Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKKIOJ1)

• DOT Name: Nitric oxide synthase, inducible (NOS2)
• Synonyms: EC 1.14.13.39; Hepatocyte NOS; HEP-NOS; Inducible NO synthase; Inducible NOS; iNOS; NOS type II; Peptidyl-cysteine S-nitrosylase NOS2
• Gene Name: NOS2
• Related Disease: Schizophrenia
• UniProt ID: NOS2_HUMAN
• PDB ID: 1NSI; 2LL6; 2NSI; 3E7G; 3EJ8; 3HR4; 4CX7; 4NOS; 5TP6; 5XN3; 6JWM; 6JWN; 6KEY
• EC Number: 1.14.13.39
• Pfam ID: PF00667 ; PF00258 ; PF00175 ; PF02898
• Sequence:
  MACPWKFLFKTKFHQYAMNGEKDINNNVEKAPCATSSPVTQDDLQYHNLSKQQNESPQPL
  VETGKKSPESLVKLDATPLSSPRHVRIKNWGSGMTFQDTLHHKAKGILTCRSKSCLGSIM
  TPKSLTRGPRDKPTPPDELLPQAIEFVNQYYGSFKEAKIEEHLARVEAVTKEIETTGTYQ
  LTGDELIFATKQAWRNAPRCIGRIQWSNLQVFDARSCSTAREMFEHICRHVRYSTNNGNI
  RSAITVFPQRSDGKHDFRVWNAQLIRYAGYQMPDGSIRGDPANVEFTQLCIDLGWKPKYG
  RFDVVPLVLQANGRDPELFEIPPDLVLEVAMEHPKYEWFRELELKWYALPAVANMLLEVG
  GLEFPGCPFNGWYMGTEIGVRDFCDVQRYNILEEVGRRMGLETHKLASLWKDQAVVEINI
  AVLHSFQKQNVTIMDHHSAAESFMKYMQNEYRSRGGCPADWIWLVPPMSGSITPVFHQEM
  LNYVLSPFYYYQVEAWKTHVWQDEKRRPKRREIPLKVLVKAVLFACMLMRKTMASRVRVT
  ILFATETGKSEALAWDLGALFSCAFNPKVVCMDKYRLSCLEEERLLLVVTSTFGNGDCPG
  NGEKLKKSLFMLKELNNKFRYAVFGLGSSMYPRFCAFAHDIDQKLSHLGASQLTPMGEGD
  ELSGQEDAFRSWAVQTFKAACETFDVRGKQHIQIPKLYTSNVTWDPHHYRLVQDSQPLDL
  SKALSSMHAKNVFTMRLKSRQNLQSPTSSRATILVELSCEDGQGLNYLPGEHLGVCPGNQ
  PALVQGILERVVDGPTPHQTVRLEALDESGSYWVSDKRLPPCSLSQALTYFLDITTPPTQ
  LLLQKLAQVATEEPERQRLEALCQPSEYSKWKFTNSPTFLEVLEEFPSLRVSAGFLLSQL
  PILKPRFYSISSSRDHTPTEIHLTVAVVTYHTRDGQGPLHHGVCSTWLNSLKPQDPVPCF
  VRNASGFHLPEDPSHPCILIGPGTGIAPFRSFWQQRLHDSQHKGVRGGRMTLVFGCRRPD
  EDHIYQEEMLEMAQKGVLHAVHTAYSRLPGKPKVYVQDILRQQLASEVLRVLHKEPGHLY
  VCGDVRMARDVAHTLKQLVAAKLKLNEEQVEDYFFQLKSQKRYHEDIFGAVFPYEAKKDR
  VAVQPSSLEMSAL
• Function: Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such PTGS2/COX2. As component of the iNOS-S100A8/9 transnitrosylase complex involved in the selective inflammatory stimulus-dependent S-nitrosylation of GAPDH on 'Cys-247' implicated in regulation of the GAIT complex activity and probably multiple targets including ANXA5, EZR, MSN and VIM. Involved in inflammation, enhances the synthesis of pro-inflammatory mediators such as IL6 and IL8.
• Tissue Specificity: Expressed in the liver, retina, bone cells and airway epithelial cells of the lung. Not expressed in the platelets. Expressed in chondrocytes .
• KEGG Pathway:
  Arginine biosynthesis (hsa00220)
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
  Calcium sig.ling pathway (hsa04020)
  HIF-1 sig.ling pathway (hsa04066)
  Peroxisome (hsa04146)
  Apelin sig.ling pathway (hsa04371)
  Relaxin sig.ling pathway (hsa04926)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Pertussis (hsa05133)
  Leishmaniasis (hsa05140)
  Chagas disease (hsa05142)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Pathways in cancer (hsa05200)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  Nitric oxide stimulates guanylate cyclase (R-HSA-392154)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Peroxisomal protein import (R-HSA-9033241)
  Inhibition of nitric oxide production (R-HSA-9636249)
  ROS and RNS production in phagocytes (R-HSA-1222556)
• BioCyc Pathway: MetaCyc:HS00205-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	No Known	Unknown	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	Nitric oxide synthase, inducible (NOS2) decreases the response to substance of DTI-015.	[74]
Dobutamine	DMD1B8Z	Approved	Nitric oxide synthase, inducible (NOS2) affects the response to substance of Dobutamine.	[75]
Serotonin	DMOFCRY	Investigative	Nitric oxide synthase, inducible (NOS2) increases the Gastrointestinal tract mucosal discolouration ADR of Serotonin.	[76]

76 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 Nitric oxide synthase, inducible (NOS2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nitric oxide synthase, inducible (NOS2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nitric oxide synthase, inducible (NOS2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nitric oxide synthase, inducible (NOS2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nitric oxide synthase, inducible (NOS2).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Nitric oxide synthase, inducible (NOS2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nitric oxide synthase, inducible (NOS2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Nitric oxide synthase, inducible (NOS2).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Nitric oxide synthase, inducible (NOS2).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Nitric oxide synthase, inducible (NOS2).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Nitric oxide synthase, inducible (NOS2).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Nitric oxide synthase, inducible (NOS2).	[14]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Nitric oxide synthase, inducible (NOS2).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Nitric oxide synthase, inducible (NOS2).	[16]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Nitric oxide synthase, inducible (NOS2).	[17]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Nitric oxide synthase, inducible (NOS2).	[18]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Nitric oxide synthase, inducible (NOS2).	[19]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Nitric oxide synthase, inducible (NOS2).	[20]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Nitric oxide synthase, inducible (NOS2).	[21]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Nitric oxide synthase, inducible (NOS2).	[22]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Nitric oxide synthase, inducible (NOS2).	[19]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Nitric oxide synthase, inducible (NOS2).	[23]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Nitric oxide synthase, inducible (NOS2).	[24]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Nitric oxide synthase, inducible (NOS2).	[23]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Nitric oxide synthase, inducible (NOS2).	[25]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Nitric oxide synthase, inducible (NOS2).	[26]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Nitric oxide synthase, inducible (NOS2).	[27]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Nitric oxide synthase, inducible (NOS2).	[28]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the activity of Nitric oxide synthase, inducible (NOS2).	[29]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol decreases the expression of Nitric oxide synthase, inducible (NOS2).	[30]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide increases the expression of Nitric oxide synthase, inducible (NOS2).	[31]
Isoproterenol	DMK7MEY	Approved	Isoproterenol decreases the expression of Nitric oxide synthase, inducible (NOS2).	[32]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone decreases the expression of Nitric oxide synthase, inducible (NOS2).	[33]
Penicillamine	DM40EF6	Approved	Penicillamine increases the expression of Nitric oxide synthase, inducible (NOS2).	[34]
Ammonia	DMOEVK6	Approved	Ammonia increases the expression of Nitric oxide synthase, inducible (NOS2).	[36]
Naltrexone	DMUL45H	Approved	Naltrexone decreases the activity of Nitric oxide synthase, inducible (NOS2).	[37]
Prilocaine	DMI7DZ2	Approved	Prilocaine increases the expression of Nitric oxide synthase, inducible (NOS2).	[38]
Beclomethasone dipropionate	DM5NW1E	Phase 4	Beclomethasone dipropionate decreases the expression of Nitric oxide synthase, inducible (NOS2).	[39]
Glyceryl trinitrate	DMF72W3	Phase 4	Glyceryl trinitrate decreases the expression of Nitric oxide synthase, inducible (NOS2).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Nitric oxide synthase, inducible (NOS2).	[40]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Nitric oxide synthase, inducible (NOS2).	[40]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Nitric oxide synthase, inducible (NOS2).	[41]
Puerarin	DMJIMXH	Phase 2	Puerarin decreases the expression of Nitric oxide synthase, inducible (NOS2).	[40]
Apilimod dimesylate	DM4N2O0	Phase 2	Apilimod dimesylate decreases the expression of Nitric oxide synthase, inducible (NOS2).	[42]
CR-3294	DMHJEZS	Phase 2	CR-3294 decreases the expression of Nitric oxide synthase, inducible (NOS2).	[43]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nitric oxide synthase, inducible (NOS2).	[44]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nitric oxide synthase, inducible (NOS2).	[45]
LY294002	DMY1AFS	Phase 1	LY294002 increases the expression of Nitric oxide synthase, inducible (NOS2).	[46]
Aminoguanidine	DMJQDUC	Phase 1	Aminoguanidine decreases the expression of Nitric oxide synthase, inducible (NOS2).	[47]
Flavonoid derivative 1	DMCQP0B	Patented	Flavonoid derivative 1 decreases the expression of Nitric oxide synthase, inducible (NOS2).	[19]
GGTI-298	DM1CG0J	Terminated	GGTI-298 increases the expression of Nitric oxide synthase, inducible (NOS2).	[48]
Spermine	DMD4BFY	Terminated	Spermine increases the activity of Nitric oxide synthase, inducible (NOS2).	[49]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Nitric oxide synthase, inducible (NOS2).	[50]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Nitric oxide synthase, inducible (NOS2).	[51]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the expression of Nitric oxide synthase, inducible (NOS2).	[52]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Nitric oxide synthase, inducible (NOS2).	[53]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Nitric oxide synthase, inducible (NOS2).	[54]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Nitric oxide synthase, inducible (NOS2).	[55]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Nitric oxide synthase, inducible (NOS2).	[56]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Nitric oxide synthase, inducible (NOS2).	[57]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Nitric oxide synthase, inducible (NOS2).	[58]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Nitric oxide synthase, inducible (NOS2).	[59]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Nitric oxide synthase, inducible (NOS2).	[61]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Nitric oxide synthase, inducible (NOS2).	[62]
Rutin	DMEHRAJ	Investigative	Rutin increases the activity of Nitric oxide synthase, inducible (NOS2).	[63]
Kaempferol	DMHEMUB	Investigative	Kaempferol decreases the expression of Nitric oxide synthase, inducible (NOS2).	[9]
Phenanthrene-9,10-dione	DMG8KS9	Investigative	Phenanthrene-9,10-dione increases the expression of Nitric oxide synthase, inducible (NOS2).	[64]
Icariside II	DM3DB8X	Investigative	Icariside II decreases the expression of Nitric oxide synthase, inducible (NOS2).	[65]
DIECKOL	DMBCK4G	Investigative	DIECKOL decreases the expression of Nitric oxide synthase, inducible (NOS2).	[66]
Buthionine sulfoximine	DMJ46CB	Investigative	Buthionine sulfoximine increases the expression of Nitric oxide synthase, inducible (NOS2).	[67]
25-hydroxycholesterol	DMCHAQ7	Investigative	25-hydroxycholesterol increases the expression of Nitric oxide synthase, inducible (NOS2).	[68]
CYCLOPAMINE	DMEM2SW	Investigative	CYCLOPAMINE decreases the expression of Nitric oxide synthase, inducible (NOS2).	[69]
AMENTOFLAVONE	DMLRNV2	Investigative	AMENTOFLAVONE decreases the expression of Nitric oxide synthase, inducible (NOS2).	[70]
Sanggenon C	DMSF5DW	Investigative	Sanggenon C decreases the expression of Nitric oxide synthase, inducible (NOS2).	[71]
CORILAGIN	DMAC698	Investigative	CORILAGIN decreases the expression of Nitric oxide synthase, inducible (NOS2).	[72]
PB28	DMMNQ1B	Investigative	PB28 increases the expression of Nitric oxide synthase, inducible (NOS2).	[73]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the degradation of Nitric oxide synthase, inducible (NOS2).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ergotidine	DM78IME	Approved	Ergotidine increases the phosphorylation of Nitric oxide synthase, inducible (NOS2).	[35]
Manganese	DMKT129	Investigative	Manganese decreases the methylation of Nitric oxide synthase, inducible (NOS2).	[60]

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