Target Information
| Target General Information | Top | |||||
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| Target ID |
T06046
(Former ID: TTDC00097)
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| Target Name |
Nitric-oxide synthase endothelial (NOS3)
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| Synonyms |
Nitric oxide synthase, endothelial; NOSIII; NOS,type III; NOS type III; Endothelial nitric oxide synthase; Endothelial NOS; ENOS; EC-NOS; Constitutive NOS; CNOS
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| Gene Name |
NOS3
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Myocardial infarction [ICD-11: BA41-BA43] | |||||
| 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.
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| BioChemical Class |
Paired donor oxygen oxidoreductase
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| UniProt ID | ||||||
| EC Number |
EC 1.14.13.39
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| Sequence |
MGNLKSVAQEPGPPCGLGLGLGLGLCGKQGPATPAPEPSRAPASLLPPAPEHSPPSSPLT
QPPEGPKFPRVKNWEVGSITYDTLSAQAQQDGPCTPRRCLGSLVFPRKLQGRPSPGPPAP EQLLSQARDFINQYYSSIKRSGSQAHEQRLQEVEAEVAATGTYQLRESELVFGAKQAWRN APRCVGRIQWGKLQVFDARDCRSAQEMFTYICNHIKYATNRGNLRSAITVFPQRCPGRGD FRIWNSQLVRYAGYRQQDGSVRGDPANVEITELCIQHGWTPGNGRFDVLPLLLQAPDDPP ELFLLPPELVLEVPLEHPTLEWFAALGLRWYALPAVSNMLLEIGGLEFPAAPFSGWYMST EIGTRNLCDPHRYNILEDVAVCMDLDTRTTSSLWKDKAAVEINVAVLHSYQLAKVTIVDH HAATASFMKHLENEQKARGGCPADWAWIVPPISGSLTPVFHQEMVNYFLSPAFRYQPDPW KGSAAKGTGITRKKTFKEVANAVKISASLMGTVMAKRVKATILYGSETGRAQSYAQQLGR LFRKAFDPRVLCMDEYDVVSLEHETLVLVVTSTFGNGDPPENGESFAAALMEMSGPYNSS PRPEQHKSYKIRFNSISCSDPLVSSWRRKRKESSNTDSAGALGTLRFCVFGLGSRAYPHF CAFARAVDTRLEELGGERLLQLGQGDELCGQEEAFRGWAQAAFQAACETFCVGEDAKAAA RDIFSPKRSWKRQRYRLSAQAEGLQLLPGLIHVHRRKMFQATIRSVENLQSSKSTRATIL VRLDTGGQEGLQYQPGDHIGVCPPNRPGLVEALLSRVEDPPAPTEPVAVEQLEKGSPGGP PPGWVRDPRLPPCTLRQALTFFLDITSPPSPQLLRLLSTLAEEPREQQELEALSQDPRRY EEWKWFRCPTLLEVLEQFPSVALPAPLLLTQLPLLQPRYYSVSSAPSTHPGEIHLTVAVL AYRTQDGLGPLHYGVCSTWLSQLKPGDPVPCFIRGAPSFRLPPDPSLPCILVGPGTGIAP FRGFWQERLHDIESKGLQPTPMTLVFGCRCSQLDHLYRDEVQNAQQRGVFGRVLTAFSRE PDNPKTYVQDILRTELAAEVHRVLCLERGHMFVCGDVTMATNVLQTVQRILATEGDMELD EAGDVIGVLRDQQRYHEDIFGLTLRTQEVTSRIRTQSFSLQERQLRGAVPWAFDPPGSDT NSP Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| ADReCS ID | BADD_A02149 ; BADD_A02564 ; BADD_A02600 | |||||
| HIT2.0 ID | T64UH1 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 6 Clinical Trial Drugs | + | ||||
| 1 | Tilarginine acetate | Drug Info | Phase 3 | Myocardial infarction | [2] | |
| 2 | ACCLAIM | Drug Info | Phase 2 | Coronary artery disease | [3] | |
| 3 | L-NAME | Drug Info | Phase 2 | Hypertension | [4], [5] | |
| 4 | MTR105 | Drug Info | Phase 2 | Hypotension | [6] | |
| 5 | VAS-203 | Drug Info | Phase 2 | Brain injury | [7] | |
| 6 | Autologous cell based gene therapy | Drug Info | Phase 1 | Pulmonary hypertension | [8] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | Tilarginine acetate | Drug Info | [1] | |||
| 2 | Autologous cell based gene therapy | Drug Info | [15] | |||
| Stimulator | [+] 1 Stimulator drugs | + | ||||
| 1 | ACCLAIM | Drug Info | [9] | |||
| Inhibitor | [+] 85 Inhibitor drugs | + | ||||
| 1 | L-NAME | Drug Info | [10], [11], [12] | |||
| 2 | MTR105 | Drug Info | [13] | |||
| 3 | VAS-203 | Drug Info | [14] | |||
| 4 | L-NIL | Drug Info | [16] | |||
| 5 | (5-Imino-[1,4]thiazepan-3-yl)-methanol | Drug Info | [17] | |||
| 6 | (5S,6R)-[Octahydro-quinolin-(2E)-ylidene]amine | Drug Info | [18] | |||
| 7 | (5S,6S)-[Octahydro-quinolin-(2E)-ylidene]amine | Drug Info | [18] | |||
| 8 | (6r,1'r,2's)-5,6,7,8 Tetrahydrobiopterin | Drug Info | [19] | |||
| 9 | (S)-2-Amino-5-(N-methyl-guanidino)-pentanoic acid | Drug Info | [20] | |||
| 10 | (S)-3-Propyl-[1,4]thiazepan-(5E)-ylideneamine | Drug Info | [17] | |||
| 11 | (S)-6-Amino-2-(2-imino-ethylamino)-hexanoic acid | Drug Info | [17] | |||
| 12 | 1,2,4-Triazole-Carboxamidine | Drug Info | [19] | |||
| 13 | 1-(2-amino-benzothiazol-5-yl)-2-ethyl-isothiourea | Drug Info | [21] | |||
| 14 | 1-(2-amino-benzothiazol-6-yl)-2-ethyl-isothiourea | Drug Info | [21] | |||
| 15 | 1400W | Drug Info | [22] | |||
| 16 | 2,4-Diamino-6-Phenyl-5,6,7,8,-Tetrahydropteridine | Drug Info | [22] | |||
| 17 | 2-amino-4-methylpyridine | Drug Info | [23] | |||
| 18 | 2-Amino-5-(N-nitro-guanidino)-pentanoic acid | Drug Info | [20] | |||
| 19 | 2-Aminothiazoline | Drug Info | [19], [24] | |||
| 20 | 2-Methyl-2,4-Pentanediol | Drug Info | [19] | |||
| 21 | 2-Methyl-[1,4]thiazepan-(5E)-ylideneamine | Drug Info | [17] | |||
| 22 | 2-Propanol, Isopropanol | Drug Info | [19] | |||
| 23 | 3,4-Dimethyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [24] | |||
| 24 | 3-Bromo-1H-indazole-7-carbonitrile | Drug Info | [25] | |||
| 25 | 3-bromo-7-nitro-1H-indazole | Drug Info | [19], [25] | |||
| 26 | 3-Ethyl-[1,4]thiazepan-(5E)-ylideneamine | Drug Info | [17] | |||
| 27 | 3-Methyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [24] | |||
| 28 | 3-Methyl-[1,4]thiazepan-(5E)-ylideneamine | Drug Info | [17] | |||
| 29 | 4,5-Dimethyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [24] | |||
| 30 | 4-Ethyl-5,6-dihydro-1H-pyridin-(2Z)-ylideneamine | Drug Info | [26] | |||
| 31 | 4-Ethyl-5-methyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [24] | |||
| 32 | 4-Ethyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [24] | |||
| 33 | 4-Methyl-3,6-dihydro-1H-pyridin-(2Z)-ylideneamine | Drug Info | [26] | |||
| 34 | 4-Methyl-5,6-dihydro-1H-pyridin-(2Z)-ylideneamine | Drug Info | [26] | |||
| 35 | 4-methyl-6-propylpyridin-2-amine | Drug Info | [23] | |||
| 36 | 4-Methyl-piperidin-(2E)-ylideneamine | Drug Info | [18] | |||
| 37 | 4-Methyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [24] | |||
| 38 | 5,6-Cyclic-Tetrahydropteridine | Drug Info | [27] | |||
| 39 | 5-Ethyl-3-methyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [24] | |||
| 40 | 5-Ethyl-4-methyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [24] | |||
| 41 | 5-Methyl-pyrrolidin-(2Z)-ylideneamine | Drug Info | [24] | |||
| 42 | 5-Nitroindazole | Drug Info | [19] | |||
| 43 | 6-(2-Fluoropropyl)-4-methylpyridin-2-amine | Drug Info | [28] | |||
| 44 | 6-(3-Fluoropropyl)-4-methylpyridin-2-amine | Drug Info | [28] | |||
| 45 | 6-isobutyl-4-methylpyridin-2-amine | Drug Info | [28] | |||
| 46 | 6-Nitroindazole | Drug Info | [19] | |||
| 47 | 6s-5,6,7,8-Tetrahydrobiopterin | Drug Info | [19] | |||
| 48 | 7-(2-Nitro-ethyl)-azepan-(2Z)-ylideneamine | Drug Info | [29] | |||
| 49 | 7-Methyl-[1,4]thiazepan-(5E)-ylideneamine | Drug Info | [17] | |||
| 50 | 7-nitro-1H-indazole | Drug Info | [19] | |||
| 51 | 7-Nitroindazole-2-Carboxamidine | Drug Info | [22] | |||
| 52 | Acetate Ion | Drug Info | [19] | |||
| 53 | AP-Cav | Drug Info | [30] | |||
| 54 | Azepan-(2Z)-ylideneamine | Drug Info | [29] | |||
| 55 | Cacodylate Ion | Drug Info | [19] | |||
| 56 | Ethylisothiourea | Drug Info | [19] | |||
| 57 | Heme | Drug Info | [22] | |||
| 58 | Hexahydro-cyclopenta[c]pyrrol-(1Z)-ylideneamine | Drug Info | [24] | |||
| 59 | Hydroxydimethylarsine Oxide | Drug Info | [19] | |||
| 60 | L-2-Amino-4-(Guanidinooxy)Butyric Acid | Drug Info | [19] | |||
| 61 | L-Homoarginine | Drug Info | [19] | |||
| 62 | L-NIO | Drug Info | [27], [31] | |||
| 63 | N,N-dimethylarginine | Drug Info | [32] | |||
| 64 | N-(5-Amino-6-oxo-heptyl)-acetamidine | Drug Info | [24] | |||
| 65 | N-(Chlorophenyl)-N'-Hydroxyguanidine | Drug Info | [22] | |||
| 66 | N-omega-allyl-L-arginine | Drug Info | [31] | |||
| 67 | N-Omega-Hydroxy-L-Arginine | Drug Info | [19] | |||
| 68 | N-omega-propargyl-L-arginine | Drug Info | [31] | |||
| 69 | N1,N14-Bis((S-Methyl)Isothioureido)Tetradecane | Drug Info | [19] | |||
| 70 | N5-(1-iminobut-3-enyl)-L-ornithine | Drug Info | [31] | |||
| 71 | N5-(1-iminobutyl)-L-ornithine | Drug Info | [31] | |||
| 72 | N5-(1-iminopropyl)-L-ornithine | Drug Info | [31] | |||
| 73 | Nitroarginine | Drug Info | [33] | |||
| 74 | Piperidin-(2E)-ylideneamine | Drug Info | [18] | |||
| 75 | Pyrrolidin-(2Z)-ylideneamine | Drug Info | [24] | |||
| 76 | S-(Dimethylarsenic)Cysteine | Drug Info | [19] | |||
| 77 | S-Ethyl-N-Phenyl-Isothiourea | Drug Info | [22] | |||
| 78 | S-Isopropyl-Isothiourea | Drug Info | [19] | |||
| 79 | Se-Ethyl-Isoselenourea | Drug Info | [19] | |||
| 80 | THIOCITRULLINE | Drug Info | [34] | |||
| 81 | [1,3]Oxazinan-(2E)-ylideneamine | Drug Info | [20] | |||
| 82 | [1,3]Thiazinan-(2E)-ylideneamine | Drug Info | [20] | |||
| 83 | [1,4]Oxazepan-(3E)-ylideneamine | Drug Info | [17] | |||
| 84 | [1,4]Thiazepan-(3E)-ylideneamine | Drug Info | [17] | |||
| 85 | [1,4]Thiazepan-(5E)-ylideneamine | Drug Info | [17] | |||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-regulating Transcription Factors | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 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. | |||||
| REF 2 | ClinicalTrials.gov (NCT00112281) A Study of the Safety and Efficacy of Nitric Oxide Reduction in Patients With Cardiogenic Shock After a Heart Attack. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT01116427) A Cooperative Clinical Study of Abatacept in Multiple Sclerosis. U.S. National Institutes of Health. | |||||
| REF 4 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5213). | |||||
| REF 5 | Inhibition of nitric oxide synthase by L-NAME speeds phase II pulmonary .VO2 kinetics in the transition to moderate-intensity exercise in man. J Physiol. 2003 Oct 1;552(Pt 1):265-72. | |||||
| REF 6 | ClinicalTrials.gov (NCT00482287) Pharmacokinetics and Pharmacodynamics of MTR105 in Hypotensive Cardiac Surgery Patients. U.S. National Institutes of Health. | |||||
| REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800023224) | |||||
| REF 8 | A Phase I study of the transplantation of genetically marked autologous bone marrow stromal cells. Hum Gene Ther. 1998 Mar 1;9(4):591-600. | |||||
| REF 9 | CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008. | |||||
| REF 10 | 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. | |||||
| REF 11 | Enhanced pulmonary expression of the TrkB neurotrophin receptor in hypoxic rats is associated with increased acetylcholine-induced airway contracti... Acta Physiol (Oxf). 2009 Nov;197(3):253-64. | |||||
| REF 12 | L-NAME causes antinociception by stimulation of the arginine-NO-cGMP pathway. Mediators Inflamm. 2000;9(1):25-30. | |||||
| REF 13 | 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. | |||||
| REF 14 | 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. | |||||
| REF 15 | 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. | |||||
| REF 16 | Discovery of a series of aminopiperidines as novel iNOS inhibitors. Bioorg Med Chem Lett. 2008 Jan 1;18(1):336-43. | |||||
| REF 17 | 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. | |||||
| REF 18 | 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. | |||||
| REF 19 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 20 | 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. | |||||
| REF 21 | Novel 2-aminobenzothiazoles as selective neuronal nitric oxide synthase inhibitors. Bioorg Med Chem Lett. 2007 May 1;17(9):2540-4. | |||||
| REF 22 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 23 | Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase. Nat Chem Biol. 2008 Nov;4(11):700-7. | |||||
| REF 24 | 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. | |||||
| REF 25 | 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. | |||||
| REF 26 | 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. | |||||
| REF 27 | DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41. | |||||
| REF 28 | 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. | |||||
| REF 29 | Selective heterocyclic amidine inhibitors of human inducible nitric oxide synthase. Bioorg Med Chem Lett. 2001 Oct 8;11(19):2651-3. | |||||
| REF 30 | Endothelial nitric oxide synthase: the Cinderella of inflammation Trends Pharmacol Sci. 2003 Feb;24(2):91-5. | |||||
| REF 31 | 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. | |||||
| REF 32 | 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. | |||||
| REF 33 | Crystal structure of nitric oxide synthase bound to nitro indazole reveals a novel inactivation mechanism. Biochemistry. 2001 Nov 13;40(45):13448-55. | |||||
| REF 34 | 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. | |||||
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