Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLDT7NR)

• DOT Name: Nitric oxide synthase 3 (NOS3)
• Synonyms: EC 1.14.13.39; Constitutive NOS; cNOS; EC-NOS; NOS type III; NOSIII; Nitric oxide synthase, endothelial; Endothelial NOS; eNOS
• Gene Name: NOS3
• UniProt ID: NOS3_HUMAN
• PDB ID: 1M9J ; 1M9K ; 1M9M ; 1M9Q ; 1M9R ; 1NIW ; 2LL7 ; 2MG5 ; 2N8J ; 3EAH ; 3NOS ; 4D1O ; 4D1P ; 5UO8 ; 5UO9 ; 5UOA ; 5UOB ; 5UOC ; 5VVB ; 5VVC ; 5VVD ; 5XOF ; 6AV6 ; 6AV7 ; 6CIE ; 6CIF ; 6NH1 ; 6NH2 ; 6NH3 ; 6NH4 ; 6NH5 ; 6NH6 ; 6NH7 ; 6NH8 ; 6NHF ; 6POU ; 6POV ; 6POW ; 6POX ; 6POY ; 6POZ ; 6PP0 ; 6PP1 ; 6PP2 ; 6PP3 ; 6PP4 ; 7M56 ; 7TSG ; 7TSH ; 7TSI ; 7TSK ; 7TSL ; 7TSM ; 7TSN ; 7TSO ; 7TSP ; 7UAO ; 8FGN ; 8FGO ; 8FGP ; 8FGQ ; 8FGR ; 8FGS ; 8FGT ; 8FGU
• EC Number: 1.14.13.39
• Pfam ID: PF00667 ; PF00258 ; PF00175 ; PF02898
• Sequence:
  MGNLKSVAQEPGPPCGLGLGLGLGLCGKQGPATPAPEPSRAPASLLPPAPEHSPPSSPLT
  QPPEGPKFPRVKNWEVGSITYDTLSAQAQQDGPCTPRRCLGSLVFPRKLQGRPSPGPPAP
  EQLLSQARDFINQYYSSIKRSGSQAHEQRLQEVEAEVAATGTYQLRESELVFGAKQAWRN
  APRCVGRIQWGKLQVFDARDCRSAQEMFTYICNHIKYATNRGNLRSAITVFPQRCPGRGD
  FRIWNSQLVRYAGYRQQDGSVRGDPANVEITELCIQHGWTPGNGRFDVLPLLLQAPDDPP
  ELFLLPPELVLEVPLEHPTLEWFAALGLRWYALPAVSNMLLEIGGLEFPAAPFSGWYMST
  EIGTRNLCDPHRYNILEDVAVCMDLDTRTTSSLWKDKAAVEINVAVLHSYQLAKVTIVDH
  HAATASFMKHLENEQKARGGCPADWAWIVPPISGSLTPVFHQEMVNYFLSPAFRYQPDPW
  KGSAAKGTGITRKKTFKEVANAVKISASLMGTVMAKRVKATILYGSETGRAQSYAQQLGR
  LFRKAFDPRVLCMDEYDVVSLEHETLVLVVTSTFGNGDPPENGESFAAALMEMSGPYNSS
  PRPEQHKSYKIRFNSISCSDPLVSSWRRKRKESSNTDSAGALGTLRFCVFGLGSRAYPHF
  CAFARAVDTRLEELGGERLLQLGQGDELCGQEEAFRGWAQAAFQAACETFCVGEDAKAAA
  RDIFSPKRSWKRQRYRLSAQAEGLQLLPGLIHVHRRKMFQATIRSVENLQSSKSTRATIL
  VRLDTGGQEGLQYQPGDHIGVCPPNRPGLVEALLSRVEDPPAPTEPVAVEQLEKGSPGGP
  PPGWVRDPRLPPCTLRQALTFFLDITSPPSPQLLRLLSTLAEEPREQQELEALSQDPRRY
  EEWKWFRCPTLLEVLEQFPSVALPAPLLLTQLPLLQPRYYSVSSAPSTHPGEIHLTVAVL
  AYRTQDGLGPLHYGVCSTWLSQLKPGDPVPCFIRGAPSFRLPPDPSLPCILVGPGTGIAP
  FRGFWQERLHDIESKGLQPTPMTLVFGCRCSQLDHLYRDEVQNAQQRGVFGRVLTAFSRE
  PDNPKTYVQDILRTELAAEVHRVLCLERGHMFVCGDVTMATNVLQTVQRILATEGDMELD
  EAGDVIGVLRDQQRYHEDIFGLTLRTQEVTSRIRTQSFSLQERQLRGAVPWAFDPPGSDT
  NSP
• Function: Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets; [Isoform eNOS13C]: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1.
• Tissue Specificity: Platelets, placenta, liver and kidney.
• KEGG Pathway:
  Arginine biosynthesis (hsa00220)
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  HIF-1 sig.ling pathway (hsa04066)
  Sphingolipid sig.ling pathway (hsa04071)
  PI3K-Akt sig.ling pathway (hsa04151)
  VEGF sig.ling pathway (hsa04370)
  Apelin sig.ling pathway (hsa04371)
  Platelet activation (hsa04611)
  Estrogen sig.ling pathway (hsa04915)
  Oxytocin sig.ling pathway (hsa04921)
  Relaxin sig.ling pathway (hsa04926)
  Insulin resistance (hsa04931)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151)
  eNOS activation (R-HSA-203615)
  NOSTRIN mediated eNOS trafficking (R-HSA-203641)
  NOSIP mediated eNOS trafficking (R-HSA-203754)
  Nitric oxide stimulates guanylate cyclase (R-HSA-392154)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  ROS and RNS production in phagocytes (R-HSA-1222556)
• BioCyc Pathway: MetaCyc:HS09149-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nitric Oxide	DM1RBYG	Approved	Nitric oxide synthase 3 (NOS3) decreases the chemical synthesis of Nitric Oxide.	[63]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Bosentan	DMIOGBU	Approved	Nitric oxide synthase 3 (NOS3) increases the Liver disorder ADR of Bosentan.	[64]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Milchsaure	DM462BT	Investigative	Nitric oxide synthase 3 (NOS3) affects the transport of Milchsaure.	[65]

62 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 Nitric oxide synthase 3 (NOS3).	[1]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nitric oxide synthase 3 (NOS3).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Nitric oxide synthase 3 (NOS3).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nitric oxide synthase 3 (NOS3).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Nitric oxide synthase 3 (NOS3).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Nitric oxide synthase 3 (NOS3).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Nitric oxide synthase 3 (NOS3).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Nitric oxide synthase 3 (NOS3).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Nitric oxide synthase 3 (NOS3).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Nitric oxide synthase 3 (NOS3).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Nitric oxide synthase 3 (NOS3).	[13]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Nitric oxide synthase 3 (NOS3).	[14]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Nitric oxide synthase 3 (NOS3).	[16]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Nitric oxide synthase 3 (NOS3).	[17]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Nitric oxide synthase 3 (NOS3).	[18]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Nitric oxide synthase 3 (NOS3).	[19]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the activity of Nitric oxide synthase 3 (NOS3).	[20]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Nitric oxide synthase 3 (NOS3).	[12]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Nitric oxide synthase 3 (NOS3).	[22]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Nitric oxide synthase 3 (NOS3).	[23]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the activity of Nitric oxide synthase 3 (NOS3).	[24]
Ritonavir	DMU764S	Approved	Ritonavir decreases the expression of Nitric oxide synthase 3 (NOS3).	[25]
Tacrolimus	DMZ7XNQ	Approved	Tacrolimus increases the expression of Nitric oxide synthase 3 (NOS3).	[1]
Cantharidin	DMBP5N3	Approved	Cantharidin affects the expression of Nitric oxide synthase 3 (NOS3).	[27]
Estriol	DMOEM2I	Approved	Estriol increases the expression of Nitric oxide synthase 3 (NOS3).	[28]
Fructose	DM43AN2	Approved	Fructose decreases the expression of Nitric oxide synthase 3 (NOS3).	[29]
Benzoic acid	DMKB9FI	Approved	Benzoic acid increases the expression of Nitric oxide synthase 3 (NOS3).	[6]
Digitoxin	DMWVIGP	Approved	Digitoxin increases the activity of Nitric oxide synthase 3 (NOS3).	[30]
Levamisole	DM5EN79	Approved	Levamisole decreases the expression of Nitric oxide synthase 3 (NOS3).	[32]
3,4-Dihydroxycinnamic Acid	DMVZL26	Phase 4	3,4-Dihydroxycinnamic Acid increases the expression of Nitric oxide synthase 3 (NOS3).	[6]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Nitric oxide synthase 3 (NOS3).	[35]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Nitric oxide synthase 3 (NOS3).	[36]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin increases the expression of Nitric oxide synthase 3 (NOS3).	[37]
Guaiacol	DMN4E7T	Phase 3	Guaiacol increases the expression of Nitric oxide synthase 3 (NOS3).	[38]
ICARIIN	DMOJQGT	Phase 3	ICARIIN increases the expression of Nitric oxide synthase 3 (NOS3).	[39]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Nitric oxide synthase 3 (NOS3).	[36]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Nitric oxide synthase 3 (NOS3).	[14]
Puerarin	DMJIMXH	Phase 2	Puerarin increases the expression of Nitric oxide synthase 3 (NOS3).	[38]
L-NAME	DM01SR6	Phase 2	L-NAME decreases the expression of Nitric oxide synthase 3 (NOS3).	[41]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nitric oxide synthase 3 (NOS3).	[43]
Bradykinin	DM4R6UV	Phase 1	Bradykinin decreases the expression of Nitric oxide synthase 3 (NOS3).	[44]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib decreases the expression of Nitric oxide synthase 3 (NOS3).	[45]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Nitric oxide synthase 3 (NOS3).	[49]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Nitric oxide synthase 3 (NOS3).	[50]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Nitric oxide synthase 3 (NOS3).	[51]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the expression of Nitric oxide synthase 3 (NOS3).	[16]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Nitric oxide synthase 3 (NOS3).	[53]
Daidzein	DMRFTJX	Investigative	Daidzein increases the activity of Nitric oxide synthase 3 (NOS3).	[54]
Oleic acid	DM54O1Z	Investigative	Oleic acid decreases the expression of Nitric oxide synthase 3 (NOS3).	[55]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid increases the expression of Nitric oxide synthase 3 (NOS3).	[38]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX decreases the expression of Nitric oxide synthase 3 (NOS3).	[56]
Linoleic acid	DMDGPY9	Investigative	Linoleic acid decreases the expression of Nitric oxide synthase 3 (NOS3).	[55]
P-Coumaric Acid	DMGJSVD	Investigative	P-Coumaric Acid increases the expression of Nitric oxide synthase 3 (NOS3).	[6]
Phenanthrene-9,10-dione	DMG8KS9	Investigative	Phenanthrene-9,10-dione decreases the expression of Nitric oxide synthase 3 (NOS3).	[57]
25-hydroxycholesterol	DMCHAQ7	Investigative	25-hydroxycholesterol decreases the expression of Nitric oxide synthase 3 (NOS3).	[58]
Phloretin	DMYA50U	Investigative	Phloretin decreases the expression of Nitric oxide synthase 3 (NOS3).	[36]
Cinnamic acid	DM340FH	Investigative	Cinnamic acid increases the expression of Nitric oxide synthase 3 (NOS3).	[6]
Fascaplysin	DMG5OZP	Investigative	Fascaplysin decreases the expression of Nitric oxide synthase 3 (NOS3).	[60]
Phlorizin	DMNARGO	Investigative	Phlorizin decreases the expression of Nitric oxide synthase 3 (NOS3).	[36]
24(S), 25-epoxycholesterol	DMW2KI5	Investigative	24(S), 25-epoxycholesterol decreases the expression of Nitric oxide synthase 3 (NOS3).	[58]
EGTA	DMW9MRO	Investigative	EGTA decreases the expression of Nitric oxide synthase 3 (NOS3).	[61]
CYANIDIN	DMZBDO1	Investigative	CYANIDIN increases the expression of Nitric oxide synthase 3 (NOS3).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[3]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[15]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[21]
Ximelegatran	DMU8ANS	Approved	Ximelegatran increases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[26]
Cilostazol	DMZMSCT	Approved	Cilostazol increases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[31]
Lamivudine	DMI347A	Approved	Lamivudine decreases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[21]
Iron Dextran	DM5OY70	Approved	Iron Dextran decreases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[34]
SEN-196	DMLDBQ5	Phase 2	SEN-196 decreases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[40]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nitric oxide synthase 3 (NOS3).	[42]
Wortmannin	DM8EVK5	Terminated	Wortmannin decreases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Nitric oxide synthase 3 (NOS3).	[48]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate decreases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[52]
Ginsenoside Re	DM46FVD	Investigative	Ginsenoside Re increases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[59]
L-165041	DMZP7YM	Investigative	L-165041 increases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[62]
GW0742X	DMGKEO5	Investigative	GW0742X increases the phosphorylation of Nitric oxide synthase 3 (NOS3).	[62]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
MCI-186	DM8ZHP1	Approved	MCI-186 decreases the degradation of Nitric oxide synthase 3 (NOS3).	[33]
MG-132	DMKA2YS	Preclinical	MG-132 decreases the degradation of Nitric oxide synthase 3 (NOS3).	[46]

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