7. doi: 10.1124/jpet.102.036939.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.