Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4IE164)

• DOT Name: Tumor necrosis factor (TNF)
• Synonyms: Cachectin; TNF-alpha; Tumor necrosis factor ligand superfamily member 2; TNF-a
• Gene Name: TNF
• UniProt ID: TNFA_HUMAN
• PDB ID: 1A8M ; 1TNF ; 2AZ5 ; 2E7A ; 2TUN ; 2ZJC ; 2ZPX ; 3ALQ ; 3IT8 ; 3L9J ; 3WD5 ; 4G3Y ; 4TSV ; 4TWT ; 4Y6O ; 5M2I ; 5M2J ; 5M2M ; 5MU8 ; 5TSW ; 5UUI ; 5WUX ; 5YOY ; 6OOY ; 6OOZ ; 6OP0 ; 6RMJ ; 6X81 ; 6X82 ; 6X83 ; 6X85 ; 6X86 ; 7ASY ; 7AT7 ; 7ATB ; 7JRA ; 7KP9 ; 7KPA ; 7KPB ; 7QLF ; 7TA3 ; 7TA6
• Pfam ID: PF00229
• Sequence:
  MSTESMIRDVELAEEALPKKTGGPQGSRRCLFLSLFSFLIVAGATTLFCLLHFGVIGPQR
  EEFPRDLSLISPLAQAVRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELR
  DNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRE
  TPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL
• Function: Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Up-regulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective. Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line. Induces insulin resistance in adipocytes via inhibition of insulin-induced IRS1 tyrosine phosphorylation and insulin-induced glucose uptake. Induces GKAP42 protein degradation in adipocytes which is partially responsible for TNF-induced insulin resistance. Plays a role in angiogenesis by inducing VEGF production synergistically with IL1B and IL6. Promotes osteoclastogenesis and therefore mediates bone resorption; The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.
• KEGG Pathway:
  Antifolate resistance (hsa01523)
  MAPK sig.ling pathway (hsa04010)
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  NF-kappa B sig.ling pathway (hsa04064)
  Sphingolipid sig.ling pathway (hsa04071)
  mTOR sig.ling pathway (hsa04150)
  Apoptosis (hsa04210)
  Necroptosis (hsa04217)
  TGF-beta sig.ling pathway (hsa04350)
  Osteoclast differentiation (hsa04380)
  Antigen processing and presentation (hsa04612)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Hematopoietic cell lineage (hsa04640)
  .tural killer cell mediated cytotoxicity (hsa04650)
  IL-17 sig.ling pathway (hsa04657)
  T cell receptor sig.ling pathway (hsa04660)
  Fc epsilon RI sig.ling pathway (hsa04664)
  TNF sig.ling pathway (hsa04668)
  Adipocytokine sig.ling pathway (hsa04920)
  Type II diabetes mellitus (hsa04930)
  Insulin resistance (hsa04931)
  Non-alcoholic fatty liver disease (hsa04932)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Alcoholic liver disease (hsa04936)
  Type I diabetes mellitus (hsa04940)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Yersinia infection (hsa05135)
  Leishmaniasis (hsa05140)
  Chagas disease (hsa05142)
  African trypanosomiasis (hsa05143)
  Malaria (hsa05144)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coro.virus disease - COVID-19 (hsa05171)
  Proteoglycans in cancer (hsa05205)
  Asthma (hsa05310)
  Inflammatory bowel disease (hsa05321)
  Systemic lupus erythematosus (hsa05322)
  Rheumatoid arthritis (hsa05323)
  Allograft rejection (hsa05330)
  Graft-versus-host disease (hsa05332)
  Hypertrophic cardiomyopathy (hsa05410)
  Dilated cardiomyopathy (hsa05414)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956)
  TNFR1-mediated ceramide production (R-HSA-5626978)
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)
  Interleukin-10 signaling (R-HSA-6783783)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  TNF signaling (R-HSA-75893)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 13 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	Tumor necrosis factor (TNF) affects the response to substance of Carbamazepine.	[93]
Aspirin	DM672AH	Approved	Tumor necrosis factor (TNF) affects the response to substance of Aspirin.	[94]
Clozapine	DMFC71L	Approved	Tumor necrosis factor (TNF) affects the response to substance of Clozapine.	[95]
Fructose	DM43AN2	Approved	Tumor necrosis factor (TNF) increases the Autonomic nervous system imbalance ADR of Fructose.	[98]
Trovafloxacin	DM6AN32	Approved	Tumor necrosis factor (TNF) increases the response to substance of Trovafloxacin.	[99]
Ketoprofen	DMRKXPT	Approved	Tumor necrosis factor (TNF) increases the Gastrointestinal toxicity ADR of Ketoprofen.	[98]
Phosphate	DMUXQG7	Approved	Tumor necrosis factor (TNF) increases the response to substance of Phosphate.	[100]
Pentoxifylline	DMU3DNC	Approved	Tumor necrosis factor (TNF) increases the Inflammation ADR of Pentoxifylline.	[98]
Methylene blue	DMJAPE7	Approved	Tumor necrosis factor (TNF) increases the Mucosal findings abnormal ADR of Methylene blue.	[98]
Rituximab	DM1YVZT	Approved	Tumor necrosis factor (TNF) increases the Adverse drug reaction ADR of Rituximab.	[98]
Reteplase	DML0D1P	Approved	Tumor necrosis factor (TNF) increases the Tumour necrosis ADR of Reteplase.	[98]
Dihydrotestosterone	DM3S8XC	Phase 4	Tumor necrosis factor (TNF) increases the response to substance of Dihydrotestosterone.	[101]
Cycloheximide	DMGDA3C	Investigative	Tumor necrosis factor (TNF) increases the response to substance of Cycloheximide.	[104]

This DOT Affected the Regulation of Drug Effects of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dopamine	DMPGUCF	Approved	Tumor necrosis factor (TNF) increases the uptake of Dopamine.	[96]
PGF2alpha	DM4XAU7	Clinical trial	Tumor necrosis factor (TNF) increases the abundance of PGF2alpha.	[102]
Arachidonic acid	DMUOQZD	Investigative	Tumor necrosis factor (TNF) increases the secretion of Arachidonic acid.	[103]
PGD2	DMYDW6J	Investigative	Tumor necrosis factor (TNF) increases the abundance of PGD2.	[102]
Prostaglandin A2	DMWC4X8	Investigative	Tumor necrosis factor (TNF) increases the abundance of Prostaglandin A2.	[102]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Tumor necrosis factor (TNF) decreases the chemical synthesis of Adenosine triphosphate.	[97]

80 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 Tumor necrosis factor (TNF).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tumor necrosis factor (TNF).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tumor necrosis factor (TNF).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tumor necrosis factor (TNF).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tumor necrosis factor (TNF).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tumor necrosis factor (TNF).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tumor necrosis factor (TNF).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Tumor necrosis factor (TNF).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tumor necrosis factor (TNF).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tumor necrosis factor (TNF).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Tumor necrosis factor (TNF).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Tumor necrosis factor (TNF).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Tumor necrosis factor (TNF).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Tumor necrosis factor (TNF).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Tumor necrosis factor (TNF).	[16]
Selenium	DM25CGV	Approved	Selenium increases the expression of Tumor necrosis factor (TNF).	[17]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Tumor necrosis factor (TNF).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Tumor necrosis factor (TNF).	[18]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Tumor necrosis factor (TNF).	[19]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Tumor necrosis factor (TNF).	[20]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the activity of Tumor necrosis factor (TNF).	[21]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Tumor necrosis factor (TNF).	[23]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Tumor necrosis factor (TNF).	[24]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Tumor necrosis factor (TNF).	[26]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Tumor necrosis factor (TNF).	[27]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Tumor necrosis factor (TNF).	[28]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Tumor necrosis factor (TNF).	[29]
Diclofenac	DMPIHLS	Approved	Diclofenac increases the expression of Tumor necrosis factor (TNF).	[30]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Tumor necrosis factor (TNF).	[32]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Tumor necrosis factor (TNF).	[33]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Tumor necrosis factor (TNF).	[34]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Tumor necrosis factor (TNF).	[35]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Tumor necrosis factor (TNF).	[36]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Tumor necrosis factor (TNF).	[37]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Tumor necrosis factor (TNF).	[39]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the activity of Tumor necrosis factor (TNF).	[40]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Tumor necrosis factor (TNF).	[41]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Tumor necrosis factor (TNF).	[42]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Tumor necrosis factor (TNF).	[44]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Tumor necrosis factor (TNF).	[45]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Tumor necrosis factor (TNF).	[46]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Tumor necrosis factor (TNF).	[47]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Tumor necrosis factor (TNF).	[48]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Tumor necrosis factor (TNF).	[49]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Tumor necrosis factor (TNF).	[50]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Tumor necrosis factor (TNF).	[18]
Lindane	DMB8CNL	Approved	Lindane decreases the expression of Tumor necrosis factor (TNF).	[51]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Tumor necrosis factor (TNF).	[52]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Tumor necrosis factor (TNF).	[53]
Prednisolone	DMQ8FR2	Approved	Prednisolone increases the expression of Tumor necrosis factor (TNF).	[55]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of Tumor necrosis factor (TNF).	[56]
Gefitinib	DM15F0X	Approved	Gefitinib decreases the expression of Tumor necrosis factor (TNF).	[57]
Fluoxetine	DM3PD2C	Approved	Fluoxetine decreases the activity of Tumor necrosis factor (TNF).	[58]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Tumor necrosis factor (TNF).	[59]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Tumor necrosis factor (TNF).	[60]
Dinoprostone	DMTYOPD	Approved	Dinoprostone decreases the expression of Tumor necrosis factor (TNF).	[62]
Docetaxel	DMDI269	Approved	Docetaxel decreases the expression of Tumor necrosis factor (TNF).	[64]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol decreases the expression of Tumor necrosis factor (TNF).	[65]
Isoproterenol	DMK7MEY	Approved	Isoproterenol decreases the expression of Tumor necrosis factor (TNF).	[67]
Ardeparin	DMYRX8B	Approved	Ardeparin increases the expression of Tumor necrosis factor (TNF).	[69]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid decreases the expression of Tumor necrosis factor (TNF).	[71]
Gentamicin	DMKINJO	Approved	Gentamicin decreases the expression of Tumor necrosis factor (TNF).	[73]
Glutathione	DMAHMT9	Approved	Glutathione decreases the expression of Tumor necrosis factor (TNF).	[74]
Eicosapentaenoic acid/docosa-hexaenoic acid	DMMUCG4	Approved	Eicosapentaenoic acid/docosa-hexaenoic acid decreases the expression of Tumor necrosis factor (TNF).	[75]
Ximelegatran	DMU8ANS	Approved	Ximelegatran decreases the activity of Tumor necrosis factor (TNF).	[40]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone increases the expression of Tumor necrosis factor (TNF).	[78]
Bleomycin	DMNER5S	Approved	Bleomycin increases the expression of Tumor necrosis factor (TNF).	[79]
Mebendazole	DMO14SG	Approved	Mebendazole increases the expression of Tumor necrosis factor (TNF).	[80]
Hesperetin	DMKER83	Approved	Hesperetin decreases the expression of Tumor necrosis factor (TNF).	[81]
Gamolenic acid	DMQN30Z	Approved	Gamolenic acid decreases the expression of Tumor necrosis factor (TNF).	[75]
Busulfan	DMXYJ9C	Approved	Busulfan increases the expression of Tumor necrosis factor (TNF).	[83]
Nelfinavir mesylate	DMFX6G8	Approved	Nelfinavir mesylate increases the expression of Tumor necrosis factor (TNF).	[84]
Nicotinamide	DMUPE07	Approved	Nicotinamide increases the expression of Tumor necrosis factor (TNF).	[74]
Allopurinol	DMLPAOB	Approved	Allopurinol increases the expression of Tumor necrosis factor (TNF).	[85]
Budesonide	DMJIBAW	Approved	Budesonide decreases the expression of Tumor necrosis factor (TNF).	[86]
Methoxsalen	DME8FZ9	Approved	Methoxsalen decreases the expression of Tumor necrosis factor (TNF).	[87]
Benzbromarone	DMC3YUA	Approved	Benzbromarone increases the expression of Tumor necrosis factor (TNF).	[88]
Prednisone	DM2HG4X	Approved	Prednisone increases the expression of Tumor necrosis factor (TNF).	[26]
Terbinafine	DMI6HUW	Approved	Terbinafine increases the expression of Tumor necrosis factor (TNF).	[89]
Ibrutinib	DMHZCPO	Approved	Ibrutinib decreases the expression of Tumor necrosis factor (TNF).	[90]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the response to substance of Tumor necrosis factor (TNF).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the secretion of Tumor necrosis factor (TNF).	[22]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the secretion of Tumor necrosis factor (TNF).	[25]
Nicotine	DMWX5CO	Approved	Nicotine increases the degradation of Tumor necrosis factor (TNF).	[31]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the response to substance of Tumor necrosis factor (TNF).	[38]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the secretion of Tumor necrosis factor (TNF).	[43]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea increases the secretion of Tumor necrosis factor (TNF).	[54]
Ritonavir	DMU764S	Approved	Ritonavir decreases the secretion of Tumor necrosis factor (TNF).	[61]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the response to substance of Tumor necrosis factor (TNF).	[63]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide increases the secretion of Tumor necrosis factor (TNF).	[66]
Bezafibrate	DMZDCS0	Approved	Bezafibrate decreases the response to substance of Tumor necrosis factor (TNF).	[68]
Melatonin	DMKWFBT	Approved	Melatonin decreases the secretion of Tumor necrosis factor (TNF).	[70]
Isoniazid	DM5JVS3	Approved	Isoniazid increases the secretion of Tumor necrosis factor (TNF).	[72]
2-deoxyglucose	DMIAHVU	Approved	2-deoxyglucose decreases the response to substance of Tumor necrosis factor (TNF).	[76]
Tacrolimus	DMZ7XNQ	Approved	Tacrolimus decreases the secretion of Tumor necrosis factor (TNF).	[77]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine increases the response to substance of Tumor necrosis factor (TNF).	[82]
Masoprocol	DMMVNZ0	Approved	Masoprocol decreases the response to substance of Tumor necrosis factor (TNF).	[76]
Flucloxacillin	DMNUWST	Approved	Flucloxacillin increases the secretion of Tumor necrosis factor (TNF).	[72]
Furosemide	DMMQ8ZG	Approved	Furosemide decreases the secretion of Tumor necrosis factor (TNF).	[91]
Cilostazol	DMZMSCT	Approved	Cilostazol decreases the response to substance of Tumor necrosis factor (TNF).	[92]

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