General Information of Drug Therapeutic Target (DTT) (ID: TTCM4B3)

DTT Name Nitric-oxide synthase endothelial (NOS3)
Synonyms Nitric oxide synthase, endothelial; NOSIII; NOS,type III; NOS type III; Endothelial nitric oxide synthase; Endothelial NOS; ENOS; EC-NOS; Constitutive NOS; CNOS
Gene Name NOS3
DTT Type
Clinical trial target
[1]
BioChemical Class
Paired donor oxygen oxidoreductase
UniProt ID
NOS3_HUMAN
TTD ID
T06046
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
EC Number
EC 1.14.13.39
Sequence
MGNLKSVAQEPGPPCGLGLGLGLGLCGKQGPATPAPEPSRAPASLLPPAPEHSPPSSPLT
QPPEGPKFPRVKNWEVGSITYDTLSAQAQQDGPCTPRRCLGSLVFPRKLQGRPSPGPPAP
EQLLSQARDFINQYYSSIKRSGSQAHEQRLQEVEAEVAATGTYQLRESELVFGAKQAWRN
APRCVGRIQWGKLQVFDARDCRSAQEMFTYICNHIKYATNRGNLRSAITVFPQRCPGRGD
FRIWNSQLVRYAGYRQQDGSVRGDPANVEITELCIQHGWTPGNGRFDVLPLLLQAPDDPP
ELFLLPPELVLEVPLEHPTLEWFAALGLRWYALPAVSNMLLEIGGLEFPAAPFSGWYMST
EIGTRNLCDPHRYNILEDVAVCMDLDTRTTSSLWKDKAAVEINVAVLHSYQLAKVTIVDH
HAATASFMKHLENEQKARGGCPADWAWIVPPISGSLTPVFHQEMVNYFLSPAFRYQPDPW
KGSAAKGTGITRKKTFKEVANAVKISASLMGTVMAKRVKATILYGSETGRAQSYAQQLGR
LFRKAFDPRVLCMDEYDVVSLEHETLVLVVTSTFGNGDPPENGESFAAALMEMSGPYNSS
PRPEQHKSYKIRFNSISCSDPLVSSWRRKRKESSNTDSAGALGTLRFCVFGLGSRAYPHF
CAFARAVDTRLEELGGERLLQLGQGDELCGQEEAFRGWAQAAFQAACETFCVGEDAKAAA
RDIFSPKRSWKRQRYRLSAQAEGLQLLPGLIHVHRRKMFQATIRSVENLQSSKSTRATIL
VRLDTGGQEGLQYQPGDHIGVCPPNRPGLVEALLSRVEDPPAPTEPVAVEQLEKGSPGGP
PPGWVRDPRLPPCTLRQALTFFLDITSPPSPQLLRLLSTLAEEPREQQELEALSQDPRRY
EEWKWFRCPTLLEVLEQFPSVALPAPLLLTQLPLLQPRYYSVSSAPSTHPGEIHLTVAVL
AYRTQDGLGPLHYGVCSTWLSQLKPGDPVPCFIRGAPSFRLPPDPSLPCILVGPGTGIAP
FRGFWQERLHDIESKGLQPTPMTLVFGCRCSQLDHLYRDEVQNAQQRGVFGRVLTAFSRE
PDNPKTYVQDILRTELAAEVHRVLCLERGHMFVCGDVTMATNVLQTVQRILATEGDMELD
EAGDVIGVLRDQQRYHEDIFGLTLRTQEVTSRIRTQSFSLQERQLRGAVPWAFDPPGSDT
NSP
Function
NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets. Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway.
KEGG Pathway
Arginine and proline metabolism (hsa00330 )
Metabolic pathways (hsa01100 )
Calcium signaling pathway (hsa04020 )
cGMP-PKG signaling pathway (hsa04022 )
HIF-1 signaling pathway (hsa04066 )
Sphingolipid signaling pathway (hsa04071 )
PI3K-Akt signaling pathway (hsa04151 )
VEGF signaling pathway (hsa04370 )
Platelet activation (hsa04611 )
Estrogen signaling pathway (hsa04915 )
Oxytocin signaling pathway (hsa04921 )
Reactome Pathway
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151 )
eNOS activation (R-HSA-203615 )
Nitric oxide stimulates guanylate cyclase (R-HSA-392154 )
VEGFR2 mediated vascular permeability (R-HSA-5218920 )
ROS production in response to bacteria (R-HSA-1222556 )
BioCyc Pathway
MetaCyc:HS09149-MON

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
6 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Tilarginine acetate DMZBGI8 Myocardial infarction BA41-BA43 Phase 3 [1]
ACCLAIM DM0FGDO Angina pectoris BA40 Phase 2 [2]
L-NAME DM01SR6 Hypertension BA00-BA04 Phase 2 [3]
MTR105 DMT0K4F Hypotension BA20-BA21 Phase 2 [4]
VAS-203 DMKU93J Brain injury NA07.Z Phase 2 [5]
Autologous cell based gene therapy DMQA1VT Pulmonary hypertension BB01 Phase 1 [6]
------------------------------------------------------------------------------------
⏷ Show the Full List of 6 Clinical Trial Drug(s)
1 Discontinued Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
L-NIL DM6Y49D N. A. N. A. Terminated [7]
------------------------------------------------------------------------------------
81 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
(5-Imino-[1,4]thiazepan-3-yl)-methanol DMBKZDJ Discovery agent N.A. Investigative [8]
(5S,6R)-[Octahydro-quinolin-(2E)-ylidene]amine DMT9CXD Discovery agent N.A. Investigative [9]
(5S,6S)-[Octahydro-quinolin-(2E)-ylidene]amine DMP4UC1 Discovery agent N.A. Investigative [9]
(6r,1'r,2's)-5,6,7,8 Tetrahydrobiopterin DMOD9R7 Discovery agent N.A. Investigative [10]
(S)-2-Amino-5-(N-methyl-guanidino)-pentanoic acid DMZSWDM Discovery agent N.A. Investigative [11]
(S)-3-Propyl-[1,4]thiazepan-(5E)-ylideneamine DMIG9H3 Discovery agent N.A. Investigative [8]
(S)-6-Amino-2-(2-imino-ethylamino)-hexanoic acid DMG58HM Discovery agent N.A. Investigative [8]
1,2,4-Triazole-Carboxamidine DMOXLHT Discovery agent N.A. Investigative [10]
1-(2-amino-benzothiazol-5-yl)-2-ethyl-isothiourea DMAE8BF Discovery agent N.A. Investigative [12]
1-(2-amino-benzothiazol-6-yl)-2-ethyl-isothiourea DMCSHRL Discovery agent N.A. Investigative [12]
1400W DMLZT64 Discovery agent N.A. Investigative [13]
2,4-Diamino-6-Phenyl-5,6,7,8,-Tetrahydropteridine DMQPKWM Discovery agent N.A. Investigative [13]
2-amino-4-methylpyridine DM1OED2 Discovery agent N.A. Investigative [14]
2-Amino-5-(N-nitro-guanidino)-pentanoic acid DMDUZ2H Discovery agent N.A. Investigative [11]
2-Aminothiazoline DM9YCAH Discovery agent N.A. Investigative [10]
2-Methyl-2,4-Pentanediol DMD45CU Discovery agent N.A. Investigative [10]
2-Methyl-[1,4]thiazepan-(5E)-ylideneamine DMX1IC4 Discovery agent N.A. Investigative [8]
2-Propanol, Isopropanol DML5O0H Discovery agent N.A. Investigative [10]
3,4-Dimethyl-pyrrolidin-(2Z)-ylideneamine DMMO6QI Discovery agent N.A. Investigative [15]
3-Bromo-1H-indazole-7-carbonitrile DMZGWL2 Discovery agent N.A. Investigative [16]
3-bromo-7-nitro-1H-indazole DMM7DHB Discovery agent N.A. Investigative [10]
3-Ethyl-[1,4]thiazepan-(5E)-ylideneamine DMX2JKQ Discovery agent N.A. Investigative [8]
3-Methyl-pyrrolidin-(2Z)-ylideneamine DMHVUF8 Discovery agent N.A. Investigative [15]
3-Methyl-[1,4]thiazepan-(5E)-ylideneamine DMCOH46 Discovery agent N.A. Investigative [8]
4,5-Dimethyl-pyrrolidin-(2Z)-ylideneamine DMB9CJM Discovery agent N.A. Investigative [15]
4-Ethyl-5,6-dihydro-1H-pyridin-(2Z)-ylideneamine DMTM1VD Discovery agent N.A. Investigative [17]
4-Ethyl-5-methyl-pyrrolidin-(2Z)-ylideneamine DMOAQ1E Discovery agent N.A. Investigative [15]
4-Ethyl-pyrrolidin-(2Z)-ylideneamine DMYIWAH Discovery agent N.A. Investigative [15]
4-Methyl-3,6-dihydro-1H-pyridin-(2Z)-ylideneamine DM5FWYG Discovery agent N.A. Investigative [17]
4-Methyl-5,6-dihydro-1H-pyridin-(2Z)-ylideneamine DMUP8NS Discovery agent N.A. Investigative [17]
4-methyl-6-propylpyridin-2-amine DMY04D1 Discovery agent N.A. Investigative [14]
4-Methyl-piperidin-(2E)-ylideneamine DMNMXCE Discovery agent N.A. Investigative [9]
4-Methyl-pyrrolidin-(2Z)-ylideneamine DM0YS36 Discovery agent N.A. Investigative [15]
5,6-Cyclic-Tetrahydropteridine DMDE7XJ Discovery agent N.A. Investigative [18]
5-Ethyl-3-methyl-pyrrolidin-(2Z)-ylideneamine DMS9TFC Discovery agent N.A. Investigative [15]
5-Ethyl-4-methyl-pyrrolidin-(2Z)-ylideneamine DMQWOIG Discovery agent N.A. Investigative [15]
5-Methyl-pyrrolidin-(2Z)-ylideneamine DM4QB3G Discovery agent N.A. Investigative [15]
5-Nitroindazole DMH7SIX Discovery agent N.A. Investigative [10]
6-(2-Fluoropropyl)-4-methylpyridin-2-amine DME1JLM Discovery agent N.A. Investigative [19]
6-(3-Fluoropropyl)-4-methylpyridin-2-amine DMTJPZU Discovery agent N.A. Investigative [19]
6-isobutyl-4-methylpyridin-2-amine DM2XB68 Discovery agent N.A. Investigative [19]
6-Nitroindazole DM2WZCX Discovery agent N.A. Investigative [10]
6s-5,6,7,8-Tetrahydrobiopterin DMIA7ND Discovery agent N.A. Investigative [10]
7-(2-Nitro-ethyl)-azepan-(2Z)-ylideneamine DMK28IS Discovery agent N.A. Investigative [20]
7-Methyl-[1,4]thiazepan-(5E)-ylideneamine DMUCJA6 Discovery agent N.A. Investigative [8]
7-nitro-1H-indazole DMW4XKQ Discovery agent N.A. Investigative [10]
7-Nitroindazole-2-Carboxamidine DMGLWOM Discovery agent N.A. Investigative [13]
Acetate Ion DMD08RH Discovery agent N.A. Investigative [10]
AP-Cav DMT9Z5A Discovery agent N.A. Investigative [21]
Azepan-(2Z)-ylideneamine DMZHV39 Discovery agent N.A. Investigative [20]
Cacodylate Ion DMK4XLD Discovery agent N.A. Investigative [10]
Ethylisothiourea DMV9OCU N. A. N. A. Investigative [10]
Heme DMGC287 Discovery agent N.A. Investigative [13]
Hexahydro-cyclopenta[c]pyrrol-(1Z)-ylideneamine DMG0UVT Discovery agent N.A. Investigative [15]
Hydroxydimethylarsine Oxide DMPS2B1 Discovery agent N.A. Investigative [10]
L-2-Amino-4-(Guanidinooxy)Butyric Acid DMWQCRD Discovery agent N.A. Investigative [10]
L-Homoarginine DML83XP Discovery agent N.A. Investigative [10]
L-NIO DME9FAV Discovery agent N.A. Investigative [18]
N,N-dimethylarginine DM0Y8OW Discovery agent N.A. Investigative [22]
N-(5-Amino-6-oxo-heptyl)-acetamidine DM47XR8 Discovery agent N.A. Investigative [15]
N-(Chlorophenyl)-N'-Hydroxyguanidine DMFGSLO Discovery agent N.A. Investigative [13]
N-omega-allyl-L-arginine DM0BPCT Discovery agent N.A. Investigative [23]
N-Omega-Hydroxy-L-Arginine DMOXQ3N Discovery agent N.A. Investigative [10]
N-omega-propargyl-L-arginine DM9X3B7 Discovery agent N.A. Investigative [23]
N1,N14-Bis((S-Methyl)Isothioureido)Tetradecane DMVIGCJ Discovery agent N.A. Investigative [10]
N5-(1-iminobut-3-enyl)-L-ornithine DMB62OI Discovery agent N.A. Investigative [23]
N5-(1-iminobutyl)-L-ornithine DMT893N Discovery agent N.A. Investigative [23]
N5-(1-iminopropyl)-L-ornithine DM05O7J Discovery agent N.A. Investigative [23]
Nitroarginine DM7T80N N. A. N. A. Investigative [24]
Piperidin-(2E)-ylideneamine DMN8OR2 Discovery agent N.A. Investigative [9]
Pyrrolidin-(2Z)-ylideneamine DMS4ZFU Discovery agent N.A. Investigative [15]
S-(Dimethylarsenic)Cysteine DMSCHL0 Discovery agent N.A. Investigative [10]
S-Ethyl-N-Phenyl-Isothiourea DM6DT9Z Discovery agent N.A. Investigative [13]
S-Isopropyl-Isothiourea DMZ30AM Discovery agent N.A. Investigative [10]
Se-Ethyl-Isoselenourea DM9BJ27 Discovery agent N.A. Investigative [10]
THIOCITRULLINE DM7X8MH Discovery agent N.A. Investigative [25]
[1,3]Oxazinan-(2E)-ylideneamine DMDX6W4 Discovery agent N.A. Investigative [11]
[1,3]Thiazinan-(2E)-ylideneamine DMOEIHC Discovery agent N.A. Investigative [11]
[1,4]Oxazepan-(3E)-ylideneamine DMX58NK Discovery agent N.A. Investigative [8]
[1,4]Thiazepan-(3E)-ylideneamine DMCBFJQ Discovery agent N.A. Investigative [8]
[1,4]Thiazepan-(5E)-ylideneamine DMFQ0Z4 Discovery agent N.A. Investigative [8]
------------------------------------------------------------------------------------
⏷ Show the Full List of 81 Investigative Drug(s)

Molecular Expression Atlas (MEA) of This DTT

Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This DTT
Disease Name ICD 11 Studied Tissue p-value Fold-Change Z-score
Coronary artery disease BA80-BA8Z Peripheral blood 3.68E-01 -0.11 -0.85
------------------------------------------------------------------------------------

The Drug-Metabolizing Enzyme (DME) Role of This DTT

DTT DME Name Nitric oxide synthase endothelial (NOS3) DME Info
Gene Name NOS3
1 Approved Drug(s) Metabolized by This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Doxorubicin DMVP5YE Acute myelogenous leukaemia 2A41 Approved [26]
------------------------------------------------------------------------------------

References

1 Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock: the TRIUMPH randomized controlled trial. JAMA. 2007 Apr 18;297(15):1657-66.
2 CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.
3 Counter-regulation by atorvastatin of gene modulations induced by L-NAME hypertension is associated with vascular protection. Vascul Pharmacol. 2009 Oct;51(4):253-61.
4 Nitric oxide synthase inhibitor (MTR-105) during open-heart surgery. A pilot double-blind placebo-controlled study of hemodynamic effects and safety. Cardiology. 2008;111(3):181-7.
5 Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury: a placebo-controlled randomized Phase IIa trial (NOSTRA). J Neurotrauma. 2014 Oct 1;31(19):1599-606.
6 Feasibility of using autologous transplantation to evaluate hematopoietic stem cell-based gene therapy strategies in transgenic mouse models of human disease. Mol Ther. 2002 Sep;6(3):422-8.
7 Discovery of a series of aminopiperidines as novel iNOS inhibitors. Bioorg Med Chem Lett. 2008 Jan 1;18(1):336-43.
8 Synthesis of analogs of (1,4)-3- and 5-imino oxazepane, thiazepane, and diazepane as inhibitors of nitric oxide synthases. Bioorg Med Chem Lett. 2004 Dec 6;14(23):5907-11.
9 Bicyclic amidine inhibitors of nitric oxide synthase: discovery of perhydro-iminopyrindine and perhydro-iminoquinoline as potent, orally active inh... Bioorg Med Chem Lett. 2005 Apr 15;15(8):1997-2001.
10 How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
11 2-Iminopiperidine and other 2-iminoazaheterocycles as potent inhibitors of human nitric oxide synthase isoforms. J Med Chem. 1996 Feb 2;39(3):669-72.
12 Novel 2-aminobenzothiazoles as selective neuronal nitric oxide synthase inhibitors. Bioorg Med Chem Lett. 2007 May 1;17(9):2540-4.
13 The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
14 Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase. Nat Chem Biol. 2008 Nov;4(11):700-7.
15 Evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2-imines as inhibitors of nitric oxide synthase. Bioorg Med Chem Lett. 2004 Sep 6;14(17):4539-44.
16 Inhibitory effects of a series of 7-substituted-indazoles toward nitric oxide synthases: particular potency of 1H-indazole-7-carbonitrile. Bioorg Med Chem. 2008 Jun 1;16(11):5962-73.
17 Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. Part 1: synthesis and biological evaluation of dihydropy... Bioorg Med Chem Lett. 2002 Sep 2;12(17):2291-4.
18 DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
19 Design and synthesis of 2-amino-4-methylpyridine analogues as inhibitors for inducible nitric oxide synthase and in vivo evaluation of [18F]6-(2-fl... J Med Chem. 2009 Apr 23;52(8):2443-53.
20 Selective heterocyclic amidine inhibitors of human inducible nitric oxide synthase. Bioorg Med Chem Lett. 2001 Oct 8;11(19):2651-3.
21 Endothelial nitric oxide synthase: the Cinderella of inflammation Trends Pharmacol Sci. 2003 Feb;24(2):91-5.
22 Homocysteine and asymmetric dimethylarginine (ADMA): biochemically linked but differently related to vascular disease in chronic kidney disease. Clin Chem Lab Med. 2007;45(12):1683-7.
23 Structure-activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: alkenyl-amidines as new leads. Bioorg Med Chem. 2008 Dec 15;16(24):10205-9.
24 Crystal structure of nitric oxide synthase bound to nitro indazole reveals a novel inactivation mechanism. Biochemistry. 2001 Nov 13;40(45):13448-55.
25 Evaluation of 3-substituted arginine analogs as selective inhibitors of human nitric oxide synthase isozymes. Bioorg Med Chem Lett. 2005 Jun 2;15(11):2881-5.
26 The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage. FASEB J. 2004 Apr;18(6):664-75.