F2

Summary

F2 (coagulation factor II, thrombin, HGNC:3535) is a protein-coding gene on chromosome 11p11.2, encoding Prothrombin (P00734). Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C.

This gene encodes the prothrombin protein (also known as coagulation factor II). This protein is proteolytically cleaved in multiple steps to form the activated serine protease thrombin. The activated thrombin enzyme plays an important role in thrombosis and hemostasis by converting fibrinogen to fibrin during blood clot formation, by stimulating platelet aggregation, and by activating additional coagulation factors. Thrombin also plays a role in cell proliferation, tissue repair, and angiogenesis as well as maintaining vascular integrity during development and postnatal life. Peptides derived from the C-terminus of this protein have antimicrobial activity against E. coli and P. aeruginosa. Mutations in this gene lead to various forms of thrombosis and dysprothrombinemia. Rapid increases in cytokine levels following coronavirus infections can dysregulate the coagulation cascade and produce thrombosis, compromised blood supply, and organ failure.

Source: NCBI Gene 2147 — RefSeq curated summary.

At a glance

• Gene–disease (curated): thrombophilia due to thrombin defect (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 18
• Clinical variants (ClinVar): 481 total — 20 pathogenic, 19 likely-pathogenic (top 7% of genes corpus-wide)
• GTEx eGene: eQTL in 17 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 41
• Drug target: yes — 13 curated mechanism-of-action drugs; 48 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs (ChEMBL mechanism of action): 8 — Antithrombin Alfa, Argatroban, Bivalirudin, +5 more
• Constraint (gnomAD): pLI 0.15 (intermediate), LOEUF 0.55 (moderately constrained)
• MANE Select transcript: NM_000506
• Interaction hub: 2,064 STRING partners (top 7% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3535
Approved symbol	F2
Name	coagulation factor II, thrombin
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000180210
Ensembl biotype	protein_coding
OMIM	176930
Entrez	2147

Gene structure

Transcript identifiers

Ensembl transcripts: 69 — 43 protein_coding, 24 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000311907

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 3: 2, TSL 5: 1

ENST00000311907, ENST00000442468, ENST00000469189, ENST00000490274, ENST00000530231, ENST00000862093, ENST00000862094, ENST00000862095, ENST00000862096, ENST00000862097, ENST00000862098, ENST00000862099, ENST00000862100, ENST00000862101, ENST00000862102, ENST00000862103, ENST00000862104, ENST00000862105, ENST00000862106, ENST00000862107, ENST00000862108, ENST00000862109, ENST00000862110, ENST00000862111, ENST00000862112, ENST00000862113, ENST00000862114, ENST00000862115, ENST00000862116, ENST00000862117, ENST00000862118, ENST00000862119, ENST00000862120, ENST00000862121, ENST00000862122, ENST00000862123, ENST00001002912, ENST00001002914, ENST00001002916, ENST00001002919, ENST00001002920, ENST00001002922, ENST00001002923, ENST00001002926, ENST00001002930, ENST00001002936, ENST00001002939, ENST00001002942, ENST00001002944, ENST00001002946, ENST00001002952, ENST00001002955, ENST00001002956, ENST00001002965, ENST00001036410, ENST00001036411, ENST00001117574, ENST00001117575, ENST00001117576, ENST00001117577, ENST00001117578, ENST00001117579, ENST00001117580, ENST00001117581, ENST00001117582, ENST00001117583, ENST00001117584, ENST00001117585, ENST00001139742

RefSeq mRNA: 1 — MANE Select: NM_000506 NM_000506

CCDS: CCDS31476

Canonical transcript exons

ENST00000311907 — 14 exons

Exon	Start	End
ENSE00001181524	46723382	46723518
ENSE00001181527	46723180	46723285
ENSE00001181532	46720790	46720840
ENSE00001181538	46720523	46720547
ENSE00001181543	46719702	46719862
ENSE00001227030	46739265	46739506
ENSE00001646362	46729380	46729561
ENSE00001650441	46727996	46728163
ENSE00001657931	46728664	46728837
ENSE00001680217	46739048	46739118
ENSE00001688723	46725859	46726173
ENSE00001770269	46726711	46726837
ENSE00001931088	46719213	46719314
ENSE00003785308	46726498	46726626

Expression profiles

Bgee: expression breadth ubiquitous, 117 present calls, max score 99.46.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 8.1630 / max 3039.8244, expressed in 139 samples.

Highest expression (Bgee): lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis, oocyte, secondary oocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

F2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 17 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

18 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Liver	sqtl	5.6e-32	+1.01	11:46729088:T:C
Artery Tibial	eqtl	1.9e-16	-0.39	11:46708322:T:C
Testis	eqtl	4.1e-11	-0.47	11:46708322:T:C
Brain Cerebellum	eqtl	4.2e-11	-0.59	11:46708322:T:C
Brain Cerebellar Hemisphere	eqtl	3.6e-06	-0.39	11:46708322:T:C
Esophagus Muscularis	eqtl	4.1e-05	-0.32	11:46722818:T:C
Brain Hypothalamus	eqtl	5.4e-05	-0.46	11:46692729:T:C
Esophagus Gastroesophageal Junction	eqtl	7.2e-05	-0.33	11:46738021:A:G
Colon Transverse	eqtl	4.5e-04	-0.28	11:46708779:A:G
Colon Sigmoid	eqtl	5.4e-04	-0.25	11:46729088:T:C
Adipose Subcutaneous	eqtl	2.3e-03	-0.23	11:46708322:T:C
Nerve Tibial	eqtl	3.9e-03	+0.99	11:46366188:A:G
Brain Putamen basal ganglia	eqtl	4.4e-03	-0.37	11:46708322:T:C
Artery Coronary	eqtl	1.1e-02	-0.32	11:46708779:A:G
Brain Frontal Cortex BA9	eqtl	1.4e-02	-0.40	11:46708322:T:C
Brain Cortex	eqtl	1.9e-02	-1.14	11:46740592:C:T
Brain Nucleus accumbens basal ganglia	eqtl	2.2e-02	-0.30	11:46673864:T:C
Whole Blood	eqtl	2.4e-02	-0.42	11:46527407:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
114155	8.1508	139
114156	0.0122	7

Top tissues by expression

showing 100 of 272 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.46	gold quality
liver	UBERON:0002107	99.36	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.70	gold quality
oocyte	CL:0000023	77.83	silver quality
secondary oocyte	CL:0000655	72.79	silver quality
tongue squamous epithelium	UBERON:0006919	65.49	gold quality
Brodmann (1909) area 10	UBERON:0013541	65.32	gold quality
frontal pole	UBERON:0002795	64.95	gold quality
middle frontal gyrus	UBERON:0002702	64.67	gold quality
paraflocculus	UBERON:0005351	64.44	gold quality
hair follicle	UBERON:0002073	63.40	gold quality
triceps brachii	UBERON:0001509	61.22	gold quality
lateral nuclear group of thalamus	UBERON:0002736	61.06	gold quality
myocardium	UBERON:0002349	60.50	gold quality
heart right ventricle	UBERON:0002080	60.46	gold quality
vastus lateralis	UBERON:0001379	60.23	gold quality
biceps brachii	UBERON:0001507	60.10	gold quality
quadriceps femoris	UBERON:0001377	59.44	gold quality
vena cava	UBERON:0004087	59.10	gold quality
cerebellar vermis	UBERON:0004720	59.06	gold quality
esophagus squamous epithelium	UBERON:0006920	58.36	gold quality
gluteal muscle	UBERON:0002000	57.70	gold quality
epithelium of esophagus	UBERON:0001976	57.61	gold quality
nasal cavity epithelium	UBERON:0005384	57.37	gold quality
cerebellar hemisphere	UBERON:0002245	56.91	gold quality
cartilage tissue	UBERON:0002418	56.83	gold quality
cerebellar cortex	UBERON:0002129	56.81	gold quality
cerebellum	UBERON:0002037	56.62	gold quality
right hemisphere of cerebellum	UBERON:0014890	56.56	gold quality
postcentral gyrus	UBERON:0002581	56.09	gold quality
parotid gland	UBERON:0001831	55.71	gold quality
palpebral conjunctiva	UBERON:0001812	55.48	gold quality
metanephric glomerulus	UBERON:0004736	55.44	gold quality
inferior olivary complex	UBERON:0002127	55.13	gold quality
squamous epithelium	UBERON:0006914	55.00	gold quality
popliteal artery	UBERON:0002250	54.96	gold quality
middle temporal gyrus	UBERON:0002771	54.92	gold quality
Brodmann (1909) area 46	UBERON:0006483	54.87	gold quality
tibial artery	UBERON:0007610	54.87	gold quality
entorhinal cortex	UBERON:0002728	54.75	gold quality
kidney epithelium	UBERON:0004819	54.60	gold quality
fundus of stomach	UBERON:0001160	54.25	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	54.12	gold quality
amniotic fluid	UBERON:0000173	53.96	gold quality
renal glomerulus	UBERON:0000074	53.72	gold quality
endometrium epithelium	UBERON:0004811	53.61	gold quality
Brodmann (1909) area 23	UBERON:0013554	53.58	gold quality
parietal lobe	UBERON:0001872	53.55	gold quality
deltoid	UBERON:0001476	53.47	gold quality
superior frontal gyrus	UBERON:0002661	53.42	gold quality
trabecular bone tissue	UBERON:0002483	53.41	gold quality
skeletal muscle tissue	UBERON:0001134	53.22	gold quality
nephron tubule	UBERON:0001231	52.81	gold quality
medial globus pallidus	UBERON:0002477	52.65	gold quality
germinal epithelium of ovary	UBERON:0001304	52.62	gold quality
tibia	UBERON:0000979	52.59	gold quality
embryo	UBERON:0000922	52.45	gold quality
right coronary artery	UBERON:0001625	52.43	gold quality
globus pallidus	UBERON:0001875	51.77	gold quality
oral cavity	UBERON:0000167	51.66	gold quality
mucosa of sigmoid colon	UBERON:0004993	51.23	gold quality
pigmented layer of retina	UBERON:0001782	50.86	gold quality
ileal mucosa	UBERON:0000331	50.81	silver quality
thymus	UBERON:0002370	50.69	gold quality
mammalian vulva	UBERON:0000997	50.48	gold quality
colonic epithelium	UBERON:0000397	50.45	gold quality
pancreatic ductal cell	CL:0002079	50.43	silver quality
layer of synovial tissue	UBERON:0007616	50.28	gold quality
granulocyte	CL:0000094	50.19	silver quality
placenta	UBERON:0001987	50.03	silver quality
stomach	UBERON:0000945	50.02	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	50.01	gold quality
body of tongue	UBERON:0011876	49.70	gold quality
body of stomach	UBERON:0001161	49.68	gold quality
bone marrow	UBERON:0002371	49.68	gold quality
aorta	UBERON:0000947	49.64	gold quality
epithelial cell of pancreas	CL:0000083	49.54	gold quality
epithelium of bronchus	UBERON:0002031	49.29	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
adrenal tissue	UBERON:0018303	49.28	gold quality
sigmoid colon	UBERON:0001159	49.22	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
bronchus	UBERON:0002185	49.08	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
duodenum	UBERON:0002114	48.76	silver quality
seminal vesicle	UBERON:0000998	48.75	gold quality
muscle layer of sigmoid colon	UBERON:0035805	48.73	gold quality
oviduct epithelium	UBERON:0004804	48.57	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
cervix epithelium	UBERON:0004801	48.39	gold quality
kidney	UBERON:0002113	48.36	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
bronchial epithelial cell	CL:0002328	48.01	gold quality
dorsal plus ventral thalamus	UBERON:0001897	47.85	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	10.96
E-ANND-3	no	2.61

HPA expression

RNA tissue specificity: Tissue enriched

39 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	1138.4	medium
Olfactory bulb	tissue	8.5
Cerebellum	tissue	7.8	not detected
Cerebral cortex	tissue	6.9	not detected
Insular cortex	tissue	6.9
Amygdala	tissue	6.8
Retrosplenial cortex	tissue	6.7
Basal ganglia	tissue	6.5	not detected
Retrosplenial and cingulate cortex	tissue	6.3
Corpus callosum	tissue	6.2
Temporal cortex	tissue	6.2
Periaqueductal gray	tissue	6.0
Hippocampal formation	tissue	5.9
Entorhinal cortex	tissue	5.9
Prefrontal cortex	tissue	5.7
Ventral forebrain	tissue	5.7
Septum	tissue	5.6
Occipital cortex	tissue	5.5
Hypothalamus	tissue	5.4
Somatosensory cortex	tissue	5.3
Motor cortex	tissue	5.1
Putamen	tissue	5.1
Midbrain	tissue	4.8
Spinal cord	tissue	4.5
Medulla oblongata	tissue	4.4
Substantia nigra	tissue	4.2
Thalamus	tissue	4.1
Pons	tissue	4.0
Superior colliculi	tissue	3.8
Ovary	tissue	0.5	not detected
Nucleus accumbens	tissue	0.3
Testis	tissue	0.2	not detected
Stomach 1	tissue	0.2	not detected
Kidney	tissue	0.2	not detected
Locus coeruleus	tissue	0.2
Hippocampus	tissue	0.2	not detected
Postcentral gyrus	tissue	0.2
Pituitary gland	tissue	0.1
Gallbladder	tissue	0.1	not detected

Brain sub-regions (HPA Brain Atlas): detected in 187; highest nTPM — White matter (6.2), Ventral hippocampus (5.8), Subiculum (5.5), Dorsal hippocampus (5.2), Ventral spinal cord (4.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DEAF1, ELK1, FOXA2, HIF1A, HNF4A, NFATC1, NFKB, NR4A3, RELA, SP1, SP3, TCF3, YBX1

miRNA regulators (miRDB)

Targeting F2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

5 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-218-1-3P	98.63	67.97	832
HSA-MIR-1292-5P	96.74	62.14	238
HSA-MIR-8059	95.11	66.30	646
HSA-MIR-4471	95.11	66.84	755

Functional genomics

gnomAD constraint: pLI 0.154, LOEUF 0.552, missense Z 2.77 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000311907 — one region, missense o/e 0.76.

Literature-anchored findings (GeneRIF, showing 40)

• The abundant local thrombin demonstrated in human thrombi has implications for thrombus lysis and extension: incomplete lysis and exposure of active thrombin may lead to re-occlusion of vessels. (PMID:11686320)
• Thrombin induces increased expression and secretion of VEGF from human FS4 fibroblasts, DU145 prostate cells and CHRF megakaryocytes. (PMID:11686329)
• When recombinant provWF was incubated with increasing amounts of purified thrombin, provWF processing was dose-dependent. The specific cleavage of vWFpp was confirmed by immunoblots using an anti-vWFpp antibody and by NH2-terminal amino-acid analysis. (PMID:11776313)
• Comparison of fibrinogen clotting activity with fibrin binding activity identified twenty residues involved in fibrinogen recognition with 4 of these residues important in fibrin binding (Lys65, His66, Tyr71, Arg73). (PMID:11776315)
• Association of prothrombin gene mutation with Behcet’s disease. (PMID:11820731)
• Mothers with prothrombin A20210 mutation have a higher risk of having low birth-weight infants or fetal loss, possibly due to underperfusion of the placenta. (PMID:11836168)
• In prothrombin Perija, mutation of Gly-548 to Ala near the substrate binding pocket cavity wall blocks thrombin proteolytic activity. The methyl group blocks entry of the substrate Arg guanidino group into the cavity & catalytic Ser-525. (PMID:11858488)
• Proexosite I blockage decreases recognition of prothrombin as substrate by factor Xa-factor Va complex & prothrombinase complex. Data obtained with human platelets suggest that proexosite I may play an important role in prothrombin activation. (PMID:11858489)
• No association was found between factor II g20210A promoter variant and fatal myocardial infarction in Finland. (PMID:11858502)
• Thrombin induces increased expression and secretion of angiopoietin-2 from human umbilical vein endothelial cells. (PMID:11861279)
• In the Spanish population, the prothrombin 20210A (PT20210A) allele is the most prevalent genetic risk factor for venous thromboembolism in hemophilia A. (PMID:11869940)
• Delayed, reduced or inhibited thrombin production reduces platelet contractile force and results in weaker clot formation. (PMID:11943932)
• role of thrombin in the neo-vascularization of malignant gliomas (PMID:11956584)
• Data suggesting a physical association between factor Xa and prothrombin, and that factor Xa has an increased affinity for prothrombin in the presence of factor Va. (PMID:11983337)
• Mechanism of thrombin-induced angiogenesis. Review. (PMID:12023846)
• Role of thrombin and its major cellular receptor, protease-activated receptor-1, in pulmonary fibrosis. Review. (PMID:12023853)
• G20210A is a bifunctional polymorphism, as it not only alters the efficiency of mRNA processing, but also the decay rate of prothrombin mRNA. (PMID:12038788)
• prevalence of FVL, FII G20210A and MTHFR C677T in women with three or more pregnancy losses (PMID:12042290)
• G20210A mutation contributes to the process of arterial wall thickening and is associated with the occurrence of ischemic events in a cohort of elderly persons with established atherosclerosis. (PMID:12048131)
• TRAP causes more intense changes in signaling through tyrosine phosphorylation of proteins associated with the cytoskeletal fraction than thrombin. (PMID:12057926)
• effect of factor VIII deficiency on generation (PMID:12058364)
• This study confirms the presence of G20210A mutation in the Romanian population, and demonstrates a link between venous leg ulcers and this polymorphism in the prothrombin gene. (PMID:12067473)
• functional epitope of thrombin recognizing thrombomodulin was mapped using Ala-scanning mutagenesis of 54 residues located around the active site, the Na(+) binding loop, the 186-loop, the autolysis loop, exosite I, and exosite II (PMID:12068020)
• Thrombin functions studied during tissue factor-induced blood coagulation (PMID:12070020)
• The G20210A mutation does not affect the stability of prothrombin mRNA but, rather, effects a change in the location of the 3’-cleavage/polyadenylation reaction (PMID:12070052)
• Data show that factor V activation is associated with the stepwise release of the B-domain after incubation with thrombin, which results in a gradual exposure of the factor Xa-binding site. (PMID:12163491)
• the inhibitory sequence for prothrombinase was delineated using a synthetic peptide library representing human prothrombin fragment 2 (F2) sequence (PMID:12165293)
• The presence of the G20210A factor II gene mutation is associated with the occurrence of a previous systemic embolism. (PMID:12208422)
• prospective study of the G20210A polymorphism in the gene, plasma concentration and incidence of venous thromboembolism (PMID:12447958)
• prevalence of mutation and factor V G1691A (factor V-Leiden) mutation in a recurrent miscarriage population (PMID:12447960)
• Interaction between the FII 20210A and FXIII-A Leu34 alleles forms a synergistic coeffect that strongly predisposes for MI, placing combined carriers at high risk for MI. (PMID:12480694)
• Thrombin upregulates COX-2-derived prostaglandin E2 synthesis by both catalytic cleavage of proteinase-activated receptor 1 and bFGF-dependent noncatalytic activity. (PMID:12505789)
• Interactions within thrombin that involve autolytic loop-2 and the Na(+)-binding site primarily enhance thrombin action on fibrinogen, but impair thrombin action on protein C. (PMID:12588872)
• Prothrombin binds selectively to the surface of apoptotic, but not viable, Jurkat cells and supports the binding of systemic lupus erythematosus-derived prothrombin-dependent lupus anticoagulant antibody to apoptotic cells. (PMID:12626602)
• Data present the 1.8 A crystallographic structure of S195A thrombin in two conformational states: active site occupied and active site free. (PMID:12679024)
• relationship between serum levels and the expression of Des-gamma-carboxy prothrombin (DCP)in cancer and surrounding non-cancer liver tissues of hepatocellular carcinoma patients (PMID:12684661)
• factor V Leiden or prothrombin G20210A associated with cryptogenic stroke whereas other coagulation abnormalities did not, supporting the possibility of paradoxical embolism behind strokes in patients with patent foramen ovale (PMID:12695749)
• Results show that VR1 is a subsite of exosite 1 on thrombin’s surface, which regulates exclusive binding of either plasminogen activator inhibitor 1 or thrombomodulin. (PMID:12709053)
• investigated the distribution of the prothrombin variant G20210A (PT20210A) in patients with thrombophilic conditions living in the French Basque Country (PMID:12734676)
• prothrombin has a factor Va-dependent recognition site for the prothrombinase complex (PMID:12750382)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	F2	ENSMUSG00000027249
rattus_norvegicus	F2	ENSRNOG00000016325

Paralogs (1): PAMR1 (ENSG00000149090)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88380) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 37 distinct phenotype terms.

Mouse phenotype (MP)	Records
hemorrhage	2
postnatal lethality, complete penetrance	2
neonatal lethality, complete penetrance	2
distended pericardium	1
tremors	1
decreased exploration in new environment	1
internal hemorrhage	1
decreased embryo size	1
abnormal visceral yolk sac morphology	1
pale yolk sac	1
embryonic growth arrest	1
intracranial hemorrhage	1
decreased mean corpuscular volume	1
increased circulating serum albumin level	1
abnormal vitelline vasculature morphology	1
decreased susceptibility to induced arthritis	1
pallor	1
decreased lean body mass	1
hemopericardium	1
abnormal circulating protein level	1
increased bleeding time	1
decreased susceptibility to endotoxin shock	1
increased total body fat amount	1
increased circulating fructosamine level	1
decreased bone mineral content	1

+12 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.

Organism	UniProt	Identity	Method
Pan troglodytes	Q95ND7	99.8%	Diamond
Pongo abelii	Q5RCB6	99.5%	Diamond
Tachypleus tridentatus	P28175	97.2%	Diamond
Carcinoscorpius rotundicauda	Q26422	97.2%	Diamond
Bos taurus	P00741	96.8%	Diamond
Ovis aries	P16291	96.8%	Diamond
Macaca fascicularis	Q4R577	96.3%	Diamond
Macaca mulatta	Q28520	96.0%	Diamond
Pseudonaja textilis	Q1L658	93.4%	Diamond
Capra hircus	Q7M323	92.9%	Diamond
Canis lupus familiaris	P19540	88.5%	Diamond
Felis catus	Q6SA95	88.5%	Diamond
Oryctolagus cuniculus	Q28661	86.3%	Diamond
Sus scrofa	P16293	86.1%	Diamond
Demansia vestigiata	A6MFK7	85.8%	Diamond
Equus caballus	Q28380	84.7%	Diamond
Erinaceus europaeus	Q29485	79.5%	Diamond
Cavia porcellus	P16295	75.8%	Diamond
Notamacropus eugenii	O18783	75.4%	Diamond
Bombus pensylvanicus	Q7M4I3	67.2%	Diamond
Gallus gallus	P25155	57.3%	Diamond
Petromyzon marinus	P33574	55.6%	Diamond
Danio rerio	Q7SXB3	50.8%	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).

Symbol	Type	Entrez
SNORD67	snoRNA	692108
ZNF408	protein-coding	79797
CKAP5	protein-coding	9793
LRP4-AS1	ncRNA	100507401
MIR5582	ncRNA	100847020
LRP4	protein-coding	4038
MIR3160-2	ncRNA	100422825
MIR3160-1	ncRNA	100422827
HARBI1	protein-coding	283254
ARHGAP1	protein-coding	392
AMBRA1	protein-coding	55626
ATG13	protein-coding	9776
CSTPP1	protein-coding	79096

Protein

Protein identifiers

Prothrombin — P00734 (reviewed: P00734)

Alternative names: Coagulation factor II

All UniProt accessions (3): C9JV37, E9PIT3, P00734

UniProt curated annotations — full annotation on UniProt →

Function. Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing. Activates coagulation factor XI (F11); activation is promoted by the contact with negatively charged surfaces. Triggers the production of pro-inflammatory cytokines, such as MCP-1/CCL2 and IL8/CXCL8, in endothelial cells.

Subunit / interactions. Heterodimer (named alpha-thrombin) of a light and a heavy chain; disulfide-linked. Forms a heterodimer with SERPINA5. In plasma, interacts (via N-terminus) with alpha-1-microglobulin with molar ratio 1:2 and 1:1; this interaction does not prevent the activation of prothrombin to thrombin. Interacts (thrombin) with iripin-8, a serine protease inhibitor from Ixodes ricinus saliva. Interacts (thrombin) with iripin-3, a serine protease inhibitor from Ixodes ricinus saliva. Interacts (thrombin) with Anopheles albimanus salivary thrombin inhibitor anophelin; the interaction results in thrombin inhibition. Interacts (thrombin) with Anopheles gambiae salivary thrombin inhibitor anophelin; the interaction results in thrombin inhibition. Interacts (thrombin) with Amblyomma variegatum variegin; the interaction results in thrombin inhibition. Interacts (thrombin) with Xenopsylla cheopis salivary thrombin inhibitor XC-42. Interacts (thrombin) with Xenopsylla cheopis salivary thrombin inhibitor XC-43.

Subcellular location. Secreted. Extracellular space.

Tissue specificity. Expressed by the liver and secreted in plasma.

Post-translational modifications. The gamma-carboxyglutamyl residues, which bind calcium ions, result from the carboxylation of glutamyl residues by a microsomal enzyme, the vitamin K-dependent carboxylase. The modified residues are necessary for the calcium-dependent interaction with a negatively charged phospholipid surface, which is essential for the conversion of prothrombin to thrombin. N-glycosylated. N-glycan heterogeneity at Asn-121: Hex3HexNAc3 (minor), Hex4HexNAc3 (minor) and Hex5HexNAc4 (major). At Asn-143: Hex4HexNAc3 (minor) and Hex5HexNAc4 (major). In the penultimate step of the coagulation cascade, prothrombin is converted to thrombin by the prothrombinase complex composed of factor Xa (F10), cofactor Va (F5), and phospholipids. This activation requires factor Xa-catalyzed sequential cleavage at 2 sites, Arg-314 and Arg-363, along 2 possible pathways. In the first pathway, the first cleavage occurs at Arg-314, leading to the formation of the inactive intermediate prethrombin-2. This pathway preferentially occurs on platelets and in the absence of cofactor Va. In the second pathway, the first cleavage occurs at Arg-363, which separates protease domain into 2 chains that remain connected through a disulfide bond and generates the active intermediate meizothrombin. The presence of cofactor Va directs activation along the meizothrombin pathway and greatly accelerates the rate of cleavage at Arg-363, but has a smaller effect on the cleavage of meizothrombin at Arg-314. Meizothrombin accumulates as an intermediate when prothrombinase is assembled on the membrane of red blood cells.

Disease relevance. Factor II deficiency (FA2D) [MIM:613679] A very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels. The disease is caused by variants affecting the gene represented in this entry. Ischemic stroke (ISCHSTR) [MIM:601367] A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. Disease susceptibility is associated with variants affecting the gene represented in this entry. Thrombophilia due to thrombin defect (THPH1) [MIM:188050] A multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. The disease is caused by variants affecting the gene represented in this entry. A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. Pregnancy loss, recurrent, 2 (RPRGL2) [MIM:614390] A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Activity is promoted in the presence of negatively charged surfaces, such as polyphosphate and dextran sulfate. Inhibited by SERPINA5.

Miscellaneous. It is not known whether 1 or 2 smaller activation peptides, with additional cleavage after Arg-314, are released in natural blood clotting. Thrombin can itself cleave the N-terminal fragment (fragment 1) of the prothrombin, prior to its activation by factor Xa. The cleavage after Arg-198, observed in vitro, does not occur in plasma.

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (1): NP_000497* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000001	Kringle	Domain
IPR000294	GLA_domain	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR003966	Prothrombin/thrombin	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR013806	Kringle-like	Homologous_superfamily
IPR018056	Kringle_CS	Conserved_site
IPR018114	TRYPSIN_HIS	Active_site
IPR018992	Thrombin_light_chain	Domain
IPR033116	TRYPSIN_SER	Active_site
IPR035972	GLA-like_dom_SF	Homologous_superfamily
IPR037111	Thrombin_light_chain_sf	Homologous_superfamily
IPR038178	Kringle_sf	Homologous_superfamily
IPR043504
IPR051659	Serine_Protease_S1-Domain	Family

Pfam: PF00051, PF00089, PF00594, PF09396

Enzyme classification (BRENDA)

• EC 3.4.21.5 — thrombin (BRENDA: 10 organisms, 199 substrates, 440 inhibitors, 100 Km, 96 kcat entries)

Substrate kinetics (BRENDA)

38 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
D-PHENYLALANYL-PIPECOLYL-L-ARGININE-4-NITROANILI	0.0026–0.298	14
TOSYL-ARG METHYL ESTER	0.0063–0.3	8
D-PHE-L-PIPECOLYL-L-ARG-4-NITROANILIDE	0.0015–0.0632	7
BENZOYL-ARG ETHYL ESTER	0.0052–0.0079	5
PROTEIN C	0.002–0.0032	5
D-PHE-PRO-ARG-4-NITROANILIDE	0.0003–0.013	4
D-PHE-PRO-LYS-4-NITROANILIDE	0.004–0.072	4
D-PHE-PRO-PHE-4-NITROANILIDE	0.017–0.11	4
DI-L-GLU-L-PRO-L-ARG-4-NITROANILIDE	0.1471–0.2829	4
FIBRINOGEN	0.0032–0.0528	4
TOSYL-GLY-PRO-ARG-4-NITROANILIDE	0.0085–0.0164	4
BENZOYL-ARG METHYL ESTER	0.0075–0.0088	2
BENZOYL-L-ARG-P-NITROANILIDE	0.143–0.84	2
FIBRINOGEN AALPHA CHAIN	0.0036–0.0113	2
FIBRINOPEPTIDE A	0.0051–0.013	2

UniProt features (160 total): strand 40, helix 24, sequence conflict 24, turn 13, sequence variant 13, disulfide bond 12, modified residue 10, domain 4, active site 3, site 3, chain 3, glycosylation site 3, mutagenesis site 3, peptide 2, signal peptide 1, propeptide 1, region of interest 1

Structure

Experimental structures (PDB)

showing 30 of 480 structures by resolution:

PDB	Title	Method	Resolution (Å)
5AFY	Thrombin in complex with 3-chloro-benzamide	X-RAY DIFFRACTION	1.12
4UD9	Thrombin in complex with 5-chlorothiophene-2-carboxamide	X-RAY DIFFRACTION	1.12
4UE7	Thrombin in complex with 1-amidinopiperidine	X-RAY DIFFRACTION	1.13
4UDW	Thrombin in complex with 1-(2R)-2-amino-3-phenyl-propanoyl-N-(2 …	X-RAY DIFFRACTION	1.16
4UEH	Thrombin in complex with benzamidine	X-RAY DIFFRACTION	1.16
5AF9	Thrombin in complex with 4-Methoxy-N-(2-pyridinyl)benzamide	X-RAY DIFFRACTION	1.18
3RM2	Human Thrombin in complex with MI003	X-RAY DIFFRACTION	1.23
5AHG	Thrombin in complex with ((4-chlorophenyl)sulfamoyl))diemethylamine	X-RAY DIFFRACTION	1.24
2BVR	Human thrombin complexed with fragment-based small molecules occupying the S1 pocket	X-RAY DIFFRACTION	1.25
3VXE	Human alpha-thrombin-Bivalirudin complex at PD5.0	X-RAY DIFFRACTION	1.25
2UUF	Thrombin-hirugen binary complex at 1.26A resolution	X-RAY DIFFRACTION	1.26
3SI4	Human Thrombin In Complex With UBTHR104	X-RAY DIFFRACTION	1.27
5JZY	Thrombin in complex with …	X-RAY DIFFRACTION	1.27
6FJT	4-chloro-benzamidine in complex with thrombin	X-RAY DIFFRACTION	1.27
3U8O	Human thrombin complexed with D-Phe-Pro-D-Arg-D-Thr	X-RAY DIFFRACTION	1.28
5MM6	Thrombin Mutant A190S in complex with …	X-RAY DIFFRACTION	1.29
2CF8	Complex of recombinant human thrombin with an inhibitor	X-RAY DIFFRACTION	1.3
2CN0	Complex of Recombinant Human Thrombin with a Designed Inhibitor	X-RAY DIFFRACTION	1.3
3SV2	Human Thrombin In Complex With UBTHR105	X-RAY DIFFRACTION	1.3
6TKL	Non-cleavable tsetse thrombin inhibitor in complex with human alpha-thrombin	X-RAY DIFFRACTION	1.3
6T4A	Thrombin in Complex with a D-Phe-Pro-p-aminopyridine derivative	X-RAY DIFFRACTION	1.31
6T56	Thrombin in Complex with Benzylamine	X-RAY DIFFRACTION	1.31
2UUJ	Thrombin-hirugen-gw473178 ternary complex at 1.32A resolution	X-RAY DIFFRACTION	1.32
6T3Q	Thrombin in Complex with a D-Phe-Pro-2-aminopyridine derivative	X-RAY DIFFRACTION	1.33
6YB6	Thrombin in complex with D-Phe-Pro-3-chloro-1,3-dihydroxybenzylamide derivative (13c)	X-RAY DIFFRACTION	1.33
6YHG	Thrombin in complex with D-Phe-Pro-m-methoxybenzylamide derivative (16a)	X-RAY DIFFRACTION	1.33
6ROT	Thrombin in complex with MI2105	X-RAY DIFFRACTION	1.34
3RM0	Human Thrombin in complex with MI354	X-RAY DIFFRACTION	1.34
3QX5	Thrombin Inhibition by Pyridin Derivatives	X-RAY DIFFRACTION	1.35
6T53	Thrombin in Complex with a D-Phe-Pro-p-benzylamine derivative	X-RAY DIFFRACTION	1.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00734-F1	84.37	0.56

Antibody-complex structures (SAbDab)

2 antibodies co-crystallized with this protein: 5E8E, 8UF7

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Serine-type peptidases, Metabolic proteins, Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Candidate cardiovascular disease genes, Disease related genes, FDA approved drug targets, Biotech drugs, 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.

Catalytic / active sites (6)

Position	Role
406	charge relay system
462	charge relay system
568	charge relay system
198–199	cleavage; by thrombin
314–315	cleavage; by factor xa
363–364	cleavage; by factor xa

Post-translational modifications (10)

Type	Positions
4-carboxyglutamate	49, 50, 57, 59, 62, 63, 68, 69, 72, 75

Disulfide bonds (12)

Type	Positions
Disulfide bond	60–65, 90–103, 108–186, 129–169, 157–181, 213–291, 234–274, 262–286, 391–407, 536–550, 564–594
Interchain (between light and heavy chains)	336–482

Glycosylation sites (3)

Type	Positions
N-linked (glcnac…) (complex) asparagine	121, 143, 416

Mutagenesis-validated functional residues (3)

Position	Phenotype
314	loss of cleavage by factor xa.
363	loss of cleavage by factor xa.
568	loss of catalytic activity; no effect on cleavage at r-198 by factor xa.

Function

Pathways and Gene Ontology

Reactome pathways

17 curated (TAS) of 38; 6 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

38 pathways:

ID	Pathway	Evidence
R-HSA-9672391	Defective F8 cleavage by thrombin ⚕	curated
R-HSA-9657688	Defective factor XII causes hereditary angioedema ⚕	curated
R-HSA-9918481	Dengue Virus-Host Interactions ⚕	curated
R-HSA-9769743	Amplification and propagation of coagulation cascade	curated
R-HSA-202733	Cell surface interactions at the vascular wall	curated
R-HSA-9769733	Fibrin formation	curated
R-HSA-416476	G alpha (q) signalling events	curated
R-HSA-159740	Gamma-carboxylation of protein precursors	curated
R-HSA-9769735	Initiation of coagulation cascade	curated
R-HSA-375276	Peptide ligand-binding receptors	curated
R-HSA-76009	Platelet Aggregation (Plug Formation)	curated
R-HSA-977606	Regulation of Complement cascade	curated
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	curated
R-HSA-9769739	Regulation of clotting cascade	curated
R-HSA-159782	Removal of aminoterminal propeptides from gamma-carboxylated proteins	curated
R-HSA-456926	Thrombin signalling through proteinase activated receptors (PARs)	curated
R-HSA-159763	Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	curated
R-HSA-9662001	Defective factor VIII causes hemophilia A ⚕	—
R-HSA-1643685	Disease ⚕	—
R-HSA-9671793	Diseases of hemostasis ⚕	—
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)	—
R-HSA-166658	Complement cascade	—
R-HSA-388396	GPCR downstream signalling	—
R-HSA-500792	GPCR ligand binding	—
R-HSA-163841	Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	—
R-HSA-159854	Gamma-carboxylation, transport, and amino-terminal cleavage of proteins	—
R-HSA-109582	Hemostasis	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-76002	Platelet activation, signaling and aggregation	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-140837		—
R-HSA-140875		—
R-HSA-140877		—
R-HSA-9651496		—
R-HSA-162582	Signal Transduction	—
R-HSA-372790	Signaling by GPCR	—

MSigDB gene sets: 421 (showing top): MODULE_172, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_PROTEIN_ACTIVATION_CASCADE, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_REGULATION_OF_WOUND_HEALING, PID_HNF3B_PATHWAY, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_COAGULATION, GNF2_GSTM1

GO Biological Process (28): proteolysis (GO:0006508), acute-phase response (GO:0006953), cell surface receptor signaling pathway (GO:0007166), blood coagulation (GO:0007596), response to wounding (GO:0009611), negative regulation of platelet activation (GO:0010544), platelet activation (GO:0030168), regulation of blood coagulation (GO:0030193), positive regulation of blood coagulation (GO:0030194), negative regulation of blood coagulation (GO:0030195), positive regulation of collagen biosynthetic process (GO:0032967), fibrinolysis (GO:0042730), negative regulation of proteolysis (GO:0045861), positive regulation of receptor signaling pathway via JAK-STAT (GO:0046427), negative regulation of astrocyte differentiation (GO:0048712), positive regulation of release of sequestered calcium ion into cytosol (GO:0051281), regulation of cytosolic calcium ion concentration (GO:0051480), negative regulation of fibrinolysis (GO:0051918), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), thrombin-activated receptor signaling pathway (GO:0070493), neutrophil-mediated killing of gram-negative bacterium (GO:0070945), negative regulation of cytokine production involved in inflammatory response (GO:1900016), positive regulation of protein localization to nucleus (GO:1900182), positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway (GO:1900738), positive regulation of reactive oxygen species metabolic process (GO:2000379), G protein-coupled receptor signaling pathway (GO:0007186), hemostasis (GO:0007599), regulation of body fluid levels (GO:0050878)

GO Molecular Function (13): lipopolysaccharide binding (GO:0001530), serine-type endopeptidase activity (GO:0004252), signaling receptor binding (GO:0005102), calcium ion binding (GO:0005509), growth factor activity (GO:0008083), heparin binding (GO:0008201), receptor ligand activity (GO:0048018), thrombospondin receptor activity (GO:0070053), endopeptidase activity (GO:0004175), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (8): extracellular region (GO:0005576), endoplasmic reticulum lumen (GO:0005788), Golgi lumen (GO:0005796), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), external side of plasma membrane (GO:0009897)

Reactome top-level categories

11 top-level categories:

Category	Pathways
Coagulation pathway	4
Gamma-carboxylation, transport, and amino-terminal cleavage of proteins	3
Platelet activation, signaling and aggregation	2
Hemostasis	1
Class A/1 (Rhodopsin-like receptors)	1
Metabolism of proteins	1
GPCR downstream signalling	1
Defects of contact activation system and kallikrein-kinin system	1
Defective factor VIII causes hemophilia A	1
Complement cascade	1
Dengue Virus Infection	1

GO top-level categories

showing 60 of 78 GO namespaces:

Category	Terms
blood coagulation	4
signal transduction	2
negative regulation of blood coagulation	2
regulation of blood coagulation	2
peptidase activity	2
cellular anatomical structure	2
intracellular organelle lumen	2
protein metabolic process	1
acute inflammatory response	1
hemostasis	1
wound healing	1
coagulation	1
response to stress	1
regulation of platelet activation	1
platelet activation	1
negative regulation of cell activation	1
cell activation	1
regulation of response to external stimulus	1
regulation of coagulation	1
regulation of wound healing	1
regulation of hemostasis	1
positive regulation of coagulation	1
positive regulation of wound healing	1
positive regulation of hemostasis	1
negative regulation of coagulation	1
negative regulation of wound healing	1
negative regulation of hemostasis	1
positive regulation of biosynthetic process	1
positive regulation of collagen metabolic process	1
collagen biosynthetic process	1
regulation of collagen biosynthetic process	1
proteolysis	1
regulation of proteolysis	1
negative regulation of protein metabolic process	1
cell surface receptor signaling pathway via JAK-STAT	1
regulation of receptor signaling pathway via JAK-STAT	1
positive regulation of receptor signaling pathway via STAT	1
negative regulation of glial cell differentiation	1
astrocyte differentiation	1
regulation of astrocyte differentiation	1
release of sequestered calcium ion into cytosol	1
regulation of release of sequestered calcium ion into cytosol	1
positive regulation of calcium ion transmembrane transport	1
intracellular calcium ion homeostasis	1
positive regulation of blood coagulation	1
positive regulation of response to external stimulus	1
fibrinolysis	1
negative regulation of biological process	1
regulation of fibrinolysis	1
antimicrobial humoral response	1
G protein-coupled receptor signaling pathway	1
lipid binding	1
carbohydrate derivative binding	1
endopeptidase activity	1
serine-type peptidase activity	1
protein binding	1
metal ion binding	1
receptor ligand activity	1
glycosaminoglycan binding	1
sulfur compound binding	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 26 of 51 annotations. The rest are phylogenetic / computational / electronic (IEA).

26 experimentally-supported GO terms:

GO term	NS	Evidence
antimicrobial humoral immune response mediated by antimicrobial peptide	BP	direct assay
cell surface receptor signaling pathway	BP	direct assay
fibrinolysis	BP	direct assay
negative regulation of astrocyte differentiation	BP	direct assay
negative regulation of blood coagulation	BP	direct assay
negative regulation of cytokine production involved in inflammatory response	BP	direct assay
negative regulation of proteolysis	BP	direct assay
neutrophil-mediated killing of gram-negative bacterium	BP	direct assay
platelet activation	BP	direct assay
positive regulation of blood coagulation	BP	direct assay
positive regulation of collagen biosynthetic process	BP	direct assay
positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway	BP	direct assay
positive regulation of protein localization to nucleus	BP	direct assay
positive regulation of reactive oxygen species metabolic process	BP	direct assay
positive regulation of release of sequestered calcium ion into cytosol	BP	direct assay
regulation of cytosolic calcium ion concentration	BP	direct assay
response to wounding	BP	direct assay
thrombin-activated receptor signaling pathway	BP	direct assay
blood microparticle	CC	high-throughput assay
extracellular exosome	CC	high-throughput assay
heparin binding	MF	direct assay
lipopolysaccharide binding	MF	direct assay
receptor ligand activity	MF	direct assay
serine-type endopeptidase activity	MF	direct assay
signaling receptor binding	MF	physical interaction
thrombospondin receptor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,064 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
F2	F3	P13726	990
F2	SERPINC1	P01008	963
F2	GPT	P24298	928
F2	MTHFR	P42898	926
F2	F8	P00451	921
F2	TFPI	P10646	908
F2	FGA	P02671	886
F2	THBD	P07204	886
F2	ALB	P02768	885
F2	CRP	P02741	883
F2	AFP	P02771	883
F2	FGB	P02675	881
F2	F5	P12259	878
F2	FGG	P02679	875
F2	GPT2	Q8TD30	859

IntAct

Human interaction partners of F2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

13 partners by confidence:

Partner	Interaction type	MIscore	Records
APP	physical association	0.560	3
C1QBP	association	0.460	3
THBD	direct interaction	0.440	4
F2R	direct interaction	0.440	1
F8	direct interaction	0.440	1
SERPINA5	direct interaction	0.440	1
GP1BA	physical association	0.400	1
SERPINC1	physical association	0.400	1
DDIT3	physical association	0.370	1
ALB	association	0.350	1
CHAMP1	association	0.350	1
FGA	proximity	0.270	1
SPP1	proximity	0.270	1

BioGRID (56 interactions; top human partners by supporting records): THBD (Reconstituted Complex; 3 records), F10 (Affinity Capture-MS; 2 records), FGA (Co-localization; 2 records), ACE2 (Affinity Capture-MS), AGPAT1 (Affinity Capture-MS), ALB (Affinity Capture-MS), APOC3 (Affinity Capture-MS), BIRC3 (Affinity Capture-MS), CAMP (Protein-peptide), CCR1 (Affinity Capture-MS), CHAMP1 (Affinity Capture-MS), CPB2 (Reconstituted Complex), DDIT3 (Two-hybrid), DNMT1 (Affinity Capture-MS), F5 (Reconstituted Complex)

SIGNOR signaling

showing 22 of 38 signaling interactions:

A	Effect	B	Mechanism
F2	up-regulates	F2RL1	binding
F2	up-regulates	F2RL2	binding
dabigatran	down-regulates	F2	“chemical inhibition”
F2	up-regulates	F2RL3	binding
F2	up-regulates	F2R	cleavage
F2	up-regulates	F2R	binding
F2	“up-regulates activity”	“GPIb-IX-V complex”	binding
SERPINA1	“down-regulates activity”	F2	binding
F2	“up-regulates activity”	Fibrinogen	cleavage
F2	“up-regulates activity”	F7
F2	“up-regulates activity”	F5
F2	“form complex”	Thrombin-Thrombomodulin	binding
GGCX	“up-regulates activity”	F2	carboxylation
F2	up-regulates	LRP1	binding
F10	“up-regulates activity”	F2	cleavage
bivalirudin	“down-regulates activity”	F2	“chemical inhibition”
“Factor Va-Xa”	“up-regulates activity”	F2	cleavage
F2	“up-regulates activity”	F2R	cleavage
F2	“down-regulates activity”	F2R	cleavage
F2	“up-regulates activity”	F5	cleavage
F2	“up-regulates activity”	F8	cleavage
SERPINC1	“down-regulates activity”	F2	cleavage

Protein complexes (CORUM) (4)

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

4 complexes by size:

Complex	Subunits	Members
★ F2-SERPINC1-VTN complex	3	F2, SERPINC1, VTN
★ AMBP-F2 complex	2	AMBP, F2
★ F2-SERPINA5 complex	2	F2, SERPINA5
★ F2-SERPIND1 complex	2	F2, SERPIND1

Ligand–receptor pairs (CellPhoneDB) (7)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

7 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
ITGAV;ITGB3	ligand	Adhesion by Prothrombin
GP1BA;GP1BB	ligand	Adhesion by Prothrombin
ITGA2B;ITGB3	ligand	Adhesion by Prothrombin
F2RL2	ligand	Adhesion by Prothrombin
F2R	ligand	Adhesion by Prothrombin
THBD	ligand	Adhesion by Prothrombin
F2RL3	ligand	Adhesion by Prothrombin

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 13 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of clotting cascade	7	135.9×	2e-12
Post-translational protein phosphorylation	5	41.7×	3e-06
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	5	36.0×	4e-06
Hemostasis	5	15.0×	2e-04

Disease & clinical

Genetic variants

Variant evidence for F2: 481 ClinVar records (39 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 18 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	19
Uncertain significance	123
Likely benign	253
Benign	23

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 39 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
692073	NM_000506.5(F2):c.1787G>A (p.Arg596Gln)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
2706763	NM_000506.5(F2):c.1499G>A (p.Arg500Gln)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
627408	NM_000506.5(F2):c.941G>A (p.Arg314His)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
13303	NM_000506.3(F2):c.940C>T (p.Arg314Cys)	Pathogenic	criteria provided, single submitter	2
2735585	NM_000506.5(F2):c.1015C>T (p.Arg339Ter)	Pathogenic	criteria provided, single submitter	1
2735586	NM_000506.5(F2):c.1786C>T (p.Arg596Trp)	Pathogenic	criteria provided, single submitter	1
2806215	NM_000506.5(F2):c.13C>T (p.Arg5Ter)	Pathogenic	criteria provided, single submitter	1
2872207	NM_000506.5(F2):c.923_926del (p.Asp308fs)	Pathogenic	criteria provided, single submitter	1
2884504	NM_000506.5(F2):c.392dup (p.Trp132fs)	Pathogenic	criteria provided, single submitter	1
2957927	NM_000506.5(F2):c.349C>T (p.Arg117Ter)	Pathogenic	criteria provided, single submitter	1
2966946	NM_000506.5(F2):c.954dup (p.Glu319Ter)	Pathogenic	criteria provided, single submitter	1
3015914	NM_000506.5(F2):c.1678C>T (p.Arg560Ter)	Pathogenic	criteria provided, single submitter	1
4686696	NM_000506.5(F2):c.552del (p.Val185fs)	Pathogenic	criteria provided, single submitter	1
13305	NM_000506.3(F2):c.1273C>T (p.Arg425Cys)	Likely pathogenic	criteria provided, single submitter	2
13308	NM_000506.3(F2):c.1292G>A (p.Arg431His)	Likely pathogenic	criteria provided, single submitter	2

Per-variant reference — Sugi Variant

Explore F2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 1,176):

Position(s)	Effect	Δscore	Sites
11:46719863–46719864	donor_loss	1.0000	5
11:46723519–46723520	donor_loss	1.0000	5
11:46726945	donor_gain	1.0000
11:46727994–46727995	acceptor_loss	1.0000	6
11:46728146	donor_gain	1.0000
11:46728164–46728165	donor_loss	1.0000	4
11:46728650–46728651	acceptor_gain	1.0000	2
11:46728662–46728663	acceptor_loss	1.0000	2
11:46728793	donor_gain	1.0000
11:46739046	acceptor_gain	1.0000

AlphaMissense

1,528 missense substitutions predicted likely pathogenic (of 4,069 scored), across 342 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:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M548	9	0.942	0.983
M380	9	0.850	0.967
D462	8	0.997	0.999
D567	8	0.993	0.998
H406	8	0.987	0.996
S568	8	0.980	0.997
D562	8	0.976	0.991
F572	8	0.933	0.989
D268	8	0.932	0.971
H450	8	0.928	0.994
D349	8	0.913	0.978
F549	8	0.913	0.992
F602	8	0.911	0.994
N159	8	0.910	0.988
N264	8	0.903	0.981
H138	8	0.901	0.982
F329	8	0.895	0.985
N155	8	0.872	0.977
C550	7	0.998	0.999
C564	7	0.998	0.999

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Liver Hepatocellular Carcinoma)

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	1.23e-06
Lung Adenocarcinoma (TCGA)	unfavorable	0.00018
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	0.000497

Disease associations

OMIM: gene MIM:176930 | disease phenotypes: MIM:613679, MIM:188050, MIM:614390

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
thrombophilia due to thrombin defect	Definitive	Autosomal dominant	4
congenital prothrombin deficiency	Strong	Autosomal recessive	4

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

2 validity classifications:

Disease	Classification	Inheritance
thrombophilia due to thrombin defect	Definitive	AD
congenital prothrombin deficiency	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (4 panels, 4 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

4 panels:

Panel	Rating
Bleeding and platelet disorders	green
Factor II deficiency	green
Inherited bleeding disorders	green
Thrombophilia with a likely monogenic cause	green

Mondo (6): congenital prothrombin deficiency (MONDO:0013361), thrombophilia due to thrombin defect (MONDO:0008559), venous thromboembolism (MONDO:0005399), cerebral palsy (MONDO:0006497), pregnancy loss, recurrent, susceptibility to, 2 (MONDO:0013728), ischemic stroke (MONDO:1060198)

Orphanet (1): Congenital factor II deficiency (Orphanet:325)

HPO phenotypes

41 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000132	Menorrhagia
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000978	Bruising susceptibility
HP:0001297	Stroke
HP:0001426	Non-Mendelian inheritance
HP:0001892	Abnormal bleeding
HP:0001903	Anemia
HP:0001907	Thromboembolism
HP:0002170	Intracranial hemorrhage
HP:0002204	Pulmonary embolism
HP:0002239	Gastrointestinal hemorrhage
HP:0002625	Deep venous thrombosis
HP:0002907	Microscopic hematuria
HP:0003010	Prolonged bleeding time
HP:0003577	Congenital onset
HP:0003581	Adult onset
HP:0003645	Prolonged partial thromboplastin time
HP:0003828	Variable expressivity
HP:0004419	Recurrent thrombophlebitis
HP:0004420	Arterial thrombosis
HP:0004936	Venous thrombosis
HP:0005261	Joint hemorrhage
HP:0005305	Cerebral venous thrombosis
HP:0006298	Prolonged bleeding after dental extraction
HP:0008151	Prolonged prothrombin time
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0011884	Abnormal umbilical stump bleeding
HP:0011890	Prolonged bleeding following procedure
HP:0011891	Post-partum hemorrhage
HP:0012233	Intramuscular hematoma
HP:0012541	Cephalohematoma
HP:0030137	Prolonged bleeding following circumcision
HP:0030138	Excessive bleeding from superficial cuts
HP:0030140	Oral cavity bleeding
HP:0031364	Ecchymosis
HP:0040250	Reduced prothrombin antigen
HP:0200067	Recurrent spontaneous abortion

GWAS associations

18 associations:

Study	Trait	p-value
GCST009097_7	Venous thromboembolism	1e-59
GCST009030_16	Venous thromboembolism	1e-31
GCST003390_2	Thrombosis	1e-24
GCST007825_4	Alzheimer’s disease or fasting glucose levels (pleiotropy)	3e-16
GCST009030_17	Venous thromboembolism	1e-15
GCST004521_273	Autism spectrum disorder or schizophrenia	3e-13
GCST006803_36	Schizophrenia	3e-13
GCST004256_6	Venous thromboembolism	5e-13
GCST90002393_490	Monocyte count	1e-12
GCST90002388_177	Lymphocyte count	6e-11
GCST005580_224	Intraocular pressure	7e-11
GCST006017_6	Prothrombin time	1e-9
GCST002808_9	Venous thromboembolism	2e-9
GCST004256_8	Venous thromboembolism	8e-9
GCST004521_116	Autism spectrum disorder or schizophrenia	3e-8
GCST90010718_2	Thumb osteoarthritis severity (hand Klsum)	5e-8
GCST000763_2	Immunoglobulin A	2e-6
GCST007511_23	Alzheimer’s disease (late onset)	6e-6

EFO canonical traits (from GWAS)

7 canonical traits:

EFO ID	Trait name
EFO:0004747	protein measurement
EFO:0003907	deep vein thrombosis
EFO:0004695	intraocular pressure measurement
EFO:0008390	prothrombin time measurement
EFO:1001870	late-onset Alzheimers disease
EFO:0004587	lymphocyte count
EFO:0005091	monocyte count

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
D007020	Hypoprothrombinemias	C15.378.100.100.550; C15.378.100.141.550; C15.378.463.550; C16.320.099.550
D054556	Venous Thromboembolism	C14.907.355.590.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL204 (SINGLE PROTEIN), CHEMBL2096988 (SELECTIVITY GROUP), CHEMBL2111379 (SELECTIVITY GROUP), CHEMBL2111401 (SELECTIVITY GROUP), CHEMBL2111477 (SELECTIVITY GROUP)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the F2 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.

13 curated-mechanism drugs:

Drug	Modality	Max phase
ANTITHROMBIN ALFA	Protein	4
ARGATROBAN	Small molecule	4
BIVALIRUDIN	Protein	4
DABIGATRAN ETEXILATE MESYLATE	Small molecule	4
DESIRUDIN	Protein	4
LEPIRUDIN	Protein	4
PROTHROMBIN	Protein	4
XIMELAGATRAN	Small molecule	4
DABIGATRAN	Small molecule	3
DEFIBROTIDE	Unknown	3
PROTHROMBIN COMPLEX CONCENTRATE	Protein	3
ATECEGATRAN METOXIL	Small molecule	2
ICHORCUMAB	Antibody	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 708,884 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

48 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1166	ARGATROBAN	4	233
CHEMBL5314348	BIVALIRUDIN	4
CHEMBL539697	DABIGATRAN ETEXILATE	4	1,244
CHEMBL522038	XIMELAGATRAN	4	7,476
CHEMBL231779	APIXABAN	4	9,446
CHEMBL1200370	BENZOYL PEROXIDE	4	356,706
CHEMBL512351	BETRIXABAN	4	1,131
CHEMBL325041	BORTEZOMIB	4	13,415
CHEMBL1560	CAPTOPRIL	4	66,788
CHEMBL311498	CIANIDANOL	4	60,179
CHEMBL333826	DEQUALINIUM	4	1,128
CHEMBL1269025	EDOXABAN	4	2,478
CHEMBL64894	GENTIAN VIOLET	4	112,306
CHEMBL25105	HEXAMIDINE	4	5,713
CHEMBL1091250	INDIGOTINDISULFONATE	4	342
CHEMBL1544	LIOTHYRONINE	4	23,991
CHEMBL2107831	LUSUTROMBOPAG	4	132
CHEMBL266349	MELAGATRAN	4	5,456
CHEMBL1364144	METHYLPREDNISOLONE ACETATE	4	13,523
CHEMBL55	PENTAMIDINE	4	27,197
CHEMBL198362	RIVAROXABAN	4
CHEMBL1201073	SUCCIMER	4
CHEMBL338802	SULFAGUANIDINE	4
CHEMBL2103855	TELOTRISTAT	4
CHEMBL48361	DABIGATRAN	3
CHEMBL590799	CAMOSTAT	3
CHEMBL85164	CAMOSTAT MESILATE	3
CHEMBL87563	GABEXATE	3
CHEMBL4112929	MILVEXIAN	3
CHEMBL273264	NAFAMOSTAT	3
CHEMBL50	QUERCETIN	3
CHEMBL9509	SILIBININ	3
CHEMBL3716552	BMS-986141	2
CHEMBL1187445	CETRAXATE	2
CHEMBL30044	DIBROMPROPAMIDINE	2
CHEMBL273196	EFEGATRAN	2
CHEMBL73193	FIDEXABAN	2
CHEMBL220050	GW813893	2
CHEMBL114715	INOGATRAN	2
CHEMBL1095032	LETAXABAN	2
CHEMBL325166	NAPSAGATRAN ANHYDROUS	2
CHEMBL55400	PROFLAVINE	2
CHEMBL206335	RAZAXABAN	2
CHEMBL3139247	SEGATROXABAN	2
CHEMBL1270156	TANOGITRAN	2
CHEMBL3786896	AZD-8165	1
CHEMBL30054	DPOC-4088	1
CHEMBL44752	METHYL P-TOLUENESULFONYL-L-ARGININATE	1

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs1799963	Toxicity	2B	hormonal contraceptives for systemic use	Stroke;Venous Thrombosis

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1799963	F2	2B	3.00	1	hormonal contraceptives for systemic use

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

6 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1799963	hormonal contraceptives for systemic use	Toxicity	Genotype AG is associated with increased risk of Venous Thrombosis when treated with hormonal contraceptives for systemic use in women as compared to genotype GG.	PMID:12069454
rs1799963	hormonal contraceptives for systemic use	Toxicity	Allele A is associated with increased risk of Venous Thrombosis when treated with hormonal contraceptives for systemic use in women as compared to allele G.	PMID:28750087
rs1799963	hormonal contraceptives for systemic use	Toxicity	Allele A is associated with increased risk of venous thromboembolism when treated with hormonal contraceptives for systemic use in women as compared to allele G.	PMID:37734636
rs5896	Direct factor Xa inhibitors, Direct thrombin inhibitors	Toxicity	Genotype TT is associated with increased likelihood of Hemorrhage when treated with Direct factor Xa inhibitors null Direct thrombin inhibitors as compared to genotypes CC + CT.	PMID:38904499
rs5896	warfarin	Dosage	Genotypes CT + TT are associated with decreased warfarin dose when treated with warfarin as compared to genotype CC.	PMID:15590403
rs5896	warfarin	Dosage	Genotypes CT + TT are associated with decreased warfarin dose when treated with warfarin as compared to genotype CC.	PMID:14656880

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Blood coagulation components

Most potent curated ligand interactions (11 total), top 11:

Ligand	Action	Affinity	Parameter
lepirudin	Inhibition	13.0	pKi
desirudin	Inhibition	12.7	pKi
Dup-714	Inhibition	10.39	pKi
AZ12971554	Inhibition	9.52	pKi
melagatran	Inhibition	8.7	pKi
bivalirudin	Inhibition	8.6	pKi
AR-H067637	Inhibition	8.4	pIC50
dabigatran	Inhibition	8.3	pKi
BAY 3389934	Inhibition	8.28	pIC50
argatroban	Inhibition	7.7	pKi
WX-UK1	Inhibition	6.3	pKi

Binding affinities (BindingDB)

4854 measured of 5837 human assays (6100 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Arginyl Ketomethylene analogue	KI	0.00035 nM
Arginyl Ketomethylene analogue	KI	0.00057 nM
Arginyl Ketomethylene analogue	KI	0.00087 nM
2-(3-Carbamimidoyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [5-(2-sulfamoyl-phenyl)-pyrimidin-2-yl]-amide	KI	0.001 nM
(2-[6-CHLORO-3-{[2,2-DIFLUORO-2-(1-OXIDOPYRIDIN-2-YL)ETHYL]AMINO}-2-OXOPYRAZIN-1(2H)-YL]-N-[5-CHLORO-2-(1H-TETRAZOL-1-YL)BENZYL]ACETAMIDE	KI	0.001 nM
2-[6-Chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]-N-(5-chloro-2-tetrazol-1-yl-benzyl)-acetamide	KI	0.0014 nM
Arginyl Ketomethylene analogue	KI	0.0015 nM
Arginyl Ketomethylene analogue	KI	0.0017 nM
5-amino(imino)methylamino-2-[1-[2-amino-3-phenyl-(2S)-propanoyl]-(5S)-dihydro-1H-5-pyrrolylcarboxamido]-(2S)-pentanoic acid	IC50	0.0017 nM
Arginyl Ketomethylene analogue	KI	0.002 nM
2N-(4-Benzamidinemethyl)-1-[2-aminosulfonamido-3,3-diphenyl-(2R)-propanoyl]-(2S)-tetrahydro-1H-2-pyrrolecarboxamide;TFA	KI	0.003 nM
2N-(4-Benzamidinemethyl)-1-[2-Cyclohexylaminosulfonamido-3,3-diphenyl-(2R)-propanoyl]-(2S)-tetrahydro-1H-2-pyrrolecarboxamide;TFA	KI	0.003 nM
N-(2-Aminomethyl-5-chloro-benzyl)-2-{6-chloro-3-[2,2-difluoro-2-(1-oxy-pyridin-2-yl)-ethylamino]-2-oxo-2H-pyrazin-1-yl}-acetamide	KI	0.0034 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-{[3,4-dihydro-2H-pyrrol-5-yl(methyl)amino]methyl}thiophene-2-carboxamide	KI	0.004 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-{[2-(methylsulfanyl)-4,5-dihydro-1H-imidazol-1-yl]methyl}thiophene-2-carboxamide	KI	0.004 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-(4,5-dihydro-1H-imidazol-1-ylmethyl)thiophene-2-carboxamide	KI	0.004 nM
1-(2-sulfonamide-amino-3,3-diphenyl-propionyl)-pyrrolidine-2-carboxylic acid (5-carbamimidoyl-thiophen-2-ylmethyl)-amide	KI	0.004 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-{[2-(ethylamino)-1H-imidazol-1-yl]methyl}thiophene-2-carboxamide	KI	0.005 nM
2-(3-Carbamimidoyl-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (3-fluoro-2’-sulfamoyl-biphenyl-4-yl)-amide	KI	0.005 nM
2N-(4-Benzamidinemethyl)-1-[2-Benzylsulfonamido-3,3-diphenyl-(2R)-propanoyl]-(2S)-tetrahydro-1H-2-pyrrolecarboxamide;TFA	KI	0.005 nM
(2S)-1-[(2R)-2-amino-3-phenylpropanoyl]-N-[1-(1,3-benzothiazol-2-yl)-5-carbamimidamido-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	KI	0.0055 nM
4-[(2-amino-1H-imidazol-1-yl)methyl]-3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}thiophene-2-carboxamide	KI	0.006 nM
2-(5-carbamimidamido-2-{[(2S)-1-[(2R)-2-(methylamino)-3-phenylpropanoyl]pyrrolidin-2-yl]formamido}pentanoyl)-1,3-benzothiazole-6-carboxamide	KI	0.007 nM
2-(3-Carbamimidoyl-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid [5-(2-sulfamoyl-phenyl)-pyridin-2-yl]-amide	KI	0.007 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-{[2-(propan-2-ylamino)-1H-imidazol-1-yl]methyl}thiophene-2-carboxamide	KI	0.008 nM
2-(3-Carbamimidoyl-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (2’-methanesulfonyl-biphenyl-4-yl)-amide	KI	0.008 nM
2-(3-Carbamimidoyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (2’-methanesulfonyl-biphenyl-4-yl)-amide	KI	0.008 nM
1-(2-sulfonamideamino-3,3-diphenyl-propionyl)-pyrrolidine-2-carboxylic acid 4-carbamimidoyl-3-fluoro-benzylamide	KI	0.008 nM
2-(3-Carbamimidoyl-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (3-chloro-2’-sulfamoyl-biphenyl-4-yl)-amide	KI	0.009 nM
2-(3-Carbamimidoyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [5-(2-sulfamoyl-phenyl)-pyridin-2-yl]-amide	KI	0.009 nM
Arginyl Ketomethylene analogue	KI	0.0094 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-[(2-imino-1,3-oxazolidin-3-yl)methyl]thiophene-2-carboxamide	KI	0.01 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-[(2-imino-1,3-thiazolidin-3-yl)methyl]thiophene-2-carboxamide	KI	0.01 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-[(2-iminoimidazolidin-1-yl)methyl]thiophene-2-carboxamide	KI	0.01 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-[(2-methyl-4,5-dihydro-1H-imidazol-1-yl)methyl]thiophene-2-carboxamide	KI	0.01 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-[(N-methylethanimidamido)methyl]thiophene-2-carboxamide	KI	0.01 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-(3-methylcarbamimidamidomethyl)thiophene-2-carboxamide	KI	0.01 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-[(2-methyl-1H-imidazol-1-yl)methyl]thiophene-2-carboxamide	KI	0.01 nM
[2-[[(1R)-1-(3-chlorophenyl)-2-fluoroethyl]amino]-7-methoxy-1,3-benzoxazol-5-yl]-[(5R)-2-(2-hydroxyethyl)-2,5-dimethylmorpholin-4-yl]methanone	IC50	0.01 nM	US-9493472: Substituted benzoxazoles
2-(3-Carbamimidoyl-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (3-bromo-2’-sulfamoyl-biphenyl-4-yl)-amide	KI	0.01 nM
3-(1-Benzhydryl-2-{2-[(5-carbamimidoyl-thiophen-2-ylmethyl)-carbamoyl]-pyrrolidin-1-yl}-2-oxo-ethylamino)-propionic acid	KI	0.01 nM
1-(2-sulfonamideamino-3,3-diphenyl-propionyl)-pyrrolidine-2-carboxylic acid 4-carbamimidoyl-2-fluoro-benzylamide	KI	0.01 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-{[4,5-dihydro-1,3-oxazol-2-yl(ethyl)amino]methyl}thiophene-2-carboxamide	KI	0.012 nM
3-chloro-N-{4-chloro-2-[(5-chloropyridin-2-yl)carbamoyl]-6-methoxyphenyl}-4-{[5,6-dihydro-4H-1,3-oxazin-2-yl(methyl)amino]methyl}thiophene-2-carboxamide	KI	0.012 nM
2N-(4-Benzamidinemethyl)-1-[2-Aminoaceticacid-3,3-diphenyl-(2R)-propanoyl]-(2S)-tetrahydro-1H-2-pyrrolecarboxamide;TFA	KI	0.013 nM
2-(3-Carbamimidoyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (2’-sulfamoyl-biphenyl-4-yl)-amide	KI	0.015 nM
1-(2-sulfonamideamino-3,3-diphenyl-propionyl)-pyrrolidine-2-carboxylic acid (6-carbamimidoyl-pyridin-3-ylmethyl)-amide	KI	0.015 nM
(1-Benzhydryl-2-{2-[(5-carbamimidoyl-thiophen-2-ylmethyl)-carbamoyl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid methyl ester	KI	0.015 nM
(1-Benzhydryl-2-{2-[(6-carbamimidoyl-pyridin-3-ylmethyl)-carbamoyl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid methyl ester	KI	0.017 nM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-carbamimidamido-1-oxopentan-2-yl]-1-[(2R)-2-cyclohexyl-2-(methylamino)acetyl]pyrrolidine-2-carboxamide	KI	0.018 nM

ChEMBL bioactivities

5614 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL4108739
11.00	Ki	0.01	nM	CHEMBL121212
11.00	Ki	0.01	nM	CHEMBL120079
10.96	Ki	0.011	nM	CHEMBL285285
10.89	Ki	0.013	nM	CHEMBL323583
10.89	Ki	0.013	nM	CHEMBL330949
10.82	Ki	0.015	nM	CHEMBL1159688
10.82	Ki	0.015	nM	CHEMBL1682691
10.82	Ki	0.015	nM	CHEMBL124300
10.82	Ki	0.015	nM	CHEMBL119877
10.82	Ki	0.015	nM	CHEMBL420540
10.77	Ki	0.017	nM	CHEMBL331571
10.74	Ki	0.018	nM	CHEMBL103874
10.74	Ki	0.018	nM	CHEMBL353760
10.74	Ki	0.018	nM	CHEMBL285285
10.72	Ki	0.019	nM	CHEMBL291026
10.70	Ki	0.02	nM	CHEMBL7860
10.70	Ki	0.02	nM	CHEMBL2419745
10.70	Ki	0.02	nM	CHEMBL92615
10.70	Ki	0.02	nM	CHEMBL120308
10.70	Ki	0.02	nM	CHEMBL122410
10.64	Ki	0.023	nM	CHEMBL36012
10.62	Ki	0.024	nM	CHEMBL290577
10.57	Ki	0.027	nM	CHEMBL287918
10.55	Ki	0.028	nM	CHEMBL3349045
10.55	Ki	0.028	nM	CHEMBL291261
10.52	IC50	0.03	nM	EFEGATRAN
10.52	Ki	0.03	nM	CHEMBL120187
10.48	Ki	0.033	nM	CHEMBL103342
10.47	Ki	0.034	nM	CHEMBL291261
10.46	Ki	0.035	nM	CHEMBL415375
10.46	Ki	0.035	nM	CHEMBL306797
10.44	Ki	0.036	nM	CHEMBL1159692
10.44	Ki	0.036	nM	CHEMBL1159694
10.40	Ki	0.04	nM	CHEMBL607008
10.40	Ki	0.04	nM	CHEMBL195366
10.40	Ki	0.04	nM	CHEMBL426101
10.40	Ki	0.04	nM	CHEMBL198820
10.40	Ki	0.04	nM	CHEMBL296737
10.40	Ki	0.04	nM	CHEMBL290376
10.39	Ki	0.041	nM	CHEMBL290376
10.39	Kd	0.041	nM	CHEMBL290376
10.38	Ki	0.042	nM	CHEMBL290376
10.38	IC50	0.042	nM	CHEMBL143418
10.38	Ki	0.042	nM	CHEMBL191441
10.38	Ki	0.042	nM	CHEMBL143418
10.38	Ki	0.042	nM	CHEMBL287918
10.36	Ki	0.044	nM	CHEMBL1159690
10.35	Ki	0.045	nM	CHEMBL9582
10.35	Ki	0.045	nM	CHEMBL1159689

PubChem BioAssay actives

2708 with measured affinity, of 6100 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.

Compound	Assay	Type	Value	Unit
N-[[2-(aminomethyl)-5-chlorophenyl]methyl]-2-[6-(2,2-difluoro-2-pyridin-2-ylethyl)imino-1-hydroxy-2-pyridinyl]acetamide	238307: Binding affinity against thrombin in human plasma	ki	<0.0001	uM
N-[[5-chloro-2-(tetrazol-1-yl)phenyl]methyl]-2-[3-cyano-6-(2,2-difluoro-2-pyridin-2-ylethyl)imino-1-hydroxy-2-pyridinyl]acetamide	238307: Binding affinity against thrombin in human plasma	ki	<0.0001	uM
N-[[2-(aminomethyl)-5-chlorophenyl]methyl]-2-[3-cyano-6-(2,2-difluoro-2-pyridin-2-ylethyl)imino-1-hydroxy-2-pyridinyl]acetamide	238307: Binding affinity against thrombin in human plasma	ki	<0.0001	uM
N-[[2-(aminomethyl)-5-chlorophenyl]methyl]-2-[3-(benzylsulfonylamino)-6-methyl-2-oxo-1-pyridinyl]acetamide	211602: Inhibitory constant evaluated against thrombin (Factor IIa)	ki	<0.0001	uM
methyl N-[(2R)-1-[(2S)-2-[(6-carbamimidoyl-3-pyridinyl)methylcarbamoyl]pyrrolidin-1-yl]-1-oxo-3,3-diphenylpropan-2-yl]carbamate	211044: In vitro inhibition constant (Ki) against human thrombin	ki	<0.0001	uM
2-[6-chloro-3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-2-oxopyrazin-1-yl]-N-[[5-chloro-2-(tetrazol-1-yl)phenyl]methyl]acetamide	1381627: Binding affinity to thrombin (unknown origin)	ki	<0.0001	uM
(2S)-N-[(4-carbamimidoylphenyl)methyl]-1-[(2R)-2-(methanesulfonamido)-3,3-diphenylpropanoyl]pyrrolidine-2-carboxamide	211022: Binding affinity against human thrombin	ki	<0.0001	uM
methyl N-[(2R)-1-[(2S)-2-[(4-carbamimidoylphenyl)methylcarbamoyl]pyrrolidin-1-yl]-1-oxo-3,3-diphenylpropan-2-yl]carbamate	211044: In vitro inhibition constant (Ki) against human thrombin	ki	<0.0001	uM
2-[3-(benzylsulfonylamino)-6-methyl-2-oxo-1-pyridinyl]-N-[[5-chloro-2-(tetrazol-1-yl)phenyl]methyl]acetamide	211217: Inhibitory potency against human thrombin	ki	<0.0001	uM
2-[6-chloro-3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-2-oxopyrazin-1-yl]-N-[[5-chloro-2-(1,2,4-triazol-1-yl)phenyl]methyl]acetamide	1381627: Binding affinity to thrombin (unknown origin)	ki	<0.0001	uM
(2S)-N-[(4-carbamimidoyl-3-fluorophenyl)methyl]-1-[(2R)-3,3-diphenyl-2-(sulfamoylamino)propanoyl]pyrrolidine-2-carboxamide	211044: In vitro inhibition constant (Ki) against human thrombin	ki	<0.0001	uM
N-[[5-chloro-2-(tetrazol-1-yl)phenyl]methyl]-2-[3-[[2,2-difluoro-2-(1-oxidopyridin-1-ium-2-yl)ethyl]amino]-2-oxopyrazin-1-yl]acetamide	211217: Inhibitory potency against human thrombin	ki	<0.0001	uM
2-[[(2R)-1-[(2S)-2-[(4-carbamimidoylphenyl)methylcarbamoyl]pyrrolidin-1-yl]-1-oxo-3,3-diphenylpropan-2-yl]amino]acetic acid	211044: In vitro inhibition constant (Ki) against human thrombin	ki	<0.0001	uM
N-[[5-chloro-2-(tetrazol-1-yl)phenyl]methyl]-2-[3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-2-oxopyrazin-1-yl]acetamide	211217: Inhibitory potency against human thrombin	ki	<0.0001	uM
N-[[2-(aminomethyl)-5-chlorophenyl]methyl]-2-[6-chloro-3-[[2,2-difluoro-2-(1-oxidopyridin-1-ium-2-yl)ethyl]amino]-2-oxopyrazin-1-yl]acetamide	211602: Inhibitory constant evaluated against thrombin (Factor IIa)	ki	<0.0001	uM
(2S)-N-[(6-carbamimidoyl-3-pyridinyl)methyl]-1-[(2R)-3,3-diphenyl-2-(sulfamoylamino)propanoyl]pyrrolidine-2-carboxamide	211044: In vitro inhibition constant (Ki) against human thrombin	ki	<0.0001	uM
(2S)-N-[(4-carbamimidoyl-2-fluorophenyl)methyl]-1-[(2R)-3,3-diphenyl-2-(sulfamoylamino)propanoyl]pyrrolidine-2-carboxamide	211044: In vitro inhibition constant (Ki) against human thrombin	ki	<0.0001	uM
2-[[5-chloro-2-(1,2,4-triazol-1-yl)phenyl]methyl]-N-(2,2-difluoro-2-pyridin-2-ylethyl)-6-methyl-[1,3]oxazolo[4,5-c]pyridin-4-amine	254280: Inhibitory constant against thrombin	ki	<0.0001	uM
methyl N-[(2R)-1-[(2S)-2-[(5-carbamimidoylthiophen-2-yl)methylcarbamoyl]pyrrolidin-1-yl]-1-oxo-3,3-diphenylpropan-2-yl]carbamate	211044: In vitro inhibition constant (Ki) against human thrombin	ki	<0.0001	uM
(2S)-N-[(4-carbamimidoylthiophen-2-yl)methyl]-1-[(2R)-3,3-diphenyl-2-(sulfamoylamino)propanoyl]pyrrolidine-2-carboxamide	211044: In vitro inhibition constant (Ki) against human thrombin	ki	<0.0001	uM
(2S)-N-[(5-carbamimidoylthiophen-2-yl)methyl]-1-[(2R)-2-(methanesulfonamido)-3,3-diphenylpropanoyl]pyrrolidine-2-carboxamide	211022: Binding affinity against human thrombin	ki	<0.0001	uM
(2S)-N-[(5-carbamimidoylfuran-3-yl)methyl]-1-[(2R)-3,3-diphenyl-2-(sulfamoylamino)propanoyl]pyrrolidine-2-carboxamide	211044: In vitro inhibition constant (Ki) against human thrombin	ki	<0.0001	uM
3-[[(2R)-1-[(2S)-2-[(5-carbamimidoylthiophen-2-yl)methylcarbamoyl]pyrrolidin-1-yl]-1-oxo-3,3-diphenylpropan-2-yl]amino]propanoic acid	211044: In vitro inhibition constant (Ki) against human thrombin	ki	<0.0001	uM
2-[6-chloro-3-[[2,2-difluoro-2-(1-oxidopyridin-1-ium-2-yl)ethyl]amino]-2-oxopyrazin-1-yl]-N-[[5-chloro-2-(1,2,4-triazol-1-yl)phenyl]methyl]acetamide	1381627: Binding affinity to thrombin (unknown origin)	ki	<0.0001	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-1-[(2R)-3-cyclohexyl-2-(methylamino)propanoyl]pyrrolidine-2-carboxamide	210994: Binding affinity to human thrombin	ki	<0.0001	uM
(2S)-N-[[2-(aminomethyl)-5-chlorophenyl]methyl]-1-(7-chloro-5-hydroxyindeno[1,2-b]pyridine-5-carbonyl)pyrrolidine-2-carboxamide	238219: Inhibition of coagulation factor II (thrombin) of human	ki	<0.0001	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-1-[(2R)-2-cyclohexyl-2-(methylamino)acetyl]pyrrolidine-2-carboxamide	1797150: Enzyme Inhibition Assay from Article 10.1021/jm0303857: “In-depth study of tripeptide-based alpha-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1’ subsite and its implications to structure-based drug design.”	ki	<0.0001	uM
(2S)-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-1-[(2R)-2-(methylamino)-3,3-diphenylpropanoyl]pyrrolidine-2-carboxamide	1797150: Enzyme Inhibition Assay from Article 10.1021/jm0303857: “In-depth study of tripeptide-based alpha-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1’ subsite and its implications to structure-based drug design.”	ki	<0.0001	uM
N-[[2-(aminomethyl)-5-chlorophenyl]methyl]-2-[3-chloro-6-(2,2-difluoro-2-pyridin-2-ylethyl)imino-1-hydroxy-2-pyridinyl]acetamide	238307: Binding affinity against thrombin in human plasma	ki	<0.0001	uM
N-[(6-amino-2-methyl-3-pyridinyl)methyl]-2-[3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-6-methyl-2-oxopyrazin-1-yl]acetamide	1254752: Inhibition of Thrombin (unknown origin)	ki	<0.0001	uM
benzyl N-[(2R)-1-[(2S)-2-[[(1S)-4-methoxy-1-[(2S,6R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]carbamoyl]pyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]carbamate	210857: Binding affinity against alpha thrombin	ki	<0.0001	uM
(2S)-N-[(2S)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-1-[(2R)-2-(methylamino)-3-phenylpropanoyl]pyrrolidine-2-carboxamide	210656: Concentration required to inhibit thrombin was determined	ic50	<0.0001	uM
[(1R)-1-[[(2S)-1-[(2R)-2-acetamido-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-4-(diaminomethylideneamino)butyl]boronic acid	211182: Inhibition constant for binding with thrombin was determined	ki	<0.0001	uM
(20S)-20-benzyl-8,25-dichloro-18-methyl-12-oxa-1,4,18,21,23-pentazatricyclo[20.3.1.06,11]hexacosa-6(11),7,9,22,24-pentaene-3,26-dione	211202: Inhibitory activity against thrombin IIa	ki	<0.0001	uM
2-[2-[[2-(aminomethyl)phenyl]methylamino]-2-hydroxyethyl]-6-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-1-oxidopyridin-1-ium-3-carbonitrile	238307: Binding affinity against thrombin in human plasma	ki	<0.0001	uM
2-[5-(diaminomethylideneamino)-2-[[(2S)-1-[(2R)-2-(methylamino)-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]-1,3-benzothiazole-6-carboxamide	1797150: Enzyme Inhibition Assay from Article 10.1021/jm0303857: “In-depth study of tripeptide-based alpha-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1’ subsite and its implications to structure-based drug design.”	ki	<0.0001	uM
ethyl 2-[2-[2-[[2-[[5-chloro-2-(1,2,4-triazol-1-yl)phenyl]methyl]-[1,3]oxazolo[4,5-c]pyridin-4-yl]amino]ethyl]piperidin-1-yl]acetate	254280: Inhibitory constant against thrombin	ki	0.0001	uM
2-[3-chloro-6-(2,2-difluoro-2-pyridin-2-ylethyl)imino-1-hydroxy-2-pyridinyl]-N-[[5-chloro-2-(1,2,4-triazol-1-yl)phenyl]methyl]acetamide	238307: Binding affinity against thrombin in human plasma	ki	0.0001	uM
N-[(5-carbamimidoylthiophen-2-yl)methyl]-2-[6-methyl-2-oxo-3-(2-phenylethylamino)pyrazin-1-yl]acetamide	211179: In vitro inhibitory constant against human thrombin (FIIa).	ki	0.0001	uM
2-[6-chloro-3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-2-oxopyrazin-1-yl]-N-[[2-(tetrazol-1-yl)phenyl]methyl]acetamide	211217: Inhibitory potency against human thrombin	ki	0.0001	uM
2-[3-(benzylsulfonylamino)-6-methyl-2-oxo-1-pyridinyl]-N-[(5-carbamimidoylthiophen-2-yl)methyl]acetamide	211179: In vitro inhibitory constant against human thrombin (FIIa).	ki	0.0001	uM
N-[[5-chloro-2-(1,2,4-triazol-1-yl)phenyl]methyl]-2-[3-[[2,2-difluoro-2-(1-oxidopyridin-1-ium-2-yl)ethyl]amino]-2-oxopyrazin-1-yl]acetamide	211217: Inhibitory potency against human thrombin	ki	0.0001	uM
2-[6-chloro-3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-2-oxopyrazin-1-yl]-N-[[3-(tetrazol-1-yl)-2-pyridinyl]methyl]acetamide	211217: Inhibitory potency against human thrombin	ki	0.0001	uM
N-[[5-chloro-2-(tetrazol-1-yl)phenyl]methyl]-2-[6-(2,2-difluoro-2-pyridin-2-ylethyl)imino-1-hydroxy-2-pyridinyl]acetamide	238307: Binding affinity against thrombin in human plasma	ki	0.0001	uM
(2S)-N-[(1S)-1-(4-aminocyclohexyl)-3-(methylamino)-2,3-dioxopropyl]-1-[(2R)-2-(methylamino)-3-phenylpropanoyl]pyrrolidine-2-carboxamide	211572: Binding affinity towards thrombin	ki	0.0001	uM
N-[2-(1-benzylpiperidin-2-yl)ethyl]-2-[[5-chloro-2-(1,2,4-triazol-1-yl)phenyl]methyl]-[1,3]oxazolo[4,5-c]pyridin-4-amine	254280: Inhibitory constant against thrombin	ki	0.0001	uM
(2S)-N-[(4-aminocyclohexyl)methyl]-1-[(2R)-2-amino-3,3-dicyclohexylpropanoyl]pyrrolidine-2-carboxamide	211186: Inhibitory activity against human thrombin	ki	0.0001	uM
2-[[5-chloro-2-(1,2,4-triazol-1-yl)phenyl]methyl]-N-(2,2-difluoro-2-piperidin-2-ylethyl)-[1,3]oxazolo[4,5-c]pyridin-4-amine	254280: Inhibitory constant against thrombin	ki	0.0001	uM
N-[[2-(2-aminoethyl)-5-chlorophenyl]methyl]-2-[3-(benzylsulfonylamino)-6-methyl-2-oxo-1-pyridinyl]acetamide	211602: Inhibitory constant evaluated against thrombin (Factor IIa)	ki	0.0001	uM
tert-butyl N-[(2R)-1-[(2S)-2-[(4-aminocyclohexyl)methylcarbamoyl]pyrrolidin-1-yl]-3,3-dicyclohexyl-1-oxopropan-2-yl]carbamate	211186: Inhibitory activity against human thrombin	ki	0.0001	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bivalirudin	affects binding, decreases activity, decreases reaction, increases expression, increases cleavage	10
Heparin	increases abundance, increases activity, increases cleavage, affects binding, affects localization (+5 more)	7
ximelagatran	affects binding, decreases activity, decreases cleavage	4
Ethinyl Estradiol	affects cotreatment, increases expression, decreases activity, decreases expression	4
argatroban	affects binding, decreases activity	3
Gestodene	affects cotreatment, decreases activity, decreases expression, increases expression	3
ML 7	increases phosphorylation, decreases activity, affects activity, decreases reaction	3
Adenosine Triphosphate	decreases reaction, increases secretion, affects reaction, increases abundance, affects cotreatment	3
Calcium	increases localization, increases abundance, increases uptake, decreases reaction	3
Quercetin	increases localization, decreases reaction, increases abundance, increases expression	3
Cyclosporine	decreases expression	3
bisphenol A	affects cotreatment, decreases methylation, affects expression	2
N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide	decreases activity, decreases reaction, increases abundance	2
lepirudin	affects binding, decreases activity	2
Y 27632	decreases reaction, increases phosphorylation, decreases activity	2
Resveratrol	increases abundance, increases expression, increases phosphorylation, decreases reaction	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Contraceptives, Oral	increases activity, increases expression	2
Dexamethasone	increases reaction, affects expression, increases expression	2
Diethylhexyl Phthalate	increases expression, decreases expression, decreases reaction, affects cotreatment	2
Doxorubicin	affects expression, increases cleavage, affects reaction	2
Nickel	affects binding, decreases reaction, increases uptake	2
Nitric Oxide	decreases reaction, increases abundance, increases reaction	2
Thromboxane B2	decreases reaction, increases abundance, increases chemical synthesis	2
Warfarin	increases reaction, affects response to substance, decreases expression	2
Medroxyprogesterone Acetate	increases expression, increases reaction	2
Simvastatin	decreases activity, decreases reaction, affects localization, affects reaction, decreases expression	2
aristolochic acid I	increases expression	1
Asian ginseng	decreases expression, decreases reaction, affects cotreatment, increases expression	1
ginger extract	decreases expression, increases abundance	1

ChEMBL screening assays

1269 unique, capped per target: 1216 binding, 38 functional, 13 admet, 2 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000101	Binding	Inhibition of thrombin by spectrophotometric assay	Dysinosins B-D, inhibitors of factor VIIa and thrombin from the Australian sponge Lamellodysidea chlorea. — *J Nat Prod*
CHEMBL1614423	Functional	PUBCHEM_BIOASSAY: Thrombin 1536 HTS Dose Response Confirmation. (Class of assay: confirmatory) [Related pubchem assays: 1046 (Thrombin 1536 HTS; hits were confirmed in this assay)]	PubChem BioAssay data set
CHEMBL4016670	ADMET	Drug metabolism in human serum assessed as thrombin-mediated 2-thienylacetyl-Trp1-(alpha-Me)Trp2-Arg3-Pro4-Arg5-OH metabolite formation at 1 mM after 120 mins by RP-HPLC analysis	Discovery of a Human Neuromedin U Receptor 1-Selective Hexapeptide Agonist with Enhanced Serum Stability. — *J Med Chem*

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_4W10	GM16028	Transformed cell line	Female
CVCL_W239	GM16000	Transformed cell line	Female

Clinical trials (associated diseases)

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

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00077753	Phase 4	COMPLETED	EXCLAIM:Extended Prophylaxis for Venous ThromboEmbolism (VTE) in Acutely Ill Medical Patients With Prolonged Immobilization
NCT00196118	Phase 4	COMPLETED	Study of IVC Filter Retrieval With the Günther Tulip Vena Cava Filter
NCT00437697	Phase 4	TERMINATED	Thromboprophylaxis in Critically Ill Patients
NCT00445328	Phase 4	TERMINATED	Dalteparin vs Unfractionated Heparin For The Prevention Of Venous Thromboembolism (VTE) In Hospitalized Acutely Ill Medical Patients
NCT00689520	Phase 4	COMPLETED	Long-Term Low-Molecular-Weight Heparin Versus Oral Anticoagulants in Deep Venous Thrombosis
NCT00851864	Phase 4	COMPLETED	Safety and Efficacy of Therapeutic Anticoagulation With Tinzaparin During Pregnancy Via Weight-based Dosing
NCT00966277	Phase 4	COMPLETED	Dalteparin for Primary Venous Thromboembolism (VTE) Prophylaxis in Pancreatic Cancer Patients
NCT00967304	Phase 4	COMPLETED	Clinical Decision Rule Validation Study to Predict Low Recurrent Risk in Patients With Unprovoked Venous Thromboembolism
NCT01119261	Phase 4	COMPLETED	EUropean Pharmacogenetics of AntiCoagulant Therapy - Acenocoumarol
NCT01119274	Phase 4	COMPLETED	EUropean Pharmacogenetics of AntiCoagulant Therapy - Phenprocoumon
NCT01119300	Phase 4	COMPLETED	EUropean Pharmacogenetics of AntiCoagulant Therapy - Warfarin
NCT01210755	Phase 4	COMPLETED	Study in Healthy Volunteers of the Reversion by Haemostatic Drugs of the Anticoagulant Effect of New Anti-thrombotics
NCT01304108	Phase 4	COMPLETED	Improving Venous Thromboembolism Prophylaxis
NCT01467583	Phase 4	COMPLETED	Fondaparinux in Critically Ill Patients With Renal Failure
NCT01916707	Phase 4	UNKNOWN	Weight Based Enoxaparin in Trauma Patients
NCT02095509	Phase 4	COMPLETED	Pharmacokinetics of Enoxaparin in Intensive Care Patients
NCT02396732	Phase 4	TERMINATED	Aspirin and Enoxaparin for VTE in Trauma
NCT02412982	Phase 4	COMPLETED	Evaluation of Venous Thromboembolism Prevention in High-Risk Trauma Patients
NCT02464969	Phase 4	COMPLETED	Apixaban for the Acute Treatment of Venous Thromboembolism in Children
NCT02474212	Phase 4	COMPLETED	: Pharmacokinetics of Enoxaparin After Coronary Artery Bypass Graft Surgery
NCT02559856	Phase 4	COMPLETED	Comparison of Bleeding Risk Between Rivaroxaban and Apixaban: The Pilot Study
NCT02856295	Phase 4	COMPLETED	anti10a Levels in Women Treated With LMWH in the Postpartum Period
NCT02945280	Phase 4	TERMINATED	Apixaban for Routine Management of Upper Extremity Deep Venous Thrombosis
NCT02958969	Phase 4	COMPLETED	Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma
NCT03006562	Phase 4	TERMINATED	PREvention of VENous ThromboEmbolism Following Radical Prostatectomy
NCT03158792	Phase 4	COMPLETED	Enoxaparin 20mg Versus 30mg Subcutaneously Once Daily in Elderly Patients With Impaired Renal Function
NCT03196349	Phase 4	TERMINATED	Comparison of Oral Anticoagulants for Extended VEnous Thromboembolism
NCT03244020	Phase 4	ENROLLING_BY_INVITATION	LMWH vs Aspirin for VTE Prophylaxis in Orthopaedic Oncology
NCT03266783	Phase 4	COMPLETED	Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism
NCT03426982	Phase 4	UNKNOWN	Comparision Between Activated Partial Thromboplastin Time Versus Anti-Xa Activity in Heparin Monitoring
NCT03678506	Phase 4	TERMINATED	Apixaban for Extended Anticoagulation (APIDULCIS)
NCT03988101	Phase 4	COMPLETED	Role of Statin in Venous Dysfunction in Patients With Venous Thromboembolism Event
NCT03988231	Phase 4	WITHDRAWN	Enoxaparin Versus Placebo for Venous Thromboembolism Prevention in Low Risk Cancer Patients After Surgical Procedures: a Randomized, Double Blind, Placebo Controlled Clinical Trial Pilot Study
NCT04128254	Phase 4	UNKNOWN	A Prospective Study in Chinese Patients With Lower Extremity Ankle Fracture of Oral Anticoagulants to Prevent Venous Thromboembolism (VTE)
NCT04157881	Phase 4	COMPLETED	A Study on the Impact of Rabeprazole-induced Elevated Stomach pH on APO-Dabigatran Exposure in Healthy Volunteers
NCT04168203	Phase 4	COMPLETED	Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in High-Risk Patients With Provoked Venous Thromboembolism
NCT04169269	Phase 4	UNKNOWN	Deep Vein Thrombosis Prophylaxis Adherence: Enoxaparin vs Rivaroxaban
NCT04263038	Phase 4	RECRUITING	Clinical Surveillance vs. Anticoagulation for Low-risk Patients With Isolated Subsegmental Pulmonary Embolism
NCT04352439	Phase 4	COMPLETED	Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy
NCT04409834	Phase 4	COMPLETED	Prevention of Arteriovenous Thrombotic Events in Critically-Ill COVID-19 Patients Trial
NCT04479579	Phase 4	COMPLETED	Improved Adherence With Extended Venous Thromboembolism Prophylaxis After Major Cancer Surgery
NCT04710732	Phase 4	TERMINATED	Individual Dose Adjustment of Low-molecular-weight-heparin by Thromodynamics Test.
NCT04947514	Phase 4	COMPLETED	Use of Tranexamic Acid in Reduction Mammoplasty
NCT05735639	Phase 4	RECRUITING	THRomboprophylaxis in Individuals Undergoing Superficial endoVEnous Treatment (THRIVE)
NCT06020560	Phase 4	UNKNOWN	Study of Low Molecular Weight Heparins
NCT06452342	Phase 4	UNKNOWN	TRanEXamic Acid to Decrease Heavy Menstrual Bleeding in Individuals Anticoagulated for Venous Thromboembolism Pilot Study
NCT06523959	Phase 4	RECRUITING	Avoiding Risks of Thrombosis and Bleeding in Surgery (ARTS) Trial
NCT06581965	Phase 4	RECRUITING	inDividual, Targeted thrombosIS Prophylaxis Versus the Standard ‘One Size Fits All’ Approach in Patients Undergoing Total hIp or Total kNee replaCemenT
NCT06603870	Phase 4	RECRUITING	Secondary Prevention of VTE in Patients With Cancer and Catheter-Related Upper Extremity Deep Vein Thrombosis
NCT06635317	Phase 4	COMPLETED	Efficacy of Aspirin in Preventing Venous Thromboembolism
NCT06845423	Phase 4	RECRUITING	Prevention of Postpartum Venous Thromboembolism in Women at Intermediate Risk
NCT06958588	Phase 4	RECRUITING	Pulsed Electromagnetic Field Therapy or Pneumatic Compression VTE Prophylaxis
NCT07189897	Phase 4	RECRUITING	Apixaban or Enoxaparin After Head and Neck Cancer Surgery
NCT07303816	Phase 4	RECRUITING	Statins to Prevent Cancer Associated Blood Clots
NCT07713875	Phase 4	NOT_YET_RECRUITING	Extended Prophylactic Anticoagulation Following Spinal Surgery for Metastatic Disease
NCT00000614	Phase 3	COMPLETED	Prevention of Recurrent Venous Thromboembolism (PREVENT)
NCT00135876	Phase 3	COMPLETED	Dalteparin Low Molecular Weight Heparin for Primary Prophylaxis of Venous Thromboembolism in Brain Tumour Patients
NCT00182221	Phase 3	COMPLETED	Safety of a Diagnostic Strategy With D-Dimer Testing for PE
NCT00182403	Phase 3	COMPLETED	Fixed Dose Heparin Study
NCT00219973	Phase 3	COMPLETED	CANBESURE STUDY (Cancer, Bemiparin and Surgery Evaluation)

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for F2 across ~30M SureChEMBL compounds — explore on Sugi Predict.