Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7M8XVG)

• DOT Name: Nitric oxide synthase 1 (NOS1)
• Synonyms: EC 1.14.13.39; Constitutive NOS; NC-NOS; NOS type I; Neuronal NOS; N-NOS; nNOS; Nitric oxide synthase, brain; bNOS; Peptidyl-cysteine S-nitrosylase NOS1
• Gene Name: NOS1
• Related Disease: Idiopathic achalasia
• UniProt ID: NOS1_HUMAN
• PDB ID: 4D1N ; 4UCH ; 4UH5 ; 4UH6 ; 4V3U ; 5ADF ; 5ADG ; 5ADI ; 5FVU ; 5FVV ; 5FVW ; 5FVX ; 5UO1 ; 5UO2 ; 5UO3 ; 5UO4 ; 5UO5 ; 5UO6 ; 5UO7 ; 5VUV ; 5VUW ; 5VUX ; 5VUY ; 5VUZ ; 5VV0 ; 5VV1 ; 5VV2 ; 5VV3 ; 5VV4 ; 5VV5 ; 6AUY ; 6AUZ ; 6AV0 ; 6AV1 ; 6AV2 ; 6AV3 ; 6AV4 ; 6AV5 ; 6CIC ; 6CID ; 6NG1 ; 6NG2 ; 6NG4 ; 6NG5 ; 6NG6 ; 6NG7 ; 6NG8 ; 6NGA ; 6NGB ; 6NGC ; 6NGD ; 6NGE ; 6NGF ; 6NGH ; 6NGI ; 6NHB ; 6NHC ; 6PNA ; 6PNB ; 6PNC ; 6PND ; 6PNE ; 6PNF ; 6PNG ; 6PNH ; 6PO5 ; 6PO7 ; 6PO8 ; 6PO9 ; 6POA ; 6POB ; 6POC ; 6POT ; 7TS1 ; 7TS2 ; 7TS3 ; 7TS4 ; 7TS5 ; 7TS6 ; 7TS7 ; 7TS8 ; 7UAM ; 7US7 ; 7US8 ; 8BI8 ; 8BI9 ; 8FGF ; 8FGG ; 8FGH ; 8FGI ; 8FGJ ; 8FGK ; 8FGL ; 8FGM
• EC Number: 1.14.13.39
• Pfam ID: PF00667 ; PF00258 ; PF00175 ; PF02898 ; PF00595
• Sequence:
  MEDHMFGVQQIQPNVISVRLFKRKVGGLGFLVKERVSKPPVIISDLIRGGAAEQSGLIQA
  GDIILAVNGRPLVDLSYDSALEVLRGIASETHVVLILRGPEGFTTHLETTFTGDGTPKTI
  RVTQPLGPPTKAVDLSHQPPAGKEQPLAVDGASGPGNGPQHAYDDGQEAGSLPHANGLAP
  RPPGQDPAKKATRVSLQGRGENNELLKEIEPVLSLLTSGSRGVKGGAPAKAEMKDMGIQV
  DRDLDGKSHKPLPLGVENDRVFNDLWGKGNVPVVLNNPYSEKEQPPTSGKQSPTKNGSPS
  KCPRFLKVKNWETEVVLTDTLHLKSTLETGCTEYICMGSIMHPSQHARRPEDVRTKGQLF
  PLAKEFIDQYYSSIKRFGSKAHMERLEEVNKEIDTTSTYQLKDTELIYGAKHAWRNASRC
  VGRIQWSKLQVFDARDCTTAHGMFNYICNHVKYATNKGNLRSAITIFPQRTDGKHDFRVW
  NSQLIRYAGYKQPDGSTLGDPANVQFTEICIQQGWKPPRGRFDVLPLLLQANGNDPELFQ
  IPPELVLEVPIRHPKFEWFKDLGLKWYGLPAVSNMLLEIGGLEFSACPFSGWYMGTEIGV
  RDYCDNSRYNILEEVAKKMNLDMRKTSSLWKDQALVEINIAVLYSFQSDKVTIVDHHSAT
  ESFIKHMENEYRCRGGCPADWVWIVPPMSGSITPVFHQEMLNYRLTPSFEYQPDPWNTHV
  WKGTNGTPTKRRAIGFKKLAEAVKFSAKLMGQAMAKRVKATILYATETGKSQAYAKTLCE
  IFKHAFDAKVMSMEEYDIVHLEHETLVLVVTSTFGNGDPPENGEKFGCALMEMRHPNSVQ
  EERKSYKVRFNSVSSYSDSQKSSGDGPDLRDNFESAGPLANVRFSVFGLGSRAYPHFCAF
  GHAVDTLLEELGGERILKMREGDELCGQEEAFRTWAKKVFKAACDVFCVGDDVNIEKANN
  SLISNDRSWKRNKFRLTFVAEAPELTQGLSNVHKKRVSAARLLSRQNLQSPKSSRSTIFV
  RLHTNGSQELQYQPGDHLGVFPGNHEDLVNALIERLEDAPPVNQMVKVELLEERNTALGV
  ISNWTDELRLPPCTIFQAFKYYLDITTPPTPLQLQQFASLATSEKEKQRLLVLSKGLQEY
  EEWKWGKNPTIVEVLEEFPSIQMPATLLLTQLSLLQPRYYSISSSPDMYPDEVHLTVAIV
  SYRTRDGEGPIHHGVCSSWLNRIQADELVPCFVRGAPSFHLPRNPQVPCILVGPGTGIAP
  FRSFWQQRQFDIQHKGMNPCPMVLVFGCRQSKIDHIYREETLQAKNKGVFRELYTAYSRE
  PDKPKKYVQDILQEQLAESVYRALKEQGGHIYVCGDVTMAADVLKAIQRIMTQQGKLSAE
  DAGVFISRMRDDNRYHEDIFGVTLRTYEVTNRLRSESIAFIEESKKDTDEVFSS
• Function: Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR.
• Tissue Specificity: Isoform 1 is ubiquitously expressed: detected in skeletal muscle and brain, also in testis, lung and kidney, and at low levels in heart, adrenal gland and retina. Not detected in the platelets. Isoform 3 is expressed only in testis. Isoform 4 is detected in testis, skeletal muscle, lung, and kidney, at low levels in the brain, but not in the heart and adrenal gland.
• KEGG Pathway:
  Arginine biosynthesis (hsa00220)
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
  Calcium sig.ling pathway (hsa04020)
  Phagosome (hsa04145)
  Apelin sig.ling pathway (hsa04371)
  Circadian entrainment (hsa04713)
  Long-term depression (hsa04730)
  Relaxin sig.ling pathway (hsa04926)
  Salivary secretion (hsa04970)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  Nitric oxide stimulates guanylate cyclase (R-HSA-392154)
  Ion homeostasis (R-HSA-5578775)
  ROS and RNS production in phagocytes (R-HSA-1222556)
• BioCyc Pathway: MetaCyc:HS01647-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
Idiopathic achalasia	DISBZNRO	Supportive	Autosomal recessive	[1]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nitric Oxide	DM1RBYG	Approved	Nitric oxide synthase 1 (NOS1) increases the chemical synthesis of Nitric Oxide.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Interferon gamma-1b	DMWUMRL	Approved	Nitric oxide synthase 1 (NOS1) increases the Apoptosis ADR of Interferon gamma-1b.	[17]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Nitric oxide synthase 1 (NOS1).	[2]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Nitric oxide synthase 1 (NOS1).	[3]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Nitric oxide synthase 1 (NOS1).	[4]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Nitric oxide synthase 1 (NOS1).	[5]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Nitric oxide synthase 1 (NOS1).	[6]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of Nitric oxide synthase 1 (NOS1).	[7]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Nitric oxide synthase 1 (NOS1).	[8]
Rofecoxib	DM3P5DA	Approved	Rofecoxib affects the expression of Nitric oxide synthase 1 (NOS1).	[7]
Cantharidin	DMBP5N3	Approved	Cantharidin decreases the expression of Nitric oxide synthase 1 (NOS1).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Nitric oxide synthase 1 (NOS1).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Nitric oxide synthase 1 (NOS1).	[6]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Nitric oxide synthase 1 (NOS1).	[13]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos affects the expression of Nitric oxide synthase 1 (NOS1).	[14]
EGTA	DMW9MRO	Investigative	EGTA decreases the expression of Nitric oxide synthase 1 (NOS1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nitric oxide synthase 1 (NOS1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Nitric oxide synthase 1 (NOS1).	[12]

References

• [1] Truncating mutation in the nitric oxide synthase 1 gene is associated with infantile achalasia. Gastroenterology. 2015 Mar;148(3):533-536.e4. doi: 10.1053/j.gastro.2014.11.044. Epub 2014 Dec 3.
• [2] T cell activation-induced mitochondrial hyperpolarization is mediated by Ca2+- and redox-dependent production of nitric oxide. J Immunol. 2003 Nov 15;171(10):5188-97.
• [3] Testosterone and resistance training effects on muscle nitric oxide synthase isoforms in COPD men. Respir Med. 2012 Feb;106(2):269-75.
• [4] Increasing intratumor C/EBP- LIP and nitric oxide levels overcome resistance to doxorubicin in triple negative breast cancer. J Exp Clin Cancer Res. 2018 Nov 27;37(1):286. doi: 10.1186/s13046-018-0967-0.
• [5] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [6] Apoptosis induced by capsaicin and resveratrol in colon carcinoma cells requires nitric oxide production and caspase activation. Anticancer Res. 2009 Oct;29(10):3733-40.
• [7] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [8] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [9] Hepatoxicity mechanism of cantharidin-induced liver LO2 cells by LC-MS metabolomics combined traditional approaches. Toxicol Lett. 2020 Oct 15;333:49-61. doi: 10.1016/j.toxlet.2020.07.024. Epub 2020 Jul 26.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Mitochondria are an essential mediator of nitric oxide/cyclic guanosine 3',5'-monophosphate blocking of glucose depletion induced cytotoxicity in human HepG2 cells. Mol Cancer Res. 2007 Sep;5(9):923-32.
• [14] Angiogenesis signaling in breast cancer models is induced by hexachlorobenzene and chlorpyrifos, pesticide ligands of the aryl hydrocarbon receptor. Toxicol Appl Pharmacol. 2020 Aug 15;401:115093. doi: 10.1016/j.taap.2020.115093. Epub 2020 Jun 8.
• [15] Involvement of the nitric oxide/protein kinase G pathway in polychlorinated biphenyl-induced cell death in SH-SY 5Y neuroblastoma cells. J Neurosci Res. 2006 Aug 15;84(3):692-7.
• [16] The food-associated ribotoxin deoxynivalenol modulates inducible NO synthase in human intestinal cell model. Toxicol Sci. 2015 Jun;145(2):372-82.
• [17] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.