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NOS2

gene
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Also known as iNOSNOSHEP-NOS

Summary

NOS2 (nitric oxide synthase 2, HGNC:7873) is a protein-coding gene on chromosome 17q11.2, encoding Nitric oxide synthase, inducible (P35228). Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body.

Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. This gene encodes a nitric oxide synthase which is expressed in liver and is inducible by a combination of lipopolysaccharide and certain cytokines. Three related pseudogenes are located within the Smith-Magenis syndrome region on chromosome 17.

Source: NCBI Gene 4843 — RefSeq curated summary.

At a glance

  • Gene–disease (curated): schizophrenia (No Known Disease Relationship, GenCC)
  • Clinical variants (ClinVar): 213 total
  • GTEx eGene: eQTL in 43 tissues, sQTL in 3 (q < 0.05)
  • Drug target: yes — 2 curated mechanism-of-action drugs, 1 via a complex or family; 10 molecules with ChEMBL bioactivity (top 3% of genes corpus-wide)
  • Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.86 (unconstrained)
  • MANE Select transcript: NM_000625
  • Interaction hub: 2,454 STRING partners (top 4% of genes corpus-wide)
  • Notable: 213 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:7873
Approved symbolNOS2
Namenitric oxide synthase 2
Location17q11.2
Locus typegene with protein product
StatusApproved
AliasesiNOS, NOS, HEP-NOS
Ensembl geneENSG00000007171
Ensembl biotypeprotein_coding
OMIM163730
Entrez4843

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron

MANE Select: ENST00000313735

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000313735, ENST00000646938, ENST00000697337, ENST00000697338, ENST00000697339, ENST00000697340, ENST00000697341, ENST00000886820, ENST00001139812

RefSeq mRNA: 1 — MANE Select: NM_000625 NM_000625

CCDS: CCDS11223

Canonical transcript exons

ENST00000313735 — 27 exons

ExonStartEnd
ENSE000004066972776953527769584
ENSE000007045072777316127773243
ENSE000007048412777869027778791
ENSE000007051572778201527782106
ENSE000009463942777091327771017
ENSE000011268852776553527765716
ENSE000011269382777888227779056
ENSE000011269542778103627781177
ENSE000012516042776398127764144
ENSE000012517892778076727780906
ENSE000012928302776279827763005
ENSE000013029922779870027798882
ENSE000013041872776114427761231
ENSE000013097812776897727769151
ENSE000013109332776651027766588
ENSE000013109532778880927788931
ENSE000013120032777425727774451
ENSE000013123002778294427783106
ENSE000013220032775888127759075
ENSE000013272912778960427789688
ENSE000013274572777230827772452
ENSE000013477432776770527767837
ENSE000013479462778767827787826
ENSE000017040852775676627757353
ENSE000018422632780033927800529
ENSE000023346912776003027760178
ENSE000024111042776062327760744

Expression profiles

Bgee: expression breadth ubiquitous, 153 present calls, max score 94.55.

FANTOM5 (CAGE): breadth broad, TPM avg 8.9028 / max 1337.0827, expressed in 242 samples.

Highest expression (Bgee): cartilage tissue, olfactory segment of nasal mucosa, mucosa of paranasal sinus, mucosa of transverse colon, rectum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

NOS2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 43 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 46 significant tissue × QTL associations:

TissueQTLq-valueSlopeLead variant
Nerve Tibialeqtl7.7e-167-1.0717:27879388:C:A
Skin Sun Exposed Lower legeqtl2.0e-125-1.0917:27879388:C:A
Skin Not Sun Exposed Suprapubiceqtl1.9e-84-1.0417:27879388:C:A
Artery Tibialeqtl2.7e-79-0.8717:27879388:C:A
Esophagus Musculariseqtl8.2e-79-1.0117:27879388:C:A
Adipose Subcutaneouseqtl1.4e-72-0.8217:27879388:C:A
Esophagus Gastroesophageal Junctioneqtl6.0e-67-0.9917:27879388:C:A
Muscle Skeletaleqtl4.6e-59-0.7217:27879388:C:A
Brain Nucleus accumbens basal gangliaeqtl5.3e-54-0.9717:27879388:C:A
Brain Cerebellar Hemisphereeqtl2.7e-45-0.7617:27879388:C:A
Brain Cerebellumeqtl2.9e-44-0.8217:27879388:C:A
Breast Mammary Tissueeqtl1.5e-42-0.8317:27879388:C:A
Pancreaseqtl8.7e-42-1.0817:27879388:C:A
Brain Putamen basal gangliaeqtl8.2e-41-0.9017:27879388:C:A
Thyroideqtl2.6e-40-0.7517:27879388:C:A
Brain Caudate basal gangliaeqtl1.5e-38-0.8517:27879388:C:A
Brain Hypothalamuseqtl1.6e-33-0.9417:27879388:C:A
Stomacheqtl1.2e-32-0.7817:27879388:C:A
Colon Sigmoideqtl3.5e-31-0.6717:27879388:C:A
Artery Aortaeqtl4.2e-29-0.7017:27895494:G:A

FANTOM5 promoters

5 alternative TSS:

Promoter IDTPM avgSamples expressed
1649648.5358227
1649610.128721
1649600.083217
1649650.078614
1649620.076621

Top tissues by expression

showing 100 of 281 tissues by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
cartilage tissueUBERON:000241894.55gold quality
olfactory segment of nasal mucosaUBERON:000538689.37gold quality
mucosa of paranasal sinusUBERON:000503083.14silver quality
mucosa of transverse colonUBERON:000499178.91gold quality
rectumUBERON:000105278.33gold quality
vermiform appendixUBERON:000115477.76gold quality
male germ line stem cell (sensu Vertebrata) in testisCL:0000089 ∩ UBERON:000047372.81silver quality
caecumUBERON:000115371.55gold quality
prefrontal cortexUBERON:000045169.81gold quality
duodenumUBERON:000211468.57gold quality
right frontal lobeUBERON:000281068.40gold quality
nasal cavity mucosaUBERON:000182668.37gold quality
small intestineUBERON:000210867.13gold quality
small intestine Peyer’s patchUBERON:000345467.03gold quality
transverse colonUBERON:000115766.91gold quality
colonic epitheliumUBERON:000039765.38silver quality
Brodmann (1909) area 9UBERON:001354065.14gold quality
dorsolateral prefrontal cortexUBERON:000983464.91gold quality
frontal cortexUBERON:000187064.53gold quality
parotid glandUBERON:000183164.02gold quality
neocortexUBERON:000195063.13gold quality
Brodmann (1909) area 10UBERON:001354162.90gold quality
jejunal mucosaUBERON:000039962.05gold quality
frontal poleUBERON:000279562.00gold quality
intestineUBERON:000016061.33gold quality
ventricular zoneUBERON:000305360.66gold quality
tendon of biceps brachiiUBERON:000818860.61gold quality
cingulate cortexUBERON:000302760.41gold quality
endometrium epitheliumUBERON:000481160.31gold quality
upper lobe of left lungUBERON:000895260.28gold quality
anterior cingulate cortexUBERON:000983560.14gold quality
buccal mucosa cellCL:000233659.95gold quality
large intestineUBERON:000005959.83gold quality
colonUBERON:000115559.64gold quality
cortical plateUBERON:000534359.45gold quality
cerebral cortexUBERON:000095659.24gold quality
right lungUBERON:000216759.19gold quality
ganglionic eminenceUBERON:000402358.88gold quality
middle frontal gyrusUBERON:000270258.82gold quality
deciduaUBERON:000245058.66gold quality
upper lobe of lungUBERON:000894858.41gold quality
smooth muscle tissueUBERON:000113558.21gold quality
paraflocculusUBERON:000535158.14gold quality
medial globus pallidusUBERON:000247757.65gold quality
lymph nodeUBERON:000002956.72gold quality
telencephalonUBERON:000189356.42gold quality
pancreatic ductal cellCL:000207956.13silver quality
forebrainUBERON:000189055.86gold quality
ileal mucosaUBERON:000033155.78gold quality
adult mammalian kidneyUBERON:000008255.43gold quality
colonic mucosaUBERON:000031755.39gold quality
metanephros cortexUBERON:001053355.19gold quality
brainUBERON:000095555.13gold quality
adenohypophysisUBERON:000219655.02gold quality
central nervous systemUBERON:000101754.95gold quality
amygdalaUBERON:000187654.83gold quality
pituitary glandUBERON:000000754.74gold quality
cerebellar hemisphereUBERON:000224554.61gold quality
cerebellar cortexUBERON:000212954.58gold quality
embryoUBERON:000092254.36gold quality
right hemisphere of cerebellumUBERON:001489054.28gold quality
hindlimb stylopod muscleUBERON:000425254.20gold quality
mucosa of sigmoid colonUBERON:000499354.06gold quality
cerebellar vermisUBERON:000472054.00gold quality
globus pallidusUBERON:000187553.91gold quality
cerebellumUBERON:000203753.90gold quality
primary visual cortexUBERON:000243653.70gold quality
gall bladderUBERON:000211053.49gold quality
lungUBERON:000204853.42gold quality
muscle of legUBERON:000138353.21gold quality
nucleus accumbensUBERON:000188253.04gold quality
tibial nerveUBERON:000132353.00gold quality
muscle organUBERON:000163052.52gold quality
Brodmann (1909) area 46UBERON:000648352.47gold quality
hair follicleUBERON:000207352.43gold quality
jejunumUBERON:000211552.19gold quality
caudate nucleusUBERON:000187352.09gold quality
metanephrosUBERON:000008152.02gold quality
hypothalamusUBERON:000189851.97gold quality
quadriceps femorisUBERON:000137751.94gold quality
deltoidUBERON:000147651.93gold quality
muscle tissueUBERON:000238551.92gold quality
gastrocnemiusUBERON:000138851.91gold quality
putamenUBERON:000187451.83gold quality
cortex of kidneyUBERON:000122551.80gold quality
thymusUBERON:000237051.66silver quality
sigmoid colonUBERON:000115951.55gold quality
kidneyUBERON:000211351.38gold quality
tibial arteryUBERON:000761051.01gold quality
popliteal arteryUBERON:000225050.93gold quality
muscle layer of sigmoid colonUBERON:003580550.89gold quality
placentaUBERON:000198750.85gold quality
vastus lateralisUBERON:000137950.84gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099150.58silver quality
epithelial cell of pancreasCL:000008350.53gold quality
occipital lobeUBERON:000202150.46gold quality
left adrenal gland cortexUBERON:003582550.45gold quality
right coronary arteryUBERON:000162550.32gold quality
skeletal muscle tissueUBERON:000113450.27gold quality
left adrenal glandUBERON:000123450.05gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

ExperimentMarker?Max mean expression
E-ANND-3yes4.03

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 102 HPA tissues / cells by nTPM:

Tissue / cellAxisnTPMProtein (IHC)
Small intestinetissue19.6not detected
Appendixtissue13.8medium
Duodenumtissue11.0low
Rectumtissue8.2medium
Colontissue6.3medium
Urinary bladdertissue3.3not detected
Cerebral cortextissue2.1low
Postcentral gyrustissue2.1
Insular cortextissue2.1
Testistissue1.9high
Prefrontal cortextissue1.7
Basal gangliatissue1.7low
Retrosplenial and cingulate cortextissue1.7
Smooth muscletissue1.6low
Motor cortextissue1.6
Putamentissue1.6
Hippocampal formationtissue1.6
Ventral forebraintissue1.6
Retrosplenial cortextissue1.6
Temporal cortextissue1.6
Entorhinal cortextissue1.5
Amygdalatissue1.4
Septumtissue1.4
Somatosensory cortextissue1.4
Pituitary glandtissue1.3
Occipital cortextissue1.3
Testistissue1.2not detected
Olfactory bulbtissue1.2
Hypothalamustissue1.1
Lungtissue1.1not detected
Corpus callosumtissue0.9
Spinal cordtissue0.8
Periaqueductal graytissue0.8
Ponstissue0.7
Adipose tissuetissue0.7not detected
Medulla oblongatatissue0.7
Superior colliculitissue0.7
Lymph nodetissue0.6not detected
Skeletal muscletissue0.6low
Midbraintissue0.6
Thalamustissue0.6
Substantia nigratissue0.6
Ovarytissue0.5not detected
Tonguetissue0.5
Frontal cortextissue0.5
Nucleus accumbenstissue0.4
Placentatissue0.4not detected
Cerebellumtissue0.4not detected
Thyroid glandtissue0.3not detected
Gallbladdertissue0.3not detected
Kidneytissue0.3low
Locus coeruleustissue0.3
Hippocampustissue0.3not detected
Fallopian tubetissue0.3not detected
Caudate putamentissue0.3
Cerebral cortextissue0.3not detected
Motor cortextissue0.3
Basal gangliatissue0.3not detected
Hippocampal formationtissue0.3
Postcentral gyrustissue0.3

Brain sub-regions (HPA Brain Atlas): detected in 359; highest nTPM — Precentral gyrus (1.8), Precentral gyrus, middle (1.7), Postcentral gyrus, middle (1.6), Subiculum (1.6), Transversal temporal gyrus, anterior (1.4).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting NOS2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 55 miRNAs:

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-5692A100.0074.406850
HSA-MIR-55999.9572.283609
HSA-MIR-548AB99.9571.313488
HSA-MIR-548A-5P99.9471.273482
HSA-MIR-548AD-5P99.9471.233502
HSA-MIR-548AE-5P99.9471.233502
HSA-MIR-548AK99.9471.243488
HSA-MIR-548AM-5P99.9471.243488
HSA-MIR-548AP-5P99.9471.143489
HSA-MIR-548AQ-5P99.9471.343426
HSA-MIR-548AR-5P99.9471.283515
HSA-MIR-548AS-5P99.9471.223482
HSA-MIR-548AU-5P99.9471.243488
HSA-MIR-548AY-5P99.9471.233502
HSA-MIR-548B-5P99.9471.233502
HSA-MIR-548BB-5P99.9471.273509
HSA-MIR-548C-5P99.9471.243488
HSA-MIR-548D-5P99.9471.233502
HSA-MIR-548H-5P99.9471.243488
HSA-MIR-548I99.9471.253481
HSA-MIR-548J-5P99.9471.143489
HSA-MIR-548O-5P99.9471.243488
HSA-MIR-548W99.9471.243488
HSA-MIR-548Y99.9471.283514
HSA-MIR-452599.9464.38675
HSA-MIR-5010-5P99.9464.11705
HSA-MIR-129799.9173.413162
HSA-MIR-60999.8264.26505
HSA-MIR-34B-5P99.7867.561175
HSA-MIR-449C-5P99.7867.631168

Functional genomics

gnomAD constraint: pLI 2.06e-22, LOEUF 0.858, missense Z 2.17 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000313735 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)Missense obs / expo/eConstrained
17:27,757,249–27,774,380782 / 909.90.86no
17:27,774,381–27,778,71515 / 41.60.36no
17:27,778,716–27,798,809440 / 545.40.81no

Literature-anchored findings (GeneRIF, showing 40)

  • The specific NOS2 inhibitor, 1400W, sensitizes HepG2 cells to genotoxic, oxidative, xenobiotic, and endoplasmic reticulum stresses (PMID:11761338)
  • Inos enzyme overexpressioin is an early event in esophageal carcinogenesis and useful biomarkers for early detection. (PMID:11783017)
  • Human renal epithelial cells express iNOS in response to cytokines but not bacteria (PMID:11849384)
  • The human alveolar type II epithelium-like cell line A549 expresses nitric oxide synthase type 2 (NOS2) (PMID:11880293)
  • Immunohistochemical expression of iNOS in colorectal carcinoma (PMID:11956620)
  • Increased expression of iNOS may be responsible for gastric carcinogenesis and tumor aggressiveness of gastric cancer and correlates significantly with lymph node metastasis in northern China. (PMID:11978184)
  • demonstrated that the iNOS gene was actively transcribed in cutaneous leishmaniasis lesions (PMID:11985871)
  • Inducible nitric oxide synthase is expressed in normal human melanocytes but not in melanoma cells (PMID:12060397)
  • epithelial iNOS binds to EPB50 which directs vectorial nitric oxide output (PMID:12080081)
  • allelic polymorphism of the inducible nitric oxide synthase (iNOS) gene associated with retinopathy in an Asian Indian population (PMID:12081717)
  • enzyme expressed in septic patients is nitrated on selected tyrosine residues; implications for enzymic activity (PMID:12097137)
  • expression of inducible nitric oxide synthase in skin lesions of patients with cutaneous leishmaniasis (PMID:12117977)
  • Data show that prostacyclin receptor mediated increases in cAMP play a role in enhancing LPS/IFN-gamma-induced iNOS expression in human monocytes/macrophages and may contribute to the increased production of NO during peritonitis. (PMID:12119468)
  • expression is increased in malaria, thus producing more nitric oxide (PMID:12125143)
  • inducible nitric oxide synthase promoter polymorphism in rheumatoid arthritis (PMID:12140750)
  • iNOS is induced by HIV-1 tat in astrocytes and may play a role in HIV-associated dementia (PMID:12167619)
  • expressions of iNOS and VEGF may serve as indexes for evaluating staging of gastric carcinoma and forecasting its risk of metastasis (PMID:12174362)
  • iNOS is subject to ubiquitination and ubiquitination is required for its degradation. (PMID:12221289)
  • EGF protects against oxidative disruption of the intestinal barrier by stabilizing the cytoskeleton in large part through the activation of PKC-zeta and downregulation of iNOS (PMID:12223351)
  • These results suggest that IL-15 is a potent regulator of iNOS expression by HGEC and involved in innate immunity in the mucosal epithelium. (PMID:12237122)
  • Data demonstrate that the PI3-kinase signaling pathway is involved in basal trophoblast motility and that both mitogen-activated protein kinase and PI3-kinase signaling pathways are important in HGF-stimulated motility and iNOS expression. (PMID:12243747)
  • Synovial fluid leucocytes, in particular granulocytes, express iNOS and may thus contribute to intra-articular NO production in arthritis. (PMID:12296866)
  • iNOS may not correlate with cancer cell-proliferative activity or apoptosis (PMID:12374680)
  • role of NF-kappa B-repressing factor (NRF) in basal repression of the hiNOS gene (PMID:12381793)
  • strong upregulation of iNOS might contribute to inflammatory processes in fulminant hepatic failure (PMID:12399227)
  • Activation might be associated with malignant potential of epithelial odontogenic tumors (PMID:12406306)
  • Association analysis of five polymorphic microsatellite markers in cluster headache (CH) patients reveals that genetic variations in NOS2A do not contribute greatly to CH susceptibility. (PMID:12421162)
  • hepatic inducible nitric oxide synthase staining was significantly more intense in patients with chronic viral hepatitis; these results suggest that inducible nitric oxide synthase may have a critical role in the pathogenesis of chronic viral hepatitis (PMID:12431203)
  • NOS2 promoter -1173 C–>T single nucleotide polymorphism is associated with protection against cerebral malaria and severe malarial anaemia (PMID:12433515)
  • Increased intrahepatic iNOS expression and nitrotyrosine accumulation in biliary cirrhosis and autoimmune hepatitis, related to histological severity of liver disease. (PMID:12445411)
  • nitric oxide synthases(inducible, brain and endothelial) were expressed in human pregnant term uterus and did not change in the myometrium during labor (PMID:12445599)
  • A positive correlation was found between the positive expression of iNOS mRNA and invasive growth as well as neck lymph node metastatsis of squamous cell carcinoma of tongue. (PMID:12452003)
  • Data show that nitric oxide produced by inducible nitric oxide synthase (iNOS) increases the activity of cyclooxygenase-2 (COX-2) pathways in head and neck squamous cell carcinomas, and this effect is probably mediated by endocellular cGMP. (PMID:12459168)
  • inducible nitric oxide synthase-cyclooxygenase 2 interactions are involved in tumor cell angiogenesis and migration (PMID:12462194)
  • Upregulation of iNOS in myelodysplastic syndromes has no significant correlation with apoptosis. (PMID:12486325)
  • Immunolocalization of inducible nitric oxide synthase in gingiva in localized juvenile periodontitis patients. iNOS in gingivitis. Macrophages expressed high levels of iNOS. (PMID:12489192)
  • Altered genetic control of NOS2 transcription may be a risk factor for SLE among African-American females. (PMID:12508391)
  • study demonstrate that expression of the MDA-7 tumor suppressor can negatively regulate iNOS expression in malignant melanoma cell lines (PMID:12533668)
  • A single haplotype, uniquely defined by the NOS2A-1659T allele, was associated with cerebral malaria by a transmission disequilibrium . (PMID:12552317)
  • upregulation of hepatic iNOS, associated with peroxisomal localization, is an early molecular early molecular response to hemorrhagic shock (PMID:12578118)

Cross-species orthologs

5 orthologs

OrganismSymbolGene ID
danio_rerionos2aENSDARG00000026925
danio_rerionos2bENSDARG00000031976
mus_musculusNos2ENSMUSG00000020826
rattus_norvegicusNos2ENSRNOG00000057443
rattus_norvegicusNos2-ps1ENSRNOG00000078225

Paralogs (5): NOS1 (ENSG00000089250), MTRR (ENSG00000124275), POR (ENSG00000127948), NOS3 (ENSG00000164867), NDOR1 (ENSG00000188566)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97361) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 153 distinct phenotype terms.

Mouse phenotype (MP)Records
hyperglycemia3
abnormal glucose homeostasis3
increased circulating creatinine level3
increased body weight2
increased circulating triglyceride level2
decreased inflammatory response2
increased susceptibility to bacterial infection2
abnormal osteoclast morphology2
abnormal heart ventricle morphology2
increased T cell proliferation2
increased interferon-gamma secretion2
decreased susceptibility to endotoxin shock2
abnormal blood homeostasis2
abnormal trabecular bone morphology1
abnormal circulating glucose level1
abnormal circulating serum albumin level1
abnormal systemic arterial blood pressure1
abnormal heart morphology1
decreased digestive secretion1
abnormal immune system morphology1
abnormal corpus callosum morphology1
abnormal uterus morphology1
abnormal testis morphology1
abnormal eating behavior1
abnormal sleep pattern1

+128 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

OrganismUniProtIdentityMethod
Escherichia coli APEC O1A1AEV0100.0%Diamond
Yersinia pestis Pestoides FA4TPY5100.0%Diamond
Escherichia coli O139:H28 str. E24377AA7ZQK7100.0%Diamond
Escherichia coli ATCC 8739B1IU77100.0%Diamond
Staphylococcus aureusP0A004100.0%Diamond
Staphylococcus aureus subsp. aureus Mu50P0A092100.0%Diamond
Staphylococcus aureus subsp. aureus N315P0A093100.0%Diamond
Staphylococcus aureus subsp. aureus MW2P0A094100.0%Diamond
Shigella flexneri 5 str. 8401Q0T1I8100.0%Diamond
Escherichia coli 536Q0TEA2100.0%Diamond
Yersinia pestis AntiquaQ1C3Z0100.0%Diamond
Yersinia pestis Nepal516Q1CLS8100.0%Diamond
Escherichia coli UTI89Q1R7T4100.0%Diamond
Staphylococcus aureus subsp. aureus COLQ5HEK7100.0%Diamond
Staphylococcus aureus subsp. aureus MSSA476Q6G818100.0%Diamond
Shigella flexneriQ83QD9100.0%Diamond
Yersinia pestisQ8ZBN6100.0%Diamond
Escherichia coli K-12P3803899.8%Diamond
Shigella boydii Sb227Q31XM499.8%Diamond
Escherichia coli CFT073Q8FEI799.8%Diamond
Vibrio cholerae O395A5F3I499.7%Diamond
Yersinia pseudotuberculosis IP 31758A7FLZ099.7%Diamond
Shigella sonnei Ss046Q3YY9499.7%Diamond
Vibrio cholerae O1 biovar El Tor str. N16961Q9KUX499.7%Diamond
Escherichia coli HSA8A3P599.3%Diamond
Escherichia coli O157:H7Q8X7U199.3%Diamond
Shigella dysenteriae Sd197Q32CG399.0%Diamond
Yersinia pseudotuberculosis IP 32953Q66ED498.9%Diamond
Staphylococcus aureus subsp. aureus MRSA252Q6GFE298.6%Diamond
Salmonella enterica subsp. enterica serovar Paratyphi B str. SPB7A9N2E698.5%Diamond
Salmonella enterica subsp. enterica serovar Typhimurium str. LT2P3803998.5%Diamond
Shewanella sp. MR-4Q0HFL698.5%Diamond
Shewanella sp. MR-7Q0HYB498.5%Diamond
Neisseria meningitidis 053442A9LZ7398.3%Diamond
Neisseria meningitidis Z2491Q9JUD898.3%Diamond
Shewanella sp. ANA-3A0KTH498.2%Diamond
Neisseria meningitidis FAM18A1KU0698.0%Diamond
Salmonella enterica subsp. enterica serovar Paratyphi A str. ATCC 9150Q5PEH797.8%Diamond
Salmonella enterica subsp. enterica serovar TyphiQ8Z45897.8%Diamond
Bos taurusQ2799597.0%Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

SymbolTypeEntrez
LYRM9protein-coding201229
LINC01992ncRNA105371708

Protein

Protein identifiers

Nitric oxide synthase, inducible — P35228 (reviewed: P35228)

Alternative names: Hepatocyte NOS, Inducible NO synthase, NOS type II, Peptidyl-cysteine S-nitrosylase NOS2

All UniProt accessions (6): P35228, A0A2R8YDS4, A0A8V8TKX9, A0A8V8TKZ7, A0A8V8TLB1, A0A8V8TMI7

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Homodimer. Interacts with NHERF1. Interacts with GAPDH; induced by oxidatively-modified low-densitity lipoprotein (LDL(ox)). Interacts with S100A8 and S100A9 to form the iNOS-S100A8/9 transnitrosylase complex. Interacts with SPSB1, SPSB2 and SPSB4. Interacts with ELOC and CUL5 in the presence of SPSB1 or SPSB2 or SPSB4. Forms a complex with ASL, ASS1 and HSP90AA1; the complex regulates cell-autonomous L-arginine synthesis and citrulline recycling while channeling extracellular L-arginine to nitric oxide synthesis pathway.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Expressed in the liver, retina, bone cells and airway epithelial cells of the lung. Not expressed in the platelets. Expressed in chondrocytes.

Post-translational modifications. Polyubiquitinated; mediated by SPSB1, SPSB2 and SPSB4, leading to proteasomal degradation.

Activity regulation. Regulated by calcium/calmodulin. Aspirin inhibits expression and function of this enzyme and effects may be exerted at the level of translational/post-translational modification and directly on the catalytic activity.

Cofactor. Binds 1 FAD. Binds 1 FMN. Tetrahydrobiopterin (BH4). May stabilize the dimeric form of the enzyme.

Induction. By endotoxins and cytokines. Induced by IFNG/IFN-gamma acting synergistically with bacterial lipopolysaccharides (LPS), TNF or IL1B/interleukin-1 beta. Down-regulated by zinc due to inhibition of NF-kappa-B transactivation activity. By oxidatively-modified low-densitity lipoprotein (LDL(ox)).

Polymorphism. Genetic variations in NOS2 are involved in resistance to malaria [MIM:611162].

Similarity. Belongs to the NOS family.

Isoforms (2)

UniProt IDNamesCanonical?
P35228-11yes
P35228-22

RefSeq proteins (1): NP_000616* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR001094Flavdoxin-likeDomain
IPR001433OxRdtase_FAD/NAD-bdDomain
IPR001709Flavoprot_Pyr_Nucl_cyt_RdtaseDomain
IPR003097CysJ-like_FAD-bindingDomain
IPR004030NOS_NDomain
IPR008254Flavodoxin/NO_synthDomain
IPR012144NOS_eukFamily
IPR017927FAD-bd_FR_typeDomain
IPR017938Riboflavin_synthase-like_b-brlHomologous_superfamily
IPR023173NADPH_Cyt_P450_Rdtase_alphaHomologous_superfamily
IPR029039Flavoprotein-like_sfHomologous_superfamily
IPR036119NOS_N_sfHomologous_superfamily
IPR039261FNR_nucleotide-bdHomologous_superfamily
IPR044940NOS_dom_2Homologous_superfamily
IPR044943NOS_dom_1Homologous_superfamily
IPR044944NOS_dom_3Homologous_superfamily
IPR050607NOSFamily

Pfam: PF00175, PF00258, PF00667, PF02898

Enzyme classification (BRENDA)

  • EC 1.14.13.39 — nitric-oxide synthase (NADPH) (BRENDA: 31 organisms, 140 substrates, 179 inhibitors, 88 Km, 25 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

SubstrateKm (mM)Measurements
L-ARGININE0.0019–68.528
NADPH0.0003–0.00419
TETRAHYDROBIOPTERIN—6
ADRIAMYCIN0.012–0.0785
MENADIONE0.01–0.0415
MITOMYCIN C0.0073–0.0555
NGAMMA-HYDROXY-L-ARGININE0.019–0.1295
2’,3’-DIALDEHYDE-NADPH0.00081
CALMODULIN—1
NITROBLUE TETRAZOLIUM0.0161
NITRIC OXIDE—0

Catalyzed reactions (Rhea)

  • 2 L-arginine + 3 NADPH + 4 O2 + H(+) = 2 L-citrulline + 2 nitric oxide + 3 NADP(+) + 4 H2O (RHEA:19897)

UniProt features (143 total): binding site 45, helix 36, strand 26, sequence conflict 15, sequence variant 5, turn 4, modified residue 4, domain 2, splice variant 2, chain 1, region of interest 1, short sequence motif 1, mutagenesis site 1

Structure

Experimental structures (PDB)

13 structures by resolution:

PDBTitleMethodResolution (Å)
6JWMCrystal structure of the SPRY domain of SPSB2 in complex with cR7, a potent cyclic …X-RAY DIFFRACTION1.23
6KEYStructural basis for the regulation of inducible nitric oxide synthase (iNOS) by the SPRY …X-RAY DIFFRACTION1.24
5XN3Crystal structure of SPSB2 in complex with a rational designed RGD containing cyclic …X-RAY DIFFRACTION1.34
6JWNCrystal structure of the SPRY domain of SPSB2 in complex with cR9, a cyclic peptide …X-RAY DIFFRACTION1.61
3E7GStructure of human INOSOX with inhibitor AR-C95791X-RAY DIFFRACTION2.2
4NOSHUMAN INDUCIBLE NITRIC OXIDE SYNTHASE WITH INHIBITORX-RAY DIFFRACTION2.25
3HR4Human iNOS Reductase and Calmodulin ComplexX-RAY DIFFRACTION2.5
1NSIHUMAN INDUCIBLE NITRIC OXIDE SYNTHASE, ZN-BOUND, L-ARG COMPLEXX-RAY DIFFRACTION2.55
3EJ8Structure of double mutant of human iNOS oxygenase domain with bound immidazoleX-RAY DIFFRACTION2.55
2NSIHUMAN INDUCIBLE NITRIC OXIDE SYNTHASE, ZN-FREE, SEITU COMPLEXX-RAY DIFFRACTION3
4CX7Structure of human iNOS heme domain in complex with (R)-6-(3-AMINO-2-(5-(2-(6-AMINO-4- …X-RAY DIFFRACTION3.16
2LL6Solution NMR structure of CaM bound to iNOS CaM binding domain peptideSOLUTION NMR
5TP6Solution structure of the CaM34 with the iNOS CaM binding domain peptideSOLUTION NMR

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-P35228-F185.660.66

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Oxidoreductases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, FDA approved drug targets, Small molecule drugs, Human disease related genes

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (45)

PositionRole
372L-arginine
373L-arginine
377L-arginine
381(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
462(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
463(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
476(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
491heme b
545FMN
546FMN
547FMN
549FMN
550FMN
591FMN
592FMN
628FMN
633FMN
635FMN
661FMN
665FMN
750NADP(+)
772FAD
906FAD
908FAD
909FAD
924FAD
926FAD
929NADP(+)
930FAD
943FAD
944FAD
945FAD
984NADP(+)
1017NADP(+)
1046NADP(+)
1047NADP(+)
1053NADP(+)
1055NADP(+)
1057NADP(+)
1090NADP(+)
110Zn(2+)
115Zn(2+)
118(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
200heme b
263L-arginine

Post-translational modifications (4)

TypePositions
Phosphoserine234, 578, 892
Phosphotyrosine575

Mutagenesis-validated functional residues (1)

PositionPhenotype
27loss of interaction with spsb1 and spsb4.

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 18; 7 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

18 pathways:

IDPathwayEvidence
R-HSA-9636249Inhibition of nitric oxide production ⚕curated
R-HSA-6785807Interleukin-4 and Interleukin-13 signalingcurated
R-HSA-392154Nitric oxide stimulates guanylate cyclasecurated
R-HSA-1222556ROS and RNS production in phagocytescurated
R-HSA-9824439Bacterial Infection Pathways ⚕—
R-HSA-1643685Disease ⚕—
R-HSA-9635486Infection with Mycobacterium tuberculosis ⚕—
R-HSA-5663205Infectious disease ⚕—
R-HSA-9637690Response of Mtb to phagocytosis ⚕—
R-HSA-9637687Suppression of phagosomal maturation ⚕—
R-HSA-1280215Cytokine Signaling in Immune system—
R-HSA-109582Hemostasis—
R-HSA-168256Immune System—
R-HSA-168249Innate Immune System—
R-HSA-9033241Peroxisomal protein importelectronic
R-HSA-418346Platelet homeostasis—
R-HSA-9609507Protein localization—
R-HSA-449147Signaling by Interleukins—

MSigDB gene sets: 351 (showing top): GOBP_CIRCADIAN_RHYTHM, LEE_NEURAL_CREST_STEM_CELL_DN, MORF_FLT1, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_BLOOD_PRESSURE, MORF_MSH3, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS

GO Biological Process (24): positive regulation of leukocyte mediated cytotoxicity (GO:0001912), innate immune response in mucosa (GO:0002227), L-arginine catabolic process (GO:0006527), superoxide metabolic process (GO:0006801), nitric oxide biosynthetic process (GO:0006809), inflammatory response (GO:0006954), circadian rhythm (GO:0007623), response to bacterium (GO:0009617), response to hormone (GO:0009725), negative regulation of gene expression (GO:0010629), peptidyl-cysteine S-nitrosylation (GO:0018119), prostaglandin secretion (GO:0032310), response to lipopolysaccharide (GO:0032496), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), Fc-gamma receptor signaling pathway involved in phagocytosis (GO:0038096), negative regulation of protein catabolic process (GO:0042177), defense response to bacterium (GO:0042742), regulation of cellular respiration (GO:0043457), cell redox homeostasis (GO:0045454), negative regulation of blood pressure (GO:0045776), regulation of insulin secretion (GO:0050796), defense response to Gram-negative bacterium (GO:0050829), regulation of cytokine production involved in inflammatory response (GO:1900015)

GO Molecular Function (12): nitric-oxide synthase activity (GO:0004517), calmodulin binding (GO:0005516), FMN binding (GO:0010181), heme binding (GO:0020037), tetrahydrobiopterin binding (GO:0034617), arginine binding (GO:0034618), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), flavin adenine dinucleotide binding (GO:0050660), NADP binding (GO:0050661), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (9): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), peroxisome (GO:0005777), peroxisomal matrix (GO:0005782), cytosol (GO:0005829), plasma membrane (GO:0005886), cortical cytoskeleton (GO:0030863), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

13 top-level categories:

CategoryPathways
Immune System2
Innate Immune System1
Platelet homeostasis1
Signaling by Interleukins1
Protein localization1
Suppression of phagosomal maturation1
Hemostasis1
Cytokine Signaling in Immune system1
Disease1
Bacterial Infection Pathways1
Response of Mtb to phagocytosis1
Infection with Mycobacterium tuberculosis1
Infectious disease1

GO top-level categories

showing 60 of 70 GO namespaces:

CategoryTerms
cellular anatomical structure4
defense response2
positive regulation of cytokine production2
anion binding2
binding2
cation binding2
cytoplasm2
leukocyte mediated cytotoxicity1
regulation of leukocyte mediated cytotoxicity1
positive regulation of leukocyte mediated immunity1
positive regulation of cell killing1
mucosal immune response1
innate immune response1
arginine metabolic process1
amino acid catabolic process1
proteinogenic amino acid catabolic process1
reactive oxygen species metabolic process1
biosynthetic process1
nitric oxide metabolic process1
rhythmic process1
response to other organism1
response to endogenous stimulus1
response to chemical1
gene expression1
regulation of gene expression1
negative regulation of macromolecule biosynthetic process1
protein nitrosylation1
prostaglandin transport1
signal release1
icosanoid secretion1
lipid export from cell1
response to molecule of bacterial origin1
response to lipid1
response to oxygen-containing compound1
interleukin-6 production1
regulation of interleukin-6 production1
interleukin-8 production1
regulation of interleukin-8 production1
Fc receptor mediated stimulatory signaling pathway1
phagocytosis1
Fc-gamma receptor signaling pathway1
negative regulation of catabolic process1
protein catabolic process1
regulation of protein catabolic process1
negative regulation of protein metabolic process1
response to bacterium1
regulation of generation of precursor metabolites and energy1
cellular respiration1
cellular homeostasis1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen1
protein binding1
ribonucleotide binding1
tetrapyrrole binding1
amino acid binding1
carboxylic acid binding1
identical protein binding1
protein dimerization activity1
nucleotide binding1
adenyl nucleotide binding1
catalytic activity1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 14 of 46 annotations. The rest are phylogenetic / computational / electronic (IEA).

14 experimentally-supported GO terms:

GO termNSEvidence
Fc-gamma receptor signaling pathway involved in phagocytosisBPmutant phenotype
L-arginine catabolic processBPdirect assay
defense response to bacteriumBPmutant phenotype
negative regulation of gene expressionBPgenetic interaction
nitric oxide biosynthetic processBPdirect assay
positive regulation of interleukin-6 productionBPdirect assay
positive regulation of interleukin-8 productionBPdirect assay
prostaglandin secretionBPdirect assay
regulation of cytokine production involved in inflammatory responseBPdirect assay
regulation of insulin secretionBPmutant phenotype
cytoplasmCCdirect assay
cytosolCCmutant phenotype
peroxisomeCCdirect assay
nitric-oxide synthase activityMFdirect assay

Protein interactions and networks

STRING

showing 15 of 2,454 interactions by confidence (×1000):

Protein AProtein BPartner UniProtScore
NOS2IL1BP01584867
NOS2PTGS2P35354857
NOS2IFNGP01579848
NOS2TNFP01375848
NOS2ARG1P05089814
NOS2IL6P05231802
NOS2TLR4O00206743
NOS2IL10P22301743
NOS2NFKB1P19838692
NOS2ARG2P78540679
NOS2IL4P05112671
NOS2TLR2O60603670
NOS2IL1AP01583660
NOS2MRC1P22897648
NOS2EDN1P05305644

IntAct

Human interaction partners of NOS2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

4 partners by confidence:

PartnerInteraction typeMIscoreRecords
GAPDHphysical association0.5007
S100A8association0.4602
ADRM1physical association0.4001
UCHL5physical association0.4001

BioGRID (224 interactions; top human partners by supporting records): SPSB2 (Biochemical Activity; 13 records), SPSB1 (Affinity Capture-Western; 7 records), CALM1 (Reconstituted Complex; 5 records), FBXO45 (Affinity Capture-MS; 3 records), HSP90AA1 (Affinity Capture-MS; 3 records), RAC2 (Affinity Capture-Western; 3 records), SPSB4 (Affinity Capture-Western; 3 records), CAV1 (Co-fractionation; 2 records), CUL5 (Affinity Capture-Western; 2 records), TCEB1 (Affinity Capture-Western; 2 records), UCHL5 (Affinity Capture-Western; 2 records), ACAA1 (FRET), AGR2 (Affinity Capture-MS), AIFM1 (Affinity Capture-MS), AKR1B10 (Affinity Capture-MS)

SIGNOR signaling

9 signaling interactions:

AEffectBMechanism
PRKAA1down-regulatesNOS2
MAPK3up-regulatesNOS2phosphorylation
SRCup-regulatesNOS2phosphorylation
STAT1“up-regulates quantity by expression”NOS2“transcriptional regulation”
NfKb-p65/p50“up-regulates quantity by expression”NOS2“transcriptional regulation”
NOS2up-regulates“nitric oxide”
NOS2up-regulatesL-citrulline
L-arginineup-regulatesNOS2
NfKb-p65/p50up-regulatesNOS2“transcriptional regulation”

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

ComplexSubunitsMembers
iNOS-S100A8/A9 complex3S100A8, S100A9, NOS2

Disease & clinical

Genetic variants

Variant evidence for NOS2: 213 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

213 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance143
Likely benign40
Benign20

AlphaMissense

2,099 missense substitutions predicted likely pathogenic (of 7,616 scored), across 553 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

ResidueLikely-pathogenic substitutionsMean am_pathogenicityMax am_pathogenicity
M22390.8200.979
F36980.9760.997
D43580.9660.989
F24780.9590.992
D9880.9540.987
D28080.9530.984
H23080.9470.987
D41280.9470.985
F44380.9410.993
D46080.9360.986
H43680.9330.986
H33380.9100.987
D38580.9090.962
N19680.9080.994
F33980.9080.990
H43780.9040.985
F112880.9030.989
N26180.9000.995
F56580.8990.981
D83380.8990.961

HPA cancer prognostics

RNA cancer specificity: Group enriched (Colon Adenocarcinoma, Glioblastoma Multiforme, Lung Squamous Cell Carcinoma, Rectum Adenocarcinoma, Stomach Adenocarcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

CancerPrognosticp-value
Kidney Renal Clear Cell Carcinoma (TCGA)favorable2.97e-06
Kidney Renal Clear Cell Carcinoma (validation)favorable0.000338

Disease associations

OMIM: gene MIM:163730 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

DiseaseClassificationInheritanceRecords
schizophreniaNo Known Disease RelationshipUnknown

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

PanelRating
COVID-19 researchgreen

Mondo (1): schizophrenia (MONDO:0005090)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2096621 (SELECTIVITY GROUP), CHEMBL2111350 (SELECTIVITY GROUP), CHEMBL4481 (SINGLE PROTEIN), CHEMBL4630725 (PROTEIN FAMILY)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the NOS2 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

2 curated-mechanism drugs:

DrugModalityMax phase
GW-274150Small molecule2
KD7040Small molecule2

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes NOS2 — the drug acts on the assembly or class, not necessarily on this subunit alone.

1 drugs via a complex or family:

DrugTarget (ChEMBL)MembersMax phase
TILARGININENitric oxide synthase33

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,049,502 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

10 molecules by phase:

MoleculeNamePhasePatents
CHEMBL1371CHLORZOXAZONE416,875
CHEMBL1485ARGININE3905,111
CHEMBL140CURCUMIN395,185
CHEMBL256147TILARGININE32,046
CHEMBL114551GW-27415021,071
CHEMBL1911882KD704028
CHEMBL1093059BARDOXOLONE2944
CHEMBL7890L-NAME21,196
CHEMBL225304PIMAGEDINE224,594
CHEMBL227744NITROARGININE12,472

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Nitric oxide synthases

Most potent curated ligand interactions (7 total), top 7:

LigandActionAffinityParameter
1400WInhibition8.2pIC50
2-amino-4-methylpyridineInhibition7.4pIC50
PIBTUInhibition7.3pIC50
GW274150Inhibition7.15pIC50
L-NNAInhibition6.17pKi
tilarginineInhibition6.07pKi
NILInhibition5.5pIC50

Binding affinities (BindingDB)

953 measured of 1094 human assays (1178 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

LigandMeasureValuePatent
2-((R)-1-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)pyrrolidin-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamideIC500.12 nM
2-((R)-1-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)pyrrolidin-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamideIC500.13 nM
methyl (3S)-3-{2-[(1,3-benzodioxol-5-ylmethyl)amino]-2-oxoethyl}-4-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperazine-1-carboxylateIC500.24 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(6-fluoropyridin-2-yl)-2-piperazineacetamideIC500.28 nM
2-((R)-1-(2-(1H-imidazol-1-yl)pyrimidin-4-yl)pyrrolidin-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamideIC500.28 nM
N-[2-(1,3-BENZODIOXOL-5-YL)ETHYL]-1-[2-(1H-IMIDAZOL-1-YL)-6-METHYLPYRIMIDIN-4-YL]-D-PROLINAMIDEIC500.29 nM
3-{[(Benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-pyrimidin-4-yl)-piperazine-1-carboxylic acid methyl esterIC500.38 nM
2-((R)-1-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)pyrrolidin-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamideIC500.48 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-methyl-2-piperazineacetamideIC500.48 nM
N-(1,3-benzodioxol-5-ylmethyl)-1-[6-chloro-2-(1H-imidazol-1-yl)-4-pyrimidinyl]-2-piperidineacetamideIC500.49 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(methylsulfonyl)-2-piperazineacetamideIC500.5 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)-4-pyrimidinyl]-2-piperidineacetamideIC500.5 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(phenylcarbonyl)-2-piperazineacetamideIC500.5 nM
N-[(1,3-benzodioxol-5-yl)methyl]-4-[2-(1H-imidazol-1-yl)-4-pyrimidinyl]-3-morpholineacetamideIC500.5 nM
(2R)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-1-(6-ethyl-2-(1H-imidazol-1-yl)pyrimidin-4-yl)pyrrolidine-2-carboxamideIC500.52 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-2-piperazineacetamideIC500.55 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(2-furylmethyl)-2-piperazineacetamideIC500.58 nM
N-(1,3-benzodioxol-5-ylmethyl)-4-(2-furanylcarbonyl)-1-[2-(1H-imidazolyl)-4-pyrimidinyl]-2-piperazineacetamideIC500.67 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(methylsulfonyl)-2-piperazineacetamideIC500.7 nM
2-((R)-4-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-1-isobutyrylpiperazin-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamideIC500.75 nM
1-[2-(1H-imidazol-1-yl)-4-pyrimidinyl]-N-[(4-methoxyphenyl-)methyl]-2-piperidineacetamideIC500.8 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-[(phenylmethoxy)carbonyl]piperazine-2-acetamideIC500.8 nM
N-(1,3-benzodioxol-5-ylmethyl)-1-[2-(1H-imidazol-yl)-4-pyrimidinyl]-4-(phenylamino)carbonyl]-2-piperazineacetamideIC500.87 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(2-furylmethyl)-2-piperazineacetamideIC500.93 nM
N-(1,3-benzodioxol-5-ylmethyl)-1-[2-(1H-imidazol-yl)-4-pyrimidinyl]-4-[[(phenylmethyl)amino]carbonyl]-2-piperazineacetamideIC500.96 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(phenylmethyl)-2-piperazineacetamideIC501 nM
3-[2-[(1,3-benzodioxol-5-ylmethyl)amino]-2-oxoethyl]-4-[2-(1H-imidazolyl)-4-pyrimidinyl]-1-piperazinecarboxylic Acid, 1-methyl ethyl esterIC501 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-[(methylamino)carbonyl]-2-piperazineacetamideIC501 nM
4-(acetyl)-N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-2-piperazineacetamideIC501 nM
N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(3-methylbutyl)-2-piperazineacetamideIC501 nM
CHEMBL106871IC501 nM
N-Benzo[1,3]dioxol-5-ylmethyl-2-[1-(6-chloro-2-imidazol-1-yl-pyrimidin-4-yl)-piperazin-2-yl]-acetamideIC501.1 nM
N-[(1,3-benzodioxol-5-yl)methyl]-4-[(5-dimethylaminonaphthyl)sulfonyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-2-piperazineacetamideIC501.1 nM
3-[2-[(1,3-benzodioxol-5-ylmethyl)amino]-2-oxoethyl]-4-[2-(1H-imidazolyl)-4-pyrimidinyl]-1-piperazinecarboxylic acid, phenyl esterIC501.4 nM
1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-N-[(3,4-dimethoxyphenyl)methyl]-2-piperidineacetamideIC501.5 nM
N-[(1,3-benzodioxol-5-yl)methyl]-4-[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]-1-[(1-methylethyl)carbonyl]-2-piperazineacetamideIC501.9 nM
8a-(imidazole-1-carbonyl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-4a,5,6,6a,7,8,9,10,12,12a-decahydropicene-2-carbonitrileIC502 nMUS-10189791: Pyridyl analogs of 1-(2-cyano-3,12-dioxooleana-1,9(11)dien-28-oyl) imidazole
N-[(1,3-benzodioxol-5-yl)methyl]hexahydro-1-[2-(1H-imidazol-1-yl)-4-pyrimidinyl]-1H-azepine-2-acetamideIC502 nM
N-(1,3-benzodioxol-5-ylmethyl)-1-[2-(1H-imidazol-yl)-4-pyrimidinyl]-4-(phenylsulfonyl)-2-piperazineacetamideIC502.7 nM
N-[(4-fluorophenyl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-2-piperidineacetamideIC503 nM
1-[2-(1H-imidazol-1-yl)-4-pyrimidinyl]-N-[2-(4-methoxyphenyl)ethyl]-2-piperidineacetamideIC503.5 nM
1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-N-[(3-methoxyphenyl-)methyl]-2-piperidineacetamideIC503.7 nM
N-(1,3-benzodioxol-5-ylmethyl)-1-[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]-2-piperidineacetamideIC504.1 nM
4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(4-pyridin-3-ylimidazole-1-carbonyl)-4a,5,6,6a,7,8,9,10,12,12a-decahydropicene-2-carbonitrileIC504.3 nMUS-10189791: Pyridyl analogs of 1-(2-cyano-3,12-dioxooleana-1,9(11)dien-28-oyl) imidazole
2-[2-[(1,3-benzodioxol-5-ylmethyl)amino]-2-oxoethyl]-4-[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]-1-piperazinecarboxylic acid, methyl esterIC505.4 nM
N-[(4-chlorophenyl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-2-piperidineacetamideIC505.7 nM
4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(4-pyridin-2-ylimidazole-1-carbonyl)-4a,5,6,6a,7,8,9,10,12,12a-decahydropicene-2-carbonitrileIC505.8 nMUS-10189791: Pyridyl analogs of 1-(2-cyano-3,12-dioxooleana-1,9(11)dien-28-oyl) imidazole
N-(3-Aminomethyl-phenyl)-furan-2-carboxamidineKI6 nM
N-(3-Aminomethyl-phenyl)-furan-2-carboxamidineKI6.3 nM
N-[(1,3-benzodioxol-5-yl)methyl]-4-[2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl]-1-(methylcarbonyl)-2-piperazineacetamideIC508.5 nM

ChEMBL bioactivities

966 potent at pChembl≥5 of 1253 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
9.92IC500.12nMCHEMBL220632
9.89IC500.13nMCHEMBL220880
9.70IC500.2nMBARDOXOLONE
9.62IC500.24nMCHEMBL385324
9.55IC500.28nMCHEMBL385325
9.55IC500.28nMCHEMBL376733
9.54IC500.29nMCHEMBL376632
9.42IC500.38nMCHEMBL290548
9.32IC500.48nMCHEMBL373623
9.32IC500.48nMCHEMBL427062
9.31IC500.49nMCHEMBL223788
9.30IC500.5nMCHEMBL376713
9.30IC500.5nMCHEMBL385334
9.30IC500.5nMCHEMBL220932
9.30IC500.5nMCHEMBL442041
9.28IC500.52nMCHEMBL221208
9.26IC500.55nMCHEMBL411343
9.24IC500.58nMCHEMBL424928
9.22IC500.6nMCHEMBL290548
9.17IC500.67nMCHEMBL223782
9.15IC500.7nMCHEMBL373881
9.12IC500.75nMCHEMBL222362
9.10IC500.8nMCHEMBL223792
9.10IC500.8nMCHEMBL374681
9.06IC500.87nMCHEMBL374319
9.03IC500.93nMCHEMBL222364
9.02IC500.96nMCHEMBL223791
9.00IC501nMCHEMBL374132
9.00IC501nMCHEMBL220834
9.00IC501nMCHEMBL375404
9.00IC501nMCHEMBL223384
9.00IC501nMCHEMBL223634
8.96IC501.1nMCHEMBL440473
8.96IC501.1nMCHEMBL223838
8.85IC501.4nMCHEMBL223385
8.82IC501.5nMCHEMBL220121
8.74Ki1.8nMCHEMBL1800346
8.74IC501.8nMTILARGININE
8.73Ki1.862nMCHEMBL1800346
8.72IC501.9nMCHEMBL220771
8.70IC502nMCHEMBL223442
8.70EC502nMCHEMBL489724
8.70Ki2nMCHEMBL105792
8.70IC502nMCHEMBL5947337
8.70IC502nMCHEMBL354788
8.66Ki2.2nMCHEMBL290548
8.57IC502.7nMCHEMBL220156
8.52IC503nMCHEMBL436535
8.52EC503nMCHEMBL491923
8.52EC503nMCHEMBL492090

PubChem BioAssay actives

865 with measured affinity, of 1588 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
N-(1,3-benzodioxol-5-ylmethyl)-2-[(2R)-1-(6-ethyl-2-imidazol-1-ylpyrimidin-4-yl)pyrrolidin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0001uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[(2R)-1-(2-imidazol-1-yl-6-methylpyrimidin-4-yl)pyrrolidin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0001uM
methyl (3S)-3-[2-(1,3-benzodioxol-5-ylmethylamino)-2-oxoethyl]-4-(2-imidazol-1-ylpyrimidin-4-yl)piperazine-1-carboxylate280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0002uM
(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,7,8,8a,14a,14b-decahydropicene-4a-carboxylic acid241425: Inhibition of inducible nitric oxide synthase in activated macrophagesic500.0002uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[4-(6-fluoro-2-pyridinyl)-1-(2-imidazol-1-ylpyrimidin-4-yl)piperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0003uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[(2R)-1-(2-imidazol-1-ylpyrimidin-4-yl)pyrrolidin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0003uM
(2R)-N-[2-(1,3-benzodioxol-5-yl)ethyl]-1-(2-imidazol-1-yl-6-methylpyrimidin-4-yl)pyrrolidine-2-carboxamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0003uM
methyl 3-[2-(1,3-benzodioxol-5-ylmethylamino)-2-oxoethyl]-4-(2-imidazol-1-ylpyrimidin-4-yl)piperazine-1-carboxylate280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0004uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[4-benzoyl-1-(2-imidazol-1-ylpyrimidin-4-yl)piperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0005uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[1-(2-imidazol-1-ylpyrimidin-4-yl)-4-(2-phenylmethoxyacetyl)piperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0005uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[1-(6-chloro-2-imidazol-1-ylpyrimidin-4-yl)piperidin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0005uM
(2R)-N-[2-(1,3-benzodioxol-5-yl)ethyl]-1-(6-ethyl-2-imidazol-1-ylpyrimidin-4-yl)pyrrolidine-2-carboxamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0005uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[4-(2-imidazol-1-ylpyrimidin-4-yl)morpholin-3-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0005uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[1-(2-imidazol-1-ylpyrimidin-4-yl)-4-methylpiperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0005uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[1-(2-imidazol-1-ylpyrimidin-4-yl)piperidin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0005uM
(2R)-N-[2-(1,3-benzodioxol-5-yl)ethyl]-1-(2-imidazol-1-ylpyrimidin-4-yl)pyrrolidine-2-carboxamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0005uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[1-(2-imidazol-1-ylpyrimidin-4-yl)piperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0006uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[4-(furan-2-ylmethyl)-1-(2-imidazol-1-ylpyrimidin-4-yl)piperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0006uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[1-(2-imidazol-1-ylpyrimidin-4-yl)-4-methylsulfonylpiperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0007uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[4-(furan-2-carbonyl)-1-(2-imidazol-1-ylpyrimidin-4-yl)piperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0007uM
2-[1-(2-imidazol-1-ylpyrimidin-4-yl)piperidin-2-yl]-N-[(4-methoxyphenyl)methyl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0008uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[(2R)-4-(2-imidazol-1-yl-6-methylpyrimidin-4-yl)-1-(2-methylpropanoyl)piperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0008uM
benzyl 3-[2-(1,3-benzodioxol-5-ylmethylamino)-2-oxoethyl]-4-(2-imidazol-1-ylpyrimidin-4-yl)piperazine-1-carboxylate280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0008uM
ethyl 2-[3-[2-(1,3-benzodioxol-5-ylmethylamino)-2-oxoethyl]-4-(2-imidazol-1-ylpyrimidin-4-yl)piperazin-1-yl]acetate280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0009uM
3-[2-(1,3-benzodioxol-5-ylmethylamino)-2-oxoethyl]-4-(2-imidazol-1-ylpyrimidin-4-yl)-N-phenylpiperazine-1-carboxamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0009uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[4-benzyl-1-(2-imidazol-1-ylpyrimidin-4-yl)piperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0010uM
3-[2-(1,3-benzodioxol-5-ylmethylamino)-2-oxoethyl]-4-(2-imidazol-1-ylpyrimidin-4-yl)-N-methylpiperazine-1-carboxamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0010uM
3-[2-(1,3-benzodioxol-5-ylmethylamino)-2-oxoethyl]-N-benzyl-4-(2-imidazol-1-ylpyrimidin-4-yl)piperazine-1-carboxamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0010uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[1-(2-imidazol-1-ylpyrimidin-4-yl)-4-(3-methylbutyl)piperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0010uM
2-[4-acetyl-1-(2-imidazol-1-ylpyrimidin-4-yl)piperazin-2-yl]-N-(1,3-benzodioxol-5-ylmethyl)acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0010uM
propan-2-yl 3-[2-(1,3-benzodioxol-5-ylmethylamino)-2-oxoethyl]-4-(2-imidazol-1-ylpyrimidin-4-yl)piperazine-1-carboxylate280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0010uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[4-[5-(dimethylamino)naphthalen-1-yl]sulfonyl-1-(2-imidazol-1-ylpyrimidin-4-yl)piperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0011uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[1-(6-chloro-2-imidazol-1-ylpyrimidin-4-yl)piperazin-2-yl]acetamide92002: Inhibitory activity against the partially purified human Inducible nitric oxide synthaseic500.0011uM
phenyl 3-[2-(1,3-benzodioxol-5-ylmethylamino)-2-oxoethyl]-4-(2-imidazol-1-ylpyrimidin-4-yl)piperazine-1-carboxylate280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0014uM
N-[(3,4-dimethoxyphenyl)methyl]-2-[1-(2-imidazol-1-ylpyrimidin-4-yl)piperidin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0015uM
(2S)-2-amino-5-[(N’-methylcarbamimidoyl)amino]pentanoic acid669683: Inhibition of human recombinant iNOS assessed as conversion of [3H]L-arginine to [3H]L-citrulline preincubated for 15 mins measured after 45 mins by liquid scintillation countingic500.0018uM
(1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-amine;hydrochloride667551: Inhibition of human iNOSki0.0018uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[4-(2-imidazol-1-yl-6-methylpyrimidin-4-yl)-1-(2-methylpropanoyl)piperazin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0019uM
5,8-difluoro-2-(furan-2-yl)-1,2-dihydroquinazolin-4-amine92004: Inhibitory activity of compound against human inducible nitric oxide synthaseic500.0020uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[1-(2-imidazol-1-ylpyrimidin-4-yl)azepan-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0020uM
N-(3-chlorophenyl)-N-[(7,8-difluoro-2-oxo-1H-quinolin-4-yl)methyl]-4-methyl-1,3-thiazole-5-carboxamide349841: Inhibition of human iNOS expressed in HEK293 cells assessed as NO production by transient transfection assayec500.0020uM
(1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-amine2007178: Inhibition of human iNOS overexpressed in baculovirus infected Sf21 cells assessed as inhibition constantki0.0020uM
2-[4-(benzenesulfonyl)-1-(2-imidazol-1-ylpyrimidin-4-yl)piperazin-2-yl]-N-(1,3-benzodioxol-5-ylmethyl)acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0027uM
N-[(4-fluorophenyl)methyl]-2-[1-(2-imidazol-1-ylpyrimidin-4-yl)piperidin-2-yl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0030uM
N-(3-chlorophenyl)-N-[(7,8-difluoro-2-oxo-1H-quinolin-4-yl)methyl]-3-methylimidazole-4-carboxamide349841: Inhibition of human iNOS expressed in HEK293 cells assessed as NO production by transient transfection assayec500.0030uM
N-(3-chlorophenyl)-N-[(7,8-difluoro-2-oxo-1H-quinolin-4-yl)methyl]-3,5-dimethyl-1,2-oxazole-4-carboxamide349841: Inhibition of human iNOS expressed in HEK293 cells assessed as NO production by transient transfection assayec500.0030uM
2-[1-(2-imidazol-1-ylpyrimidin-4-yl)piperidin-2-yl]-N-[2-(4-methoxyphenyl)ethyl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0035uM
2-[1-(2-imidazol-1-ylpyrimidin-4-yl)piperidin-2-yl]-N-[(3-methoxyphenyl)methyl]acetamide280474: Inhibition of cytokine-induced iNOS expressed in human A172 cells assessed as inhibition of NO formationic500.0037uM
N-(1,3-benzodioxol-5-ylmethyl)-2-[2-(2-imidazol-1-yl-6-methylpyrimidin-4-yl)pyrrolidin-1-yl]-N-methylethanamine626385: Inhibition of human iNOS expressed in human HEK293 cells assessed as nitrite accumulation after 18 hrs by 2,3-diaminonapthalene assayec500.0040uM
2-[(1R)-3-amino-1-phenylpropyl]sulfanyl-6-methylpyridine-3-carbonitrile;(E)-but-2-enedioic acid589858: Inhibition of human recombinant iNOSic500.0040uM

CTD chemical–gene interactions

336 total (human), top 30 by PubMed support.

ChemicalActions (top 5)PubMed papers
Lipopolysaccharidesincreases chemical synthesis, increases activity, affects cotreatment, decreases expression, increases expression (+5 more)28
Nitric Oxidedecreases reaction, increases chemical synthesis, decreases expression, affects cotreatment, decreases methylation (+10 more)24
Resveratroldecreases stability, decreases expression, decreases abundance, affects cotreatment, decreases reaction (+4 more)8
Benzo(a)pyreneaffects methylation, affects expression, affects reaction, decreases expression, decreases reaction (+2 more)7
Quercetindecreases reaction, increases expression, affects cotreatment, decreases expression7
Particulate Matteraffects methylation, decreases methylation, increases expression, affects response to substance, increases abundance7
Plant Extractsdecreases reaction, increases expression, decreases chemical synthesis, increases reaction, decreases expression (+1 more)6
pyrrolidine dithiocarbamic acidincreases expression, affects cotreatment, decreases reaction5
Air Pollutantsincreases expression, affects response to substance, affects abundance, decreases reaction, affects methylation (+2 more)5
Glucosedecreases reaction, affects expression, increases expression, affects reaction5
Tetradecanoylphorbol Acetateincreases reaction, decreases reaction, increases expression, affects cotreatment5
Valproic Acidaffects cotreatment, decreases expression, increases expression5
Cadmiumincreases abundance, increases expression, increases secretion, decreases reaction4
Cadmium Chlorideaffects cotreatment, decreases reaction, increases activity, increases abundance, increases expression4
bisphenol Aincreases expression, decreases reaction3
arseniteincreases activity, increases expression3
sodium arsenitedecreases expression, increases expression3
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-oneincreases expression, increases reaction, affects cotreatment, decreases expression, decreases reaction3
SB 203580affects cotreatment, decreases reaction, increases expression3
U 0126decreases expression, decreases reaction, increases expression3
Acetylcysteineaffects cotreatment, decreases expression, decreases reaction, increases expression3
Curcumindecreases reaction, increases expression, increases activity3
Cycloheximidedecreases reaction, increases expression, affects cotreatment3
Doxorubicindecreases expression, increases expression, increases reaction3
Chlorpyrifosincreases expression3
Glucosamineincreases reaction, affects cotreatment, decreases expression, decreases reaction, increases expression3
Melittendecreases reaction, increases chemical synthesis, increases expression, decreases expression3
Methotrexatedecreases reaction, increases chemical synthesis, increases expression3
Mustard Gasincreases expression, decreases reaction, decreases expression3
Nitroprussidedecreases reaction, increases chemical synthesis, increases expression, affects cotreatment, decreases activity3

ChEMBL screening assays

263 unique, capped per target: 255 binding, 5 functional, 2 admet, 1 unclassified

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL1003684BindingSelectivity ratio, EC50 for human iNOS over EC50 for human nNOSDiscovery of inducible nitric oxide synthase (iNOS) inhibitor development candidate KD7332, part 1: Identification of a novel, potent, and selective series of quinolinone iNOS dimerization inhibitors that are orally active in rodent pain models. — *J Med Chem*
CHEMBL4346022UnclassifiedSelectivity index, ratio of Ki for human iNOS expressed in Escherichia coli expression system to Ki for human nNOS expressed in Escherichia coli expression systemFirst Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate. — *J Med Chem*
CHEMBL4346021ADMETInhibition of human iNOS expressed in Escherichia coli expression system assessed as reduction in NO production in presence of L-arginine measured for 30 sec by hemoglobin capture assayFirst Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate. — *J Med Chem*

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

CellosaurusNameCategorySex
CVCL_B1YSAbcam HeLa NOS2 KOCancer cell lineFemale
CVCL_B7GG603B-iNOS antisenseTransformed cell lineFemale
CVCL_B8LIAbcam HCT 116 NOS2 KOCancer cell lineMale
CVCL_B8ZIAbcam MCF-7 NOS2 KOCancer cell lineFemale
CVCL_B9NNAbcam A-549 NOS2 KOCancer cell lineMale
CVCL_TA85HAP1 NOS2 (-) 1Cancer cell lineMale
CVCL_TA86HAP1 NOS2 (-) 2Cancer cell lineMale

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCTPhaseStatusTitle
NCT00000374Phase 4COMPLETEDTreatment for First-Episode Schizophrenia
NCT00001656Phase 4COMPLETEDComparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774Phase 4COMPLETEDTo Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001Phase 4COMPLETEDCATIE- Schizophrenia Trial
NCT00018668Phase 4COMPLETEDAntipsychotic Response in Schizophrenia
NCT00034801Phase 4COMPLETEDOlanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905Phase 4COMPLETEDA Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088Phase 4COMPLETEDOlanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187Phase 4COMPLETEDThe Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655Phase 4COMPLETEDSwitching Medication to Treat Schizophrenia
NCT00048828Phase 4COMPLETEDTreating Drug-Resistant Childhood Schizophrenia
NCT00053703Phase 4COMPLETEDTreatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498Phase 4COMPLETEDRisperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802Phase 4COMPLETEDEfficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327Phase 4COMPLETEDStudy of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049Phase 4COMPLETEDStudy of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012Phase 4COMPLETEDComparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776Phase 4COMPLETEDEfficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571Phase 4COMPLETEDOlanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368Phase 4COMPLETEDThe Effects of Risperidone and Olanzapine on Thinking
NCT00114595Phase 4COMPLETEDEthyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923Phase 4COMPLETEDRisperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020Phase 4COMPLETEDClinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166Phase 4COMPLETEDTreatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847Phase 4COMPLETEDNaltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564Phase 4COMPLETEDEnergy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715Phase 4COMPLETEDEfficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223Phase 4COMPLETEDEffectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081Phase 4COMPLETEDOne Year Drug Treatment in First-Episode Schizophrenia
NCT00159120Phase 4COMPLETEDMaintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133Phase 4COMPLETEDProdrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757Phase 4TERMINATED12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817Phase 4COMPLETEDEffect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026Phase 4TERMINATEDAlcoholism and Schizophrenia: Effects of Clozapine
NCT00169039Phase 4TERMINATEDClozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065Phase 4COMPLETEDEffectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091Phase 4TERMINATEDClozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423Phase 4COMPLETEDEfficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436Phase 4COMPLETEDAtomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008Phase 4COMPLETEDAripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety
NCT00177580Phase 4COMPLETEDImproving Symptoms of Schizophrenia and Schizoaffective Disorder by Supplementing Medications With Pravastatin
NCT00182442Phase 4COMPLETEDCognition, Functioning and Quality of Life
NCT00182494Phase 4UNKNOWNDiabetes Prevention Program in Schizophrenia [DPPS]
NCT00183625Phase 4COMPLETEDSupported Employment and Skills Training in Conjunction With Pharmacotherapy in Schizophrenia Patients
NCT00186771Phase 4UNKNOWNMagnetic Stimulation as a Treatment for Auditory Hallucinations in Schizophrenia
NCT00190749Phase 4COMPLETEDSafety Study of Olanzapine and a Comparator in Patients With Schizophrenia and Schizoaffective Disorder
NCT00191555Phase 4COMPLETEDEfficacy Study of Switching Stabilized Schizophrenic Patients From Conventional to Atypical Antipsychotic Treatment
NCT00194025Phase 4COMPLETEDValproate in Late Life Schizophrenia
NCT00199940Phase 4COMPLETEDSafety And Efficacy Study Of Ziprasidone In Pediatric Psychotic Illness
NCT00202306Phase 4COMPLETEDIndicated Prevention of Psychotic Disorders With Low-dose Lithium
NCT00203788Phase 4COMPLETEDImproving Work Outcome in People With Recent-onset Schizophrenia
NCT00204061Phase 4COMPLETEDEarly Pharmacological and Psychological Intervention for Late Prodromal States of Psychosis
NCT00205660Phase 4COMPLETEDChanges in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00206102Phase 4COMPLETEDA Study of the Cataractogenic Potential of Seroquel and Risperdal in the Treatment of Participants With Schizophrenia or Schizoaffective Disorder
NCT00208143Phase 4COMPLETEDSeroquel Therapy for Substance Use Disorders Comorbid With Schizophrenia
NCT00208169Phase 4COMPLETEDAbilify Therapy for Reducing Comorbid Substance Abuse
NCT00214578Phase 4COMPLETEDSeroquel on Glucose Metabolism
NCT00215579Phase 4COMPLETEDDetermining the Effects of Risperdal Consta in Patients With Psychotic Disorders and Incomplete Adherence
NCT00216528Phase 4COMPLETEDA Study to Evaluate Symptomatic Remission in Schizophrenia With Long Acting Risperidone Microspheres
NCT00216632Phase 4COMPLETEDA Study of Treatment Success in Changing From Olanzapine to Long-acting Injectable Risperidone (RISPERDAL® CONSTA™)

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for NOS2 across ~30M SureChEMBL compounds — explore on Sugi Predict.

  • Associated diseases: schizophrenia
  • Targeted by drugs: Tilarginine
  • Disease cohort memberships (association, not causation — diseases whose associated-gene cohort lists this gene; a subset are also under Associated diseases): malaria, susceptibility to
  • Pharmacogenomically associated drugs (drugs whose metabolism/response is associated with variants in this gene (PharmGKB) — not drugs that target it): Isoniazid