PLG

Summary

PLG (plasminogen, HGNC:9071) is a protein-coding gene on chromosome 6q26, encoding Plasminogen (P00747). Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation.

The plasminogen protein encoded by this gene is a serine protease that circulates in blood plasma as an inactive zymogen and is converted to the active protease, plasmin, by several plasminogen activators such as tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and factor XII (Hageman factor). The conversion of plasminogen to plasmin involves the cleavage of the peptide bond between Arg-561 and Val-562. Plasmin cleavage also releases the angiostatin protein which inhibits angiogenesis. Plasmin degrades many blood plasma proteins, including fibrin-containing blood clots. As a serine protease, plasmin cleaves many products in addition to fibrin such as fibronectin, thrombospondin, laminin, and von Willebrand factor. Plasmin is inactivated by proteins such as alpha-2-macroglobulin and alpha-2-antiplasmin in addition to inhibitors of the various plasminogen activators. Plasminogen also interacts with plasminogen receptors which results in the retention of plasmin on cell surfaces and in plasmin-induced cell signaling. The localization of plasminogen on cell surfaces plays a role in the degradation of extracellular matrices, cell migration, inflamation, wound healing, oncogenesis, metastasis, myogenesis, muscle regeneration, neurite outgrowth, and fibrinolysis. This protein may also play a role in acute respiratory distress syndrome (ARDS) which, in part, is caused by enhanced clot formation and the suppression of fibrinolysis. Compared to other mammals, the cluster of plasminogen-like genes to which this gene belongs has been rearranged in catarrhine primates.

Source: NCBI Gene 5340 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypoplasminogenemia (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 34
• Clinical variants (ClinVar): 617 total — 15 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 34
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000301

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9071
Approved symbol	PLG
Name	plasminogen
Location	6q26
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000122194
Ensembl biotype	protein_coding
OMIM	173350
Entrez	5340

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 19 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000297289, ENST00000308192, ENST00000366924, ENST00000418964, ENST00000461414, ENST00000462918, ENST00000467466, ENST00000471691, ENST00000483038, ENST00000484367, ENST00000493435, ENST00000494325, ENST00000706906, ENST00000706907, ENST00000872428, ENST00000872429, ENST00000872430, ENST00000872431, ENST00000872432, ENST00000872433, ENST00000872434, ENST00000872435, ENST00000872436, ENST00000872437, ENST00000872438, ENST00000872439, ENST00000872440, ENST00000957675

RefSeq mRNA: 2 — MANE Select: NM_000301 NM_000301, NM_001168338

CCDS: CCDS5279, CCDS55074

Canonical transcript exons

ENST00000308192 — 19 exons

Exon	Start	End
ENSE00001666516	160712986	160713125
ENSE00001864790	160752900	160754097
ENSE00001900502	160702244	160702353
ENSE00003461840	160711077	160711191
ENSE00003567290	160707700	160707806
ENSE00003636923	160706407	160706542
ENSE00003997380	160731051	160731232
ENSE00003997383	160716645	160716763
ENSE00003997384	160752115	160752260
ENSE00003997385	160718693	160718838
ENSE00003997388	160741311	160741417
ENSE00003997390	160731745	160731893
ENSE00003997391	160733995	160734088
ENSE00003997392	160714794	160714914
ENSE00003997393	160718294	160718456
ENSE00003997394	160738538	160738612
ENSE00003997397	160739068	160739208
ENSE00003997400	160736887	160737007
ENSE00003997402	160722408	160722567

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 99.82.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0792 / max 43.1083, expressed in 7 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
71031	0.0515	6
71030	0.0277	7

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.82	gold quality
liver	UBERON:0002107	99.66	gold quality
adult organism	UBERON:0007023	95.05	gold quality
adult mammalian kidney	UBERON:0000082	94.93	gold quality
nephron tubule	UBERON:0001231	91.29	gold quality
kidney epithelium	UBERON:0004819	90.41	gold quality
kidney	UBERON:0002113	88.95	gold quality
metanephric glomerulus	UBERON:0004736	87.20	gold quality
renal glomerulus	UBERON:0000074	87.17	gold quality
descending thoracic aorta	UBERON:0002345	83.63	gold quality
thoracic aorta	UBERON:0001515	83.30	gold quality
cortex of kidney	UBERON:0001225	83.28	gold quality
ascending aorta	UBERON:0001496	83.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.19	gold quality
tibial nerve	UBERON:0001323	80.08	gold quality
aorta	UBERON:0000947	79.48	gold quality
right coronary artery	UBERON:0001625	78.75	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.59	gold quality
adrenal tissue	UBERON:0018303	78.39	gold quality
left coronary artery	UBERON:0001626	77.85	gold quality
popliteal artery	UBERON:0002250	76.96	gold quality
tibial artery	UBERON:0007610	76.94	gold quality
coronary artery	UBERON:0001621	76.18	gold quality
colonic epithelium	UBERON:0000397	75.14	gold quality
metanephros	UBERON:0000081	75.06	gold quality
right uterine tube	UBERON:0001302	74.86	gold quality
left uterine tube	UBERON:0001303	73.93	gold quality
metanephros cortex	UBERON:0010533	73.59	gold quality
gastrocnemius	UBERON:0001388	73.49	gold quality
left ovary	UBERON:0002119	72.85	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-9	yes	64.02
E-CURD-119	yes	55.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, HIF1A, HMGA2, HOXB2, KLF5, KLF6, NFKBIB, NR0B1, RORA, SP1, SPDEF, SRF

miRNA regulators (miRDB)

42 targeting PLG, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-367-5P	98.84	67.18	902
HSA-MIR-1537-5P	98.70	68.33	999
HSA-MIR-1301-3P	98.64	68.27	1071

Literature-anchored findings (GeneRIF, showing 40)

• Angiostatin, an angiogenesis inhibitor, lowers intracellular pH in cultured endothelial cells under conditions of low extracellular pH, resulting in a decrease in cell migration and an increase in cell death. (PMID:11888684)
• Streptokinase (SK) and staphylokinase activate human plasminogen (PMID:12016220)
• Tissue factor is the receptor for plasminogen type 1, containing both N-linked and O-linked oligosaccharide chains, on 1-LN human prostate cancer cells. (PMID:12036889)
• substrate specificity of micro-plasminogen (PMID:12080056)
• plasmin induction of MCP-1 and CD40 in human monocytes via p38 MAPK and janus kinase/STAT signaling pathways (PMID:12093796)
• Data show that keratinocytes use an alternative plasminogen and matrix metalloproteinase-13-dependent pathway for dissolution of collagen fibrils. (PMID:12192005)
• Angiostatin inhibited HGF-induced phosphorylation of c-met, Akt, and ERK1/2. Angiostatin also significantly inhibited proliferation of human umbilical vein endothelial cells (HUVECs) induced by HGF. (PMID:12406896)
• investigation of clotting role of Kringle-1 domain from human plasminogen (PMID:12646571)
• Data suggest that dysplasminogenemia (congenital deficiency of plasminogen and molecular abnormality of plasminogen) may be a risk factor for deep vein thrombosis in the Korean population. (PMID:12692411)
• investigation of the mechanism of inhibition of plasminogen activation by lipoprotein(a) (PMID:12697748)
• Evidence is reviewed for plasminogen binding in the tumor environment; the known intrinsic functional relationship between plasminogen conformation and activation is essentially connected to cellular binding. (PMID:12700073)
• The voltage-dependent anion channel is a receptor for plasminogen kringle 5 on endothelial cells. (PMID:12736244)
• plasmin converts cell-bound Glu-plasminogen to Lys-plasminogen and this enzyme is produced by activation of monocytoid plasminogen by endogenous monocytoid plasminogen activators to enhance plasminogen activation on the monocytoid cell surface (PMID:12871329)
• A new plasminogen intron F-14T>G mutation, which was found to reduce the acceptor splicing site prediction score, suggesting a role in reducing the amount of correct plasminogen mRNA. (PMID:12876630)
• Computer model of the interaction of human TFPI-2 Kunitz-type serine protease inhibitor with human plasmin [letter] (PMID:14678821)
• presence of angiostatin in ascitic and pleural effusions from cancer patients (PMID:14719094)
• Early plasmin generation does not seem to play a role in the subsequent activation of other inflammatory pathways during human endotoxemia. (PMID:14739127)
• assembly of Plg and uPA on integrin alpha(M)beta(2) regulates Plm activity and, thereby, plays a crucial role in neutrophil-mediated thrombolysis (PMID:14769799)
• Plasminogen is an adhesive ligand for integrins alphaMbeta2 and alpha5beta1. (PMID:15090462)
• A deficiency of plasminogen reduces processing of beta-endorphin and alpha-melanocyte stimulating hormone, and interferes with normal brain function. (PMID:15099286)
• Lys-698 of human Pg plays a functional role in the so-called N-terminal insertion activation mechanism by streptokinase. (PMID:15211511)
• analysis of the kinetic mechanism in which SK binding and reversible conformational activation of plasminogen occur in a rapid equilibrium, multistep process (PMID:15215240)
• Plasminogen is bound to the cell surface by histidine-rich glycoprotein (PMID:15220341)
• Plasminogen binding in the presence of the urokinase-type plasminogen activator (uPA) promoted the invasion of HeLa cells by Mycoplasma fermentans (PMID:15321992)
• a transgene expressing human plasminogen markedly increased mortality in mice infected with group A streptococci, and this susceptibility was dependent on bacterial streptokinase expression (PMID:15333838)
• binds to Streptococcus mutans alpha-enolase (PMID:15501816)
• studies of a 1:1 complex formed by the cellular conformation of the sheep prion protein with human plasminogen; effects of pressure, temperature and presence/absence of proteolytic inhibitors (PMID:15529749)
• recombinant PrPc binds to human plasminogen (PMID:15609351)
• histidine-proline-rich glycoprotein can act as either a positive or negative effector of Plg activation in vitro (PMID:15613921)
• plasminogen binds with high affinity to IGF-II and IGF-binding protein-3 (PMID:15642732)
• Data show that bacillolysin MA (BL-MA)affects blood coagulation and fibrinolysis systems and can be used to produce angiostatin-like plasminogen fragments and active serine proteases of human plasma [BL-MA]. (PMID:15677446)
• angiostatin and plasminogen share binding to endothelial cell surface actin and, therefore, that angiostatin has the potential to inhibit plasmin-dependent processes such as cell migration-movement (PMID:15746964)
• associations suggest that PLG has the potential to simultaneously regulate calcium signaling pathways and Na+/H+ exchanges necessary for tumor cell proliferation and invasiveness (PMID:15911629)
• Plasmin and thrombin accelerate shedding of syndecan-4 ectodomain, which generates cleavage sites at Lys(114)-Arg(115) and Lys(129)-Val(130) bonds (PMID:16087677)
• The effect of conformation on the initial and secondary cleavages of plasminogen to generate active angiostatins is reported. (PMID:16097950)
• Protein S plays a role in cell-associated plasminogen activation and invasive potential of inflammatory cells. (PMID:16229836)
• The cytoprotective effect of plasminogen requires plasmin proteolytic activity and requires PAR1 (PMID:16478887)
• angiostatins K1-3, K1-4 and K1-4.5 mediate anti-angiogenesis in a process involvingp53, FasL, AKT and mRNA deregulation (PMID:16601838)
• propose that the human plasminogen system plays a critical role in group A streptococcal M1T1 systemic disease initiation. (PMID:16790522)
• Ca (2+) -dependent and -independent binding of Lys-Pg to FXa33/13 are C-terminal lysine-dependent. The N-terminal 1 - 77 amino acids of Glu-Pg confer significant C-terminal lysine-independent binding, which may play a role in PLG activation (PMID:17200769)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	plg	ENSDARG00000023111
mus_musculus	Plg	ENSMUSG00000059481
rattus_norvegicus	Plg	ENSRNOG00000017223

Paralogs (14): PRSS33 (ENSG00000103355), PLAT (ENSG00000104368), PLGLB2 (ENSG00000125551), PRSS37 (ENSG00000165076), PRSS27 (ENSG00000172382), KLK15 (ENSG00000174562), PLGLB1 (ENSG00000183281), PRSS57 (ENSG00000185198), TMPRSS12 (ENSG00000186452), OVCH1 (ENSG00000187950), PRSS48 (ENSG00000189099), GZMM (ENSG00000197540), KLK9 (ENSG00000213022), PRSS50 (ENSG00000283706)

Protein

Protein identifiers

Plasminogen — P00747 (reviewed: P00747)

All UniProt accessions (6): A0A9L9PXP2, A0A9L9PY04, A0A9L9PYG2, A6PVI2, P00747, Q5TEH5

UniProt curated annotations — full annotation on UniProt →

Function. Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1, C4 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells. Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo. (Microbial infection) ENO/enoloase from parasite P.falciparum (strain NF54) interacts with PLG present in the mosquito blood meal to promote the invasion of the mosquito midgut by the parasite ookinete. The catalytic active form, plasmin, is essential for the invasion of the mosquito midgut. (Microbial infection) Binds to OspC on the surface of B.burgdorferi cells, possibly conferring an extracellular protease activity on the bacteria that allows it to traverse host tissue. (Microbial infection) Interacts with dengue virus type 2 particles. Enhances dengue virus type 2 infection in Aedes aegypti mosquito midgut by increasing midgut internalization, resulting in higher infection rates and viral dissemination in mosquitoes.

Subunit / interactions. Interacts (both mature PLG and the angiostatin peptide) with CSPG4 and AMOT. Interacts (via the Kringle domains) with HRG; the interaction tethers PLG to the cell surface and enhances its activation. Interacts (via Kringle 4 domain) with ADA; the interaction stimulates PLG activation when in complex with DPP4. Angiostatin: Interacts with ATP5F1A; the interaction inhibits most of the angiogenic effects of angiostatin. Interacts (plasmin) with iripin-8, a serine protease inhibitor from Ixodes ricinus saliva. Interacts (plasmin) with iripin-1, a serine protease inhibitor from Ixodes ricinus saliva. Interacts (plasmin) with Kazal-type trypsin inhibitor, a serine protease inhibitor from Aedes aegypti. (Microbial infection) Interacts with C.albicans GPD2; the interaction is direct and provides active plasmin on the surface of fungal cells. (Microbial infection) Interacts with Staphylococcus aureus protein FnbB; this interaction provides active plasmin on the surface of bacterial cells. (Microbial infection) Interacts with P.falciparum (strain NF54) enolase ENO (via DKSLVK motif); the interaction occurs at the ookinete cell surface and is required for ookinete invasion of the mosquito midgut. (Microbial infection) Interacts with B.burgdorferi OspC.

Subcellular location. Secreted.

Tissue specificity. Present in plasma and many other extracellular fluids. It is synthesized in the liver.

Post-translational modifications. N-linked glycan contains N-acetyllactosamine and sialic acid. O-linked glycans consist of Gal-GalNAc disaccharide modified with up to 2 sialic acid residues (microheterogeneity). In the presence of the inhibitor, the activation involves only cleavage after Arg-580, yielding two chains held together by two disulfide bonds. In the absence of the inhibitor, the activation involves additionally the removal of the activation peptide. (Microbial infection) The Y.pestis Pla protein cleaves between Arg-580 and Val-581, generating plasmin which facilitates bacterial migration and infection.

Disease relevance. Plasminogen deficiency (PLGD) [MIM:217090] A disorder characterized by decreased serum plasminogen activity. Two forms of the disorder are distinguished: type 1 deficiency is additionally characterized by decreased plasminogen antigen levels and clinical symptoms, whereas type 2 deficiency, also known as dysplasminogenemia, is characterized by normal, or slightly reduced antigen levels, and absence of clinical manifestations. Plasminogen deficiency type 1 results in markedly impaired extracellular fibrinolysis and chronic mucosal pseudomembranous lesions due to subepithelial fibrin deposition and inflammation. The most common clinical manifestation of type 1 deficiency is ligneous conjunctivitis in which pseudomembranes formation on the palpebral surfaces of the eye progresses to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa. The disease is caused by variants affecting the gene represented in this entry. Angioedema, hereditary, 4 (HAE4) [MIM:619360] A form of angioedema, a disorder characterized by episodic local swelling involving subcutaneous or submucous tissue of the upper respiratory and gastrointestinal tracts, face, extremities, and genitalia. HAE4 is an autosomal dominant form with incomplete penetrance, variable expressivity, and female predominance. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Converted into plasmin by plasminogen activators, both plasminogen and its activator being bound to fibrin. Activated with catalytic amounts of streptokinase. Plasmin activity inhibited by SERPINE2.

Domain organisation. Kringle domains mediate interaction with CSPG4.

Miscellaneous. Plasmin is inactivated by alpha-2-antiplasmin immediately after dissociation from the clot.

Similarity. Belongs to the peptidase S1 family. Plasminogen subfamily.

RefSeq proteins (2): NP_000292, NP_001161810 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000001	Kringle	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR003609	Pan_app	Domain
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR013806	Kringle-like	Homologous_superfamily
IPR018056	Kringle_CS	Conserved_site
IPR018114	TRYPSIN_HIS	Active_site
IPR023317	Pept_S1A_plasmin	Family
IPR033116	TRYPSIN_SER	Active_site
IPR038178	Kringle_sf	Homologous_superfamily
IPR043504
IPR050759	Serine_protease_kringle	Family

Pfam: PF00024, PF00051, PF00089

Enzyme classification (BRENDA):

• EC 3.4.21.7 — plasmin (BRENDA: 7 organisms, 175 substrates, 293 inhibitors, 68 Km, 38 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
D-NORLEUCYL-HEXAHYDROTYROSYL-LYSINE-P-NITROANILI	0.0059–0.1311	13
D-VAL-L-LEU-L-LYS-4-NITROANILIDE	0.138–0.325	4
D-VAL-LEU-LYS-P-NITROANILIDE	0.21–1.26	4
TOSYL-ARG METHYL ESTER	5.3–7	4
BENZYLOXYCARBONYL-LYS-P-NITROPHENYL ESTER	0.0135–0.083	3
4-NITROPHENYL-P’-(GUANIDINIUM)BENZOATE BROMIDE	0.0052–0.0113	2
GIYRSR	0.002–0.0058	2
P-NITROPHENYL-P’-(METHYLETHYLSULFONIUMMETHYL)BEN	0.214–0.258	2
P-NITROPHENYL-P’-(PYRIDINIUMMETHYL)-BENZOATE	0.21–0.23	2
P-NITROPHENYL-P’-(THIOURONIUMMETHYL)BENZOATE	0.027–0.043	2
AIYRSR	0.003	1
CIYRSR	0.004	1
D-ILE-PHE-LYS	0.02	1
FIBRINOGEN	0.03	1
GIVRSR	0.012	1

UniProt features (169 total): strand 59, disulfide bond 24, sequence variant 21, turn 13, helix 12, domain 7, chain 5, binding site 5, site 5, sequence conflict 5, active site 3, glycosylation site 3, region of interest 2, modified residue 2, signal peptide 1, peptide 1, mutagenesis site 1

Structure

Experimental structures (PDB)

49 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5UGG	X-RAY DIFFRACTION	1.2
6D3Y	X-RAY DIFFRACTION	1.32
5UGD	X-RAY DIFFRACTION	1.38
6D40	X-RAY DIFFRACTION	1.43
8F7U	X-RAY DIFFRACTION	1.47
7UAH	X-RAY DIFFRACTION	1.57
8F7V	X-RAY DIFFRACTION	1.65
5HPG	X-RAY DIFFRACTION	1.66
1KRN	X-RAY DIFFRACTION	1.67
6OG4	X-RAY DIFFRACTION	1.7
1KI0	X-RAY DIFFRACTION	1.75
4CIK	X-RAY DIFFRACTION	1.78
6D3X	X-RAY DIFFRACTION	1.8
7THS	X-RAY DIFFRACTION	1.8
1PK4	X-RAY DIFFRACTION	1.9
7E50	X-RAY DIFFRACTION	1.95
1DDJ	X-RAY DIFFRACTION	2
1QRZ	X-RAY DIFFRACTION	2
6D3Z	X-RAY DIFFRACTION	2
4DCB	X-RAY DIFFRACTION	2.03
1CEA	X-RAY DIFFRACTION	2.06
1CEB	X-RAY DIFFRACTION	2.07
9AZK	X-RAY DIFFRACTION	2.1
1PMK	X-RAY DIFFRACTION	2.25
2PK4	X-RAY DIFFRACTION	2.25
1L4D	X-RAY DIFFRACTION	2.3
1RJX	X-RAY DIFFRACTION	2.3
2DOH	X-RAY DIFFRACTION	2.3
6Q1U	X-RAY DIFFRACTION	2.35
4DUR	X-RAY DIFFRACTION	2.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00747-F1	83.53	0.46

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 (8): 622 (charge relay system); 665 (charge relay system); 760 (charge relay system); 78–79 (cleavage; by stromelysin-1); 134 (interacts with fibrin); 136 (interacts with fibrin); 466–467 (cleavage; by stromelysin-19); 580–581 (cleavage; by plasminogen activator)

Ligand- & substrate-binding residues (5): 136; 158; 172; 432; 445

Post-translational modifications (2): 597, 688

Disulfide bonds (24): 49–73, 53–61, 103–181, 124–164, 152–176, 185–262, 188–316, 206–245, 234–257, 275–352, 296–335, 324–347, 377–454, 398–437, 426–449, 481–560, 502–543, 531–555, 567–685, 577–585 …

Glycosylation sites (3): 268, 308, 365

Mutagenesis-validated functional residues (1):

Position	Phenotype
741	proteolytically cleaved, but abolishes plasmin activity and cell detachment. prevents invasion of the mosquito vector mi

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1592389	Activation of Matrix Metalloproteinases
R-HSA-186797	Signaling by PDGF
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-75205	Dissolution of Fibrin Clot

MSigDB gene sets: 370 (showing top): MODULE_172, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_REGULATION_OF_COAGULATION, GOCC_SECRETORY_GRANULE, GOBP_REGULATION_OF_CELL_CELL_ADHESION_MEDIATED_BY_CADHERIN, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GNF2_HPN, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_COAGULATION, GOCC_CELL_SURFACE, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, GOBP_REGENERATION, HNF1_Q6

GO Biological Process (21): proteolysis (GO:0006508), blood coagulation (GO:0007596), negative regulation of cell population proliferation (GO:0008285), negative regulation of cell-substrate adhesion (GO:0010812), protein processing (GO:0016485), extracellular matrix disassembly (GO:0022617), tissue regeneration (GO:0042246), fibrinolysis (GO:0042730), positive regulation of blood vessel endothelial cell migration (GO:0043536), myoblast differentiation (GO:0045445), muscle cell cellular homeostasis (GO:0046716), tissue remodeling (GO:0048771), biological process involved in interaction with symbiont (GO:0051702), negative regulation of fibrinolysis (GO:0051918), positive regulation of fibrinolysis (GO:0051919), trophoblast giant cell differentiation (GO:0060707), labyrinthine layer blood vessel development (GO:0060716), mononuclear cell migration (GO:0071674), trans-synaptic signaling by BDNF, modulating synaptic transmission (GO:0099183), negative regulation of cell-cell adhesion mediated by cadherin (GO:2000048), hemostasis (GO:0007599)

GO Molecular Function (14): protease binding (GO:0002020), endopeptidase activity (GO:0004175), serine-type endopeptidase activity (GO:0004252), signaling receptor binding (GO:0005102), serine-type peptidase activity (GO:0008236), enzyme binding (GO:0019899), kinase binding (GO:0019900), protein domain specific binding (GO:0019904), apolipoprotein binding (GO:0034185), protein-folding chaperone binding (GO:0051087), protein antigen binding (GO:1990405), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (11): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), extracellular matrix (GO:0031012), platelet alpha granule lumen (GO:0031093), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), Schaffer collateral - CA1 synapse (GO:0098685), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Extracellular matrix organization	1
Degradation of the extracellular matrix	1
Signaling by Receptor Tyrosine Kinases	1
Metabolism of proteins	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	6
cellular anatomical structure	3
negative regulation of blood coagulation	2
fibrinolysis	2
regulation of fibrinolysis	2
enzyme binding	2
peptidase activity	2
synapse	2
protein metabolic process	1
hemostasis	1
wound healing	1
coagulation	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
negative regulation of cell adhesion	1
regulation of cell-substrate adhesion	1
cell-substrate adhesion	1
proteolysis	1
protein maturation	1
cellular component disassembly	1
extracellular matrix organization	1
regeneration	1
developmental growth	1
positive regulation of endothelial cell migration	1
blood vessel endothelial cell migration	1
regulation of blood vessel endothelial cell migration	1
cell differentiation	1
muscle structure development	1
cellular homeostasis	1
multicellular organismal process	1
biological process involved in symbiotic interaction	1
positive regulation of blood coagulation	1
positive regulation of response to external stimulus	1
negative regulation of biological process	1
positive regulation of biological process	1
cell differentiation involved in embryonic placenta development	1
embryonic organ development	1
placenta blood vessel development	1
labyrinthine layer development	1

Protein interactions and networks

STRING

3241 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLG	SERPINF2	P08697	999
PLG	HRG	P04196	998
PLG	CLEC3B	P05452	997
PLG	FN1	P02751	997
PLG	ENO1	P06733	996
PLG	ANXA2	P07355	996
PLG	SERPINF1	P36955	995
PLG	VTN	P01141	994
PLG	AMOT	Q4VCS5	993
PLG	GAPDH	P00354	991
PLG	PLAT	P00750	989
PLG	MYOM2	P54296	988
PLG	S100A10	P08206	985
PLG	PLGRKT	Q9HBL7	983
PLG	SERPINE1	P05121	978

IntAct

118 interactions, top by confidence:

A	B	Type	Score
pdhB	PLG	psi-mi:“MI:0915”(physical association)	0.830
pdhB	PLG	psi-mi:“MI:0407”(direct interaction)	0.830
PLG	pdhB	psi-mi:“MI:0915”(physical association)	0.830
PLG	pdhB	psi-mi:“MI:0407”(direct interaction)	0.830
pdhB	PLG	psi-mi:“MI:0194”(cleavage reaction)	0.830
pdhA	PLG	psi-mi:“MI:0915”(physical association)	0.660
pdhC	PLG	psi-mi:“MI:0915”(physical association)	0.660
PLG	pdhA	psi-mi:“MI:0915”(physical association)	0.660
PLG	pdhC	psi-mi:“MI:0915”(physical association)	0.660
LOX	PLG	psi-mi:“MI:0407”(direct interaction)	0.560
	PLG	psi-mi:“MI:0915”(physical association)	0.560
FOXD4L6	PLG	psi-mi:“MI:0915”(physical association)	0.560
sak	PLG	psi-mi:“MI:0407”(direct interaction)	0.560

BioGRID (82): PLG (Affinity Capture-MS), PLG (Affinity Capture-MS), PLG (Affinity Capture-MS), PLG (Reconstituted Complex), PLG (Affinity Capture-MS), PLG (Reconstituted Complex), PLG (Affinity Capture-MS), PLG (Reconstituted Complex), PLG (Affinity Capture-MS), PLG (Reconstituted Complex), SERPINE1 (Reconstituted Complex), IGFBP3 (Reconstituted Complex), IGFBP3 (Co-purification), S100A10 (Far Western), CHGA (Biochemical Activity)

ESM2 similar proteins: B3EWZ3, B3EWZ5, B3EWZ6, F7J220, O13065, O18783, O43897, O57382, O57460, O70138, O70244, O88354, O88766, P00747, P06867, P06868, P11214, P19637, P20918, P22894, P25723, P28826, P33434, P33436, P42664, P42674, P50903, P55114, P81139, P98060, P98068, P98070, P98072, P98073, Q01177, Q02157, Q06561, Q11174, Q16820, Q19204

Diamond homologs: A0A182C2Z2, B8V7S0, O08762, O60235, P00747, P00760, P00762, P00765, P00766, P00767, P00774, P03951, P03952, P04070, P04813, P05981, P06867, P06871, P06872, P07146, P07338, P07477, P08217, P08426, P08519, P12545, P14272, P15944, P17538, P19799, P20231, P20918, P26262, P27435, P29786, P35033, P40313, P47796, P50342, P56677

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
SRF	“up-regulates quantity by expression”	PLG	“transcriptional regulation”
PLAT	“up-regulates activity”	PLG	binding
PLG	“up-regulates activity”	PLAT	cleavage
PLG	up-regulates	Fibrinolysis
PLG	“down-regulates activity”	APOH	cleavage
PLG	“up-regulates activity”	F2R	cleavage
PLG	“down-regulates activity”	F2R	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	12
Uncertain significance	310
Likely benign	173
Benign	73

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
13575	NM_000301.5(PLG):c.1120G>T (p.Val374Phe)	Pathogenic
13576	NM_000301.5(PLG):c.1771T>C (p.Ser591Pro)	Pathogenic
13577	NM_000301.5(PLG):c.704G>A (p.Arg235His)	Pathogenic
13579	NM_000301.5(PLG):c.1435G>T (p.Glu479Ter)	Pathogenic
13582	NM_000301.5(PLG):c.2125+1del	Pathogenic
2001679	NM_000301.5(PLG):c.618C>A (p.Cys206Ter)	Pathogenic
2734965	NM_000301.5(PLG):c.1468C>T (p.Arg490Ter)	Pathogenic
282782	NM_000301.5(PLG):c.185+1G>T	Pathogenic
3658824	NM_000301.5(PLG):c.1755T>A (p.Cys585Ter)	Pathogenic
3717788	NM_000301.5(PLG):c.528C>A (p.Cys176Ter)	Pathogenic
4728204	NM_000301.5(PLG):c.732G>A (p.Trp244Ter)	Pathogenic
4747550	NM_000301.5(PLG):c.1675C>T (p.Gln559Ter)	Pathogenic
590291	NM_000301.5(PLG):c.988A>G (p.Lys330Glu)	Pathogenic
827591	NM_000301.5(PLG):c.2183T>A (p.Val728Glu)	Pathogenic
830236	NM_000301.5(PLG):c.886T>G (p.Cys296Gly)	Pathogenic
1179096	NM_000301.5(PLG):c.2019-1G>A	Likely pathogenic
2635544	NM_000301.5(PLG):c.1265dup (p.Met423fs)	Likely pathogenic
2734963	NM_000301.5(PLG):c.293-2A>G	Likely pathogenic
2980729	NM_000301.5(PLG):c.1256+1G>A	Likely pathogenic
3381018	NM_000301.5(PLG):c.763del (p.Glu255fs)	Likely pathogenic
3593297	NM_000301.5(PLG):c.292+1G>C	Likely pathogenic
3593317	NM_000301.5(PLG):c.910C>G (p.Pro304Ala)	Likely pathogenic
3593319	NM_000301.5(PLG):c.948C>A (p.Cys316Ter)	Likely pathogenic
3593351	NM_000301.5(PLG):c.1987C>T (p.Arg663Ter)	Likely pathogenic
3764685	NM_000301.5(PLG):c.677del (p.Asn226fs)	Likely pathogenic
4734295	NM_000301.5(PLG):c.1588-1G>C	Likely pathogenic
4820655	NM_000301.5(PLG):c.1994A>T (p.Asp665Val)	Likely pathogenic

SpliceAI

2408 predictions. Top by Δscore:

Variant	Effect	Δscore
6:160707802:GAAAG:G	donor_gain	1.0000
6:160707803:AAAGG:A	donor_loss	1.0000
6:160707804:AAGG:A	donor_loss	1.0000
6:160707805:AGG:A	donor_loss	1.0000
6:160707806:GGT:G	donor_loss	1.0000
6:160707807:GTGA:G	donor_loss	1.0000
6:160711076:GT:G	acceptor_gain	1.0000
6:160712981:CCCA:C	acceptor_loss	1.0000
6:160712982:CCA:C	acceptor_loss	1.0000
6:160712983:CA:C	acceptor_loss	1.0000
6:160712984:A:AC	acceptor_loss	1.0000
6:160714783:A:AG	acceptor_gain	1.0000
6:160714784:C:G	acceptor_gain	1.0000
6:160714915:G:GG	donor_gain	1.0000
6:160716641:TCAG:T	acceptor_loss	1.0000
6:160716643:A:AC	acceptor_loss	1.0000
6:160716643:A:AG	acceptor_gain	1.0000
6:160716644:G:GA	acceptor_gain	1.0000
6:160716644:GA:G	acceptor_gain	1.0000
6:160716644:GAT:G	acceptor_gain	1.0000
6:160716644:GATTT:G	acceptor_gain	1.0000
6:160716761:GCA:G	donor_gain	1.0000
6:160716764:G:GG	donor_gain	1.0000
6:160716768:G:GG	donor_gain	1.0000
6:160718690:CA:C	acceptor_loss	1.0000
6:160718691:A:AC	acceptor_loss	1.0000
6:160718691:A:AG	acceptor_gain	1.0000
6:160718692:G:GT	acceptor_gain	1.0000
6:160718692:GA:G	acceptor_gain	1.0000
6:160718692:GAA:G	acceptor_gain	1.0000

AlphaMissense

5320 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:160731821:G:C	W505C	1.000
6:160731821:G:T	W505C	1.000
6:160741404:G:C	W704C	1.000
6:160741404:G:T	W704C	1.000
6:160711165:G:C	W127C	0.999
6:160711165:G:T	W127C	0.999
6:160722514:G:C	W401C	0.999
6:160722514:G:T	W401C	0.999
6:160731070:T:A	C426S	0.999
6:160731071:G:C	C426S	0.999
6:160734033:G:C	W542C	0.999
6:160734033:G:T	W542C	0.999
6:160738555:G:A	C607Y	0.999
6:160741402:T:A	W704R	0.999
6:160741402:T:C	W704R	0.999
6:160714873:G:C	W209C	0.998
6:160714873:G:T	W209C	0.998
6:160731139:T:A	C449S	0.998
6:160731140:G:C	C449S	0.998
6:160731810:T:A	C502S	0.998
6:160731811:G:C	C502S	0.998
6:160733998:T:A	C531S	0.998
6:160733999:G:C	C531S	0.998
6:160734034:T:A	C543S	0.998
6:160734035:G:C	C543S	0.998
6:160736985:T:A	W594R	0.998
6:160736985:T:C	W594R	0.998
6:160736987:G:C	W594C	0.998
6:160736987:G:T	W594C	0.998
6:160738554:T:A	C607S	0.998

dbSNP variants (sampled 300 via entrez): RS1000104251 (6:160704420 C>T), RS1000114821 (6:160714298 G>A), RS1000146315 (6:160752763 T>C), RS1000182495 (6:160735026 G>A), RS1000424793 (6:160721820 G>C), RS1000509770 (6:160744221 T>C), RS1000514341 (6:160703844 A>G), RS1000674243 (6:160708445 A>G), RS1000676338 (6:160750753 C>G,T), RS1000818413 (6:160703638 A>C,T), RS1000857212 (6:160722012 G>T), RS1000889091 (6:160725278 A>T), RS1000917760 (6:160747690 T>G), RS1000970779 (6:160737977 G>T), RS1001084148 (6:160731930 T>C)

Disease associations

OMIM: gene MIM:173350 | disease phenotypes: MIM:217090, MIM:619360, MIM:166760, MIM:106100, MIM:219700

GenCC curated gene-disease

Disease	Classification	Inheritance
hypoplasminogenemia	Strong	Autosomal recessive
angioedema, hereditary, 4	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hypoplasminogenemia	Definitive	AR

Mondo (10): hypoplasminogenemia (MONDO:0009009), angioedema, hereditary, 4 (MONDO:0025712), dysplasminogenemia (MONDO:0100538), otitis media, susceptibility to (MONDO:0008162), hereditary angioedema type 1 (MONDO:0015053), hereditary angioedema (MONDO:0019623), thrombocytopenia (MONDO:0002049), cystic fibrosis (MONDO:0009061), hereditary angioedema with normal C1Inh (MONDO:0100567), atypical hemolytic-uremic syndrome (MONDO:0016244)

Orphanet (8): Hypoplasminogenemia (Orphanet:722), Hereditary angioedema type 1 (Orphanet:100050), Hereditary angioedema type 2 (Orphanet:100051), Hereditary angioedema (Orphanet:91378), Cystic fibrosis (Orphanet:586), Hereditary angioedema with normal C1Inh (Orphanet:528647), Atypical hemolytic uremic syndrome (Orphanet:2134), Ligneous conjunctivitis (Orphanet:97231)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000123	Nephritis
HP:0000137	Abnormality of the ovary
HP:0000212	Gingival overgrowth
HP:0000230	Gingivitis
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000282	Facial edema
HP:0000370	Abnormality of the middle ear
HP:0000478	Abnormality of the eye
HP:0000504	Abnormality of vision
HP:0000509	Conjunctivitis
HP:0000618	Blindness
HP:0000704	Periodontitis
HP:0000787	Nephrolithiasis
HP:0000951	Abnormality of the skin
HP:0001290	Generalized hypotonia
HP:0001305	Dandy-Walker malformation
HP:0001321	Cerebellar hypoplasia
HP:0001977	Abnormal thrombosis
HP:0002086	Abnormality of the respiratory system
HP:0002119	Ventriculomegaly
HP:0002588	Duodenal ulcer
HP:0002788	Recurrent upper respiratory tract infections
HP:0003593	Infantile onset
HP:0011027	Abnormal fallopian tube morphology
HP:0011462	Young adult onset
HP:0012027	Laryngeal edema
HP:0030160	Cervicitis

GWAS associations

34 associations (top):

Study	Trait	p-value
GCST001218_3	Lp (a) levels	3.000000e-17
GCST001599_4	Aging	3.000000e-06
GCST002601_1	Plasma plasminogen levels	2.000000e-26
GCST003075_128	Cognitive decline rate in late mild cognitive impairment	2.000000e-06
GCST003075_34	Cognitive decline rate in late mild cognitive impairment	7.000000e-07
GCST003116_14	Coronary artery disease	2.000000e-32
GCST003117_17	Myocardial infarction	2.000000e-24
GCST003127_15	Lipoprotein (a) levels	5.000000e-30
GCST003928_3	Giant cell arteritis	1.000000e-10
GCST003991_14	Childhood ear infection	4.000000e-08
GCST004787_35	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	2.000000e-49
GCST005013_45	Childhood ear infection	4.000000e-08
GCST005950_13	Body mass index x sex x age interaction (4df test)	3.000000e-07
GCST005951_54	Body mass index	4.000000e-06
GCST005952_6	Body mass index (age>50)	2.000000e-08
GCST006813_2	End stage renal disease x APOL1 genotype interaction	8.000000e-08
GCST008074_54	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	5.000000e-07
GCST008075_190	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-08
GCST008075_80	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	4.000000e-08
GCST008078_117	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	4.000000e-11
GCST008078_38	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	4.000000e-08
GCST008079_107	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	3.000000e-175
GCST008079_33	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-178
GCST008083_135	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	5.000000e-06
GCST008083_20	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	5.000000e-08
GCST008084_159	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-09
GCST008084_83	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-09
GCST008086_76	LDL cholesterol levels in current drinkers	6.000000e-08
GCST008086_87	LDL cholesterol levels in current drinkers	8.000000e-06
GCST009881_1	Lipoprotein (a) levels in response to niacin in statin-treated individuals	7.000000e-28

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0006925	lipoprotein A measurement
EFO:0022597	aging
EFO:0006309	plasma plasminogen measurement
EFO:0007710	cognitive decline measurement
EFO:0007904	susceptibility to childhood ear infection measurement
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009324	APOL1 risk genotype carrier status
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0004309	platelet count

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D054179	Angioedemas, Hereditary	C14.907.079.500; C16.320.798.500.500; C17.800.862.945.066.500; C20.543.480.904.066.500; C20.673.795.500.500
D065766	Atypical Hemolytic Uremic Syndrome	C12.050.351.968.419.936.463.500; C12.200.777.419.936.463.500; C12.950.419.936.463.500; C15.378.050.141.610.500; C15.378.140.855.925.500.500; C15.378.243.937.925.500.500
D003550	Cystic Fibrosis	C06.689.202; C08.381.187; C16.320.190; C16.614.213
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C580017	Congenital Plasminogen Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1801 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 182,348 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1046	AMINOCAPROIC ACID	4	95,343
CHEMBL231813	TELAPREVIR	4	3,301
CHEMBL266349	MELAGATRAN	4	5,421
CHEMBL5189739	BEROTRALSTAT	4	7
CHEMBL55	PENTAMIDINE	4	27,049
CHEMBL877	TRANEXAMIC ACID	4	27,519
CHEMBL273264	NAFAMOSTAT	3	7,063
CHEMBL4112929	MILVEXIAN	3	134
CHEMBL48361	DABIGATRAN	3	13,443
CHEMBL87563	GABEXATE	3	2,031
CHEMBL273196	EFEGATRAN	2	1,037

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs783145	PLG		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — S1: Chymotrypsin

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
bis-triazole derivative 10	Inhibition	9.1	pKi
aprotinin	Binding	6.8	pIC50
WX-UK1	Inhibition	5.84	pKi
6-aminocaproic acid	Binding	4.4	pIC50
tranexamic acid	Binding	3.6	pIC50

Binding affinities (BindingDB)

213 measured of 250 human assays (305 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2R)-N-[(3-aminobenzene)sulfonyl]-2-[(4-carbamimidoyl-3-hydroxyphenyl)amino]-2-(3,5-diethoxy-2-fluorophenyl)acetamide	KI	0.35 nM
substituted biphenyl derivative, 36ao	IC50	8 nM
(S)-2-((S)-2-Acetylamino-4-(S)-methyl-pentanoylamino)-4-methyl-pentanoic acid (1-formyl-4-guanidino-butyl)-amide	KI	8.2 nM
substituted biphenyl derivative, 36ab	IC50	9 nM
substituted biphenyl derivative, 36ak	IC50	9 nM
substituted biphenyl derivative, 36am	IC50	9 nM
2-oxo-4-piperidin-4-yl-10aH-pyrimido[1,2-b]indazole-10-carbonitrile	IC50	10 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
substituted biphenyl derivative, 36aa	IC50	10 nM
9-fluoro-10-phenyl-4-piperidin-4-yl-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	11 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-chloro-8-methyl-4-piperidin-4-yl-10aH-pyrimido[1,2-b]indazol-2-one	IC50	11 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
substituted biphenyl derivative, 36j	IC50	11 nM
substituted biphenyl derivative, 36ac	IC50	11 nM
substituted biphenyl derivative, 36ag	IC50	11 nM
substituted biphenyl derivative, 36n	IC50	12 nM
10-bromo-6-piperidin-4-yl-3,7,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2,5,8,11-pentaen-4-one	IC50	13 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-ethoxy-4-(2-methylpiperidin-4-yl)-10aH-pyrimido[1,2-b]indazol-2-one	IC50	13 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-(2-fluorophenyl)-4-piperidin-4-yl-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	13 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-cyclopentyl-4-piperidin-4-yl-10aH-pyrimido[1,2-b]indazol-2-one	IC50	13 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
4-piperidin-4-yl-10-[2-(trifluoromethyl)phenyl]-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	13 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
substituted biphenyl derivative, 36g	IC50	13 nM
10-bromo-4-piperidin-4-yl-10aH-pyrimido[1,2-b]indazol-2-one	IC50	14 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-bromo-4-(2-methylpiperidin-4-yl)-10aH-pyrimido[1,2-b]indazol-2-one	IC50	14 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
4-piperidin-4-yl-10-[4-(trifluoromethyl)phenyl]-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	14 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-phenyl-4-piperidin-4-yl-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	14 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-butan-2-yl-4-piperidin-4-yl-10aH-pyrimido[1,2-b]indazol-2-one	IC50	14 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-Chloro-4-(piperidin-4-yl)pyrimido[1,2-b]indazol-2(1H)-one hydrochloride	IC50	15 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
6-(2-methylpiperidin-4-yl)-13-phenyl-3,7,8,10-tetrazatricyclo[7.4.0.02,7]tridec-5-en-4-one	IC50	15 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-(4-methoxyphenyl)-4-piperidin-4-yl-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	15 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
4-piperidin-4-yl-10-pyridin-3-yl-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	15 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-bromo-7-fluoro-4-piperidin-4-yl-10aH-pyrimido[1,2-b]indazol-2-one	IC50	15 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-bromo-9-methylidene-4-piperidin-4-ylpyrimido[1,2-b]indazol-2-one	IC50	15 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
4-piperidin-4-yl-10-propan-2-yloxy-10aH-pyrimido[1,2-b]indazol-2-one	IC50	15 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-(2,6-difluorophenyl)-4-piperidin-4-yl-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	15 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-(2-methylpyrazol-3-yl)-4-piperidin-4-yl-10aH-pyrimido[1,2-b]indazol-2-one	IC50	15 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
4-piperidin-4-yl-10-pyridin-4-yl-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	16 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-bromo-7-methyl-4-piperidin-4-yl-10aH-pyrimido[1,2-b]indazol-2-one	IC50	16 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-bromo-8-fluoro-4-piperidin-4-yl-10aH-pyrimido[1,2-b]indazol-2-one	IC50	16 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
13-phenyl-6-piperidin-4-yl-3,7,8,10-tetrazatricyclo[7.4.0.02,7]tridec-5-en-4-one	IC50	17 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-methyl-4-piperidin-4-yl-10aH-pyrimido[1,2-b]indazol-2-one	IC50	18 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
4-piperidin-4-yl-10-propan-2-yl-10aH-pyrimido[1,2-b]indazol-2-one	IC50	18 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
4-piperidin-4-yl-10-[2-(trifluoromethoxy)phenyl]-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	18 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-(2-methylphenyl)-4-piperidin-4-yl-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	18 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-(2-chlorophenyl)-4-piperidin-4-yl-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	19 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
10-chloro-9-methylidene-4-piperidin-4-ylpyrimido[1,2-b]indazol-2-one	IC50	20 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
4-piperidin-4-yl-10-pyridin-2-yl-6,6a,7,8,9,10,10a,10b-octahydro-1H-pyrimido[1,2-b]indazol-2-one	IC50	20 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
substituted biphenyl derivative, 36ap	IC50	20 nM
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-pyridin-4-ylbutanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	20 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
11-fluoro-6-piperidin-4-yl-3,7,8,13-tetrazatricyclo[7.4.0.02,7]trideca-2,5,8,10,12-pentaen-4-one	IC50	21 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
substituted biphenyl derivative, 36w	IC50	21 nM
13-methyl-12-methylidene-6-piperidin-4-yl-3,7,8,10,11-pentazatricyclo[7.4.0.02,7]trideca-1(13),2,5,8,10-pentaen-4-one	IC50	22 nM	US-10098883: (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use

ChEMBL bioactivities

820 potent at pChembl≥5 of 1139 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Ki	0.01	nM	CHEMBL2448441
10.46	IC50	0.035	nM	CHEMBL505190
10.39	Ki	0.041	nM	CHEMBL4569923
10.29	Ki	0.051	nM	CHEMBL4439523
10.22	IC50	0.06	nM	CHEMBL502293
10.15	Ki	0.07	nM	CHEMBL4476141
10.15	IC50	0.07	nM	CHEMBL520364
9.90	IC50	0.127	nM	CHEMBL484615
9.89	Ki	0.13	nM	CHEMBL4458743
9.85	Ki	0.14	nM	CHEMBL4588827
9.82	Ki	0.15	nM	CHEMBL4458743
9.79	IC50	0.163	nM	CHEMBL505455
9.70	Ki	0.2	nM	CHEMBL2315243
9.68	Ki	0.21	nM	CHEMBL4454304
9.64	IC50	0.229	nM	CHEMBL507020
9.64	IC50	0.23	nM	CHEMBL105819
9.62	IC50	0.242	nM	CHEMBL451066
9.60	Ki	0.25	nM	CHEMBL3660186
9.60	IC50	0.252	nM	CHEMBL506771
9.51	IC50	0.308	nM	CHEMBL505720
9.49	IC50	0.32	nM	CHEMBL4576519
9.49	Ki	0.32	nM	CHEMBL4454130
9.45	IC50	0.358	nM	CHEMBL507281
9.40	Ki	0.4	nM	CHEMBL3660191
9.40	IC50	0.4	nM	CHEMBL4456691
9.40	IC50	0.4	nM	CHEMBL4436082
9.39	IC50	0.408	nM	CHEMBL499632
9.38	IC50	0.42	nM	CHEMBL4447001
9.38	Ki	0.42	nM	CHEMBL4454130
9.37	Ki	0.43	nM	CHEMBL4553652
9.35	Ki	0.45	nM	CHEMBL4579797
9.35	Ki	0.45	nM	CHEMBL4591922
9.34	IC50	0.457	nM	CHEMBL507279
9.32	Ki	0.48	nM	CHEMBL4462811
9.31	IC50	0.494	nM	CHEMBL524548
9.29	Ki	0.51	nM	CHEMBL4571212
9.28	Ki	0.52	nM	CHEMBL2315236
9.28	Ki	0.52	nM	CHEMBL4553652
9.27	Ki	0.54	nM	CHEMBL4560508
9.26	Ki	0.55	nM	CHEMBL3666821
9.26	IC50	0.554	nM	CHEMBL524370
9.25	Ki	0.56	nM	CHEMBL4560508
9.24	Ki	0.57	nM	CHEMBL2315246
9.22	Ki	0.6	nM	CHEMBL3660185
9.22	Ki	0.6	nM	CHEMBL3660182
9.22	Ki	0.6	nM	CHEMBL3660174
9.21	Ki	0.61	nM	CHEMBL4592533
9.18	Ki	0.66	nM	CHEMBL4435567
9.18	Ki	0.66	nM	CHEMBL4443353
9.18	IC50	0.656	nM	CHEMBL524732

PubChem BioAssay actives

863 with measured affinity, of 2383 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
2-[(1R,4S,7S,13S,19S,22S,25S,28S,31R,34S,40S,43S,49S)-25-(4-aminobutyl)-49-benzyl-4-[(2S)-butan-2-yl]-19,34-bis[3-(diaminomethylideneamino)propyl]-22-(hydroxymethyl)-28-[(4-hydroxyphenyl)methyl]-3,6,12,18,21,24,27,30,33,36,39,42,48,51-tetradecaoxo-53,54-dithia-2,5,11,17,20,23,26,29,32,35,38,41,47,50-tetradecazapentacyclo[29.20.4.07,11.013,17.043,47]pentapentacontan-40-yl]acetic acid	1574053: Inhibition of human plasmin using Ac-RM(O2)YR-pNA as substrate after 30 mins	ki	<0.0001	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-thiophen-3-ylphenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	<0.0001	uM
benzyl N-[(2S)-1-[(2S)-2-[[5-hydrazinyl-5-sulfanylidene-1-[(2S,6R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]pentyl]carbamoyl]pyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]carbamate;hydrobromide	157974: Binding affinity against plasmin	ki	<0.0001	uM
2-[(1R,4S,7S,13S,19S,22S,25S,28S,31R,34S,40S,43S,49S)-19,25-bis(4-aminobutyl)-49-benzyl-4-[(2S)-butan-2-yl]-34-[3-(diaminomethylideneamino)propyl]-22-(hydroxymethyl)-28-[(4-hydroxyphenyl)methyl]-3,6,12,18,21,24,27,30,33,36,39,42,48,51-tetradecaoxo-53,54-dithia-2,5,11,17,20,23,26,29,32,35,38,41,47,50-tetradecazapentacyclo[29.20.4.07,11.013,17.043,47]pentapentacontan-40-yl]acetic acid	1574053: Inhibition of human plasmin using Ac-RM(O2)YR-pNA as substrate after 30 mins	ki	0.0001	uM
(19S,22R)-N-[(4-carbamimidoylphenyl)methyl]-22-(cyclohexylsulfamoylamino)-3,12,21-trioxo-2,6,9,13,20-pentazatetracyclo[22.2.2.26,9.214,17]dotriaconta-1(27),14(30),15,17(29),24(28),25-hexaene-19-carboxamide;tris(2,2,2-trifluoroacetic acid)	1626133: Binding affinity to human plasmin assessed as slow binding constant in presence of Mes-DArg-Phe-Arg-AMC after 20 mins by Dixon plot analysis	ki	0.0001	uM
(19S,22R)-22-(benzenesulfonamido)-N-[(4-carbamimidoylphenyl)methyl]-3,12,21-trioxo-2,6,9,13,20-pentazatetracyclo[22.2.2.26,9.214,17]dotriaconta-1(27),14(30),15,17(29),24(28),25-hexaene-19-carboxamide;tris(2,2,2-trifluoroacetic acid)	1626135: Inhibition of human plasmin using Mes-DSer(Bzl)-Phe-Arg-AMC as substrate by Dixon plot analysis	ki	0.0001	uM
2-[(1R,4S,7S,13S,19S,22S,25S,28S,31R,34S,40S,43S,49S)-25-(4-aminobutyl)-49-benzyl-4,19-bis[(2S)-butan-2-yl]-34-[3-(diaminomethylideneamino)propyl]-22-(hydroxymethyl)-28-[(4-hydroxyphenyl)methyl]-3,6,12,18,21,24,27,30,33,36,39,42,48,51-tetradecaoxo-53,54-dithia-2,5,11,17,20,23,26,29,32,35,38,41,47,50-tetradecazapentacyclo[29.20.4.07,11.013,17.043,47]pentapentacontan-40-yl]acetic acid	1574053: Inhibition of human plasmin using Ac-RM(O2)YR-pNA as substrate after 30 mins	ki	0.0001	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-prop-1-ynylphenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0001	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-[4-(hydroxymethyl)thiophen-3-yl]phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0001	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-prop-1-en-2-ylphenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0001	uM
2-[(1R,4S,7S,13S,19S,22S,25S,28S,31R,40S,43S,49S)-25-(4-aminobutyl)-49-benzyl-4-[(2S)-butan-2-yl]-34-[4-(diaminomethylideneamino)butyl]-19-[3-(diaminomethylideneamino)propyl]-22-(hydroxymethyl)-28-[(4-hydroxyphenyl)methyl]-3,6,12,18,21,24,27,30,33,36,39,42,48,51-tetradecaoxo-53,54-dithia-2,5,11,17,20,23,26,29,32,35,38,41,47,50-tetradecazapentacyclo[29.20.4.07,11.013,17.043,47]pentapentacontan-40-yl]acetamide	1574053: Inhibition of human plasmin using Ac-RM(O2)YR-pNA as substrate after 30 mins	ki	0.0002	uM
2-[4-[4-(aminomethyl)thiophen-3-yl]-2-[(4-carbamimidoylphenyl)carbamoyl]phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0002	uM
(2S)-2-[[(2S)-2-[4-(diaminomethylideneamino)butanoylamino]-3-(4-nitrophenyl)propanoyl]-methylamino]-3-hydroxy-N-[(1R)-1-phenylethyl]butanamide	157803: Concentration required to inhibit Plasmin was determined	ic50	0.0002	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-(furan-2-yl)phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0002	uM
2-[4-[4-(azidomethyl)thiophen-3-yl]-2-[(4-carbamimidoylphenyl)carbamoyl]phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0002	uM
(19S,22R)-22-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,12,21-trioxo-2,6,9,13,20-pentazatetracyclo[22.2.2.26,9.214,17]dotriaconta-1(27),14(30),15,17(29),24(28),25-hexaene-19-carboxamide;2,2,2-trifluoroacetic acid	724901: Inhibition of human plasmin protease domain using Tos-Gly-Pro-Lys-pNA as substrate by micro plate reader analysis	ki	0.0002	uM
4-[4-[(2S)-2-[[4-(aminomethyl)cyclohexanecarbonyl]amino]-3-[(4-chloro-1H-indazol-6-yl)amino]-3-oxopropyl]phenyl]-3-methyl-N-propan-2-ylbenzamide	1558626: Inhibition of human plasmin preincubated for 15 mins followed by MeOSuc-Ala-Phe-Lys-AMC substrate addition and measured after 30 mins by fluorescence method	ic50	0.0003	uM
(17S,20R)-N-[(4-carbamimidoylphenyl)methyl]-20-(cyclohexylsulfamoylamino)-3,10,19-trioxo-2,5,8,11,18-pentazatetracyclo[20.2.2.25,8.212,15]triaconta-1(25),12,14,22(26),23,27-hexaene-17-carboxamide;tris(2,2,2-trifluoroacetic acid)	1626135: Inhibition of human plasmin using Mes-DSer(Bzl)-Phe-Arg-AMC as substrate by Dixon plot analysis	ki	0.0003	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-(furan-3-yl)phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0003	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-(3-methylbut-2-enyl)phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0003	uM
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-phenylpentanamide	1558652: Inhibition of human plasmin using tosyl-Gly-Pro-Lys-pNA as substrate	ki	0.0003	uM
4-(aminomethyl)-N-[(2S)-1-[(7-chloro-2-oxo-1,3-dihydrobenzimidazol-5-yl)amino]-3-[4-(2-cyclopropyl-6-methyl-1H-benzimidazol-5-yl)phenyl]-1-oxopropan-2-yl]cyclohexane-1-carboxamide	1558626: Inhibition of human plasmin preincubated for 15 mins followed by MeOSuc-Ala-Phe-Lys-AMC substrate addition and measured after 30 mins by fluorescence method	ic50	0.0004	uM
3-[3-[4-[[(2S)-2-[[4-(aminomethyl)cyclohexanecarbonyl]amino]-3-[4-(5-methyl-2-propan-2-yl-1H-imidazo[4,5-b]pyridin-6-yl)phenyl]propanoyl]amino]phenyl]-1H-1,2,4-triazol-5-yl]-2,2,3,3-tetrafluoropropanoic acid	1558626: Inhibition of human plasmin preincubated for 15 mins followed by MeOSuc-Ala-Phe-Lys-AMC substrate addition and measured after 30 mins by fluorescence method	ic50	0.0004	uM
(19S,22R)-N-[[4-(aminomethyl)phenyl]methyl]-22-(cyclohexylsulfamoylamino)-3,12,21-trioxo-2,6,9,13,20-pentazatetracyclo[22.2.2.26,9.214,17]dotriaconta-1(27),14(30),15,17(29),24(28),25-hexaene-19-carboxamide;tris(2,2,2-trifluoroacetic acid)	1626133: Binding affinity to human plasmin assessed as slow binding constant in presence of Mes-DArg-Phe-Arg-AMC after 20 mins by Dixon plot analysis	ki	0.0004	uM
4-(aminomethyl)-N-[(2S)-1-[(7-chloro-2-oxo-1,3-dihydrobenzimidazol-5-yl)amino]-3-[4-(2-cyclopropyl-5-methyl-1H-imidazo[4,5-b]pyridin-6-yl)phenyl]-1-oxopropan-2-yl]cyclohexane-1-carboxamide	1558626: Inhibition of human plasmin preincubated for 15 mins followed by MeOSuc-Ala-Phe-Lys-AMC substrate addition and measured after 30 mins by fluorescence method	ic50	0.0004	uM
2-[(1R,4S,7S,13S,22S,25S,28S,31S,34R,37S,43S,46S,52S)-28-(4-aminobutyl)-52-benzyl-4-[(2S)-butan-2-yl]-19-(4-carbamimidamidobutyl)-22,37-bis(3-carbamimidamidopropyl)-25-(hydroxymethyl)-31-[(4-hydroxyphenyl)methyl]-3,6,12,18,21,24,27,30,33,36,39,42,45,51,54-pentadecaoxo-56,57-dithia-2,5,11,17,20,23,26,29,32,35,38,41,44,50,53-pentadecazapentacyclo[32.20.4.07,11.013,17.046,50]octapentacontan-43-yl]acetic acid	1574053: Inhibition of human plasmin using Ac-RM(O2)YR-pNA as substrate after 30 mins	ki	0.0004	uM
(19S,22R)-22-(butylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,12,21-trioxo-2,6,9,13,20-pentazatetracyclo[22.2.2.26,9.214,17]dotriaconta-1(27),14(30),15,17(29),24(28),25-hexaene-19-carboxamide;tris(2,2,2-trifluoroacetic acid)	1626135: Inhibition of human plasmin using Mes-DSer(Bzl)-Phe-Arg-AMC as substrate by Dixon plot analysis	ki	0.0004	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-[2-(hydroxymethyl)thiophen-3-yl]phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0004	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-(4-hydroxybut-1-en-2-yl)phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0004	uM
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-pyridin-4-ylbutan-2-yl]-5-phenylpentanamide	1558645: Inhibition of human plasmin using tosyl-Gly-Pro-Lys-pNA as substrate after 10 mins by UV/Vis photometry	ki	0.0005	uM
(19S,22R)-N-[[4-(aminomethyl)phenyl]methyl]-22-(benzenesulfonamido)-3,12,21-trioxo-2,6,9,13,20-pentazatetracyclo[22.2.2.26,9.214,17]dotriaconta-1(27),14(30),15,17(29),24(28),25-hexaene-19-carboxamide;tris(2,2,2-trifluoroacetic acid)	1626133: Binding affinity to human plasmin assessed as slow binding constant in presence of Mes-DArg-Phe-Arg-AMC after 20 mins by Dixon plot analysis	ki	0.0005	uM
(17S,20R)-20-(benzenesulfonamido)-N-[(4-carbamimidoylphenyl)methyl]-3,10,19-trioxo-2,5,8,11,18-pentazatetracyclo[20.2.2.25,8.212,15]triaconta-1(25),12,14,22(26),23,27-hexaene-17-carboxamide;tris(2,2,2-trifluoroacetic acid)	1626135: Inhibition of human plasmin using Mes-DSer(Bzl)-Phe-Arg-AMC as substrate by Dixon plot analysis	ki	0.0005	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-(1,3-thiazol-2-yl)phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0005	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-[2-(hydroxymethyl)furan-3-yl]phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0005	uM
(18R,21S)-18-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,10,19-trioxo-2,5,8,11,20-pentazatetracyclo[21.2.2.25,8.213,16]hentriaconta-1(26),13(29),14,16(28),23(27),24-hexaene-21-carboxamide;2,2,2-trifluoroacetic acid	724901: Inhibition of human plasmin protease domain using Tos-Gly-Pro-Lys-pNA as substrate by micro plate reader analysis	ki	0.0005	uM
2-[(1R,4S,7S,13S,19S,22S,25S,28S,31R,34S,40S,43S,49S)-19,25-bis(4-aminobutyl)-28,49-dibenzyl-4-[(2S)-butan-2-yl]-34-[3-(diaminomethylideneamino)propyl]-22-(hydroxymethyl)-3,6,12,18,21,24,27,30,33,36,39,42,48,51-tetradecaoxo-53,54-dithia-2,5,11,17,20,23,26,29,32,35,38,41,47,50-tetradecazapentacyclo[29.20.4.07,11.013,17.043,47]pentapentacontan-40-yl]acetic acid	1574053: Inhibition of human plasmin using Ac-RM(O2)YR-pNA as substrate after 30 mins	ki	0.0006	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-[4-(hydroxymethyl)furan-3-yl]phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0006	uM
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-[1-(cyclopropanecarbonyl)piperidin-4-yl]butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	1558652: Inhibition of human plasmin using tosyl-Gly-Pro-Lys-pNA as substrate	ki	0.0006	uM
(10S,13R)-13-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,12,20-trioxo-1,4,11,19,22-pentazatetracyclo[20.3.2.25,8.215,18]hentriaconta-5,7,15(29),16,18(28),30-hexaene-10-carboxamide;2,2,2-trifluoroacetic acid	724901: Inhibition of human plasmin protease domain using Tos-Gly-Pro-Lys-pNA as substrate by micro plate reader analysis	ki	0.0006	uM
2-[(1R,4S,7S,13S,19S,22S,25S,28S,31R,34S,40S,43S,49S)-19,25-bis(4-aminobutyl)-49-benzyl-4-[(2S)-butan-2-yl]-34-[3-(diaminomethylideneamino)propyl]-22-(hydroxymethyl)-28-(1H-indol-3-ylmethyl)-3,6,12,18,21,24,27,30,33,36,39,42,48,51-tetradecaoxo-53,54-dithia-2,5,11,17,20,23,26,29,32,35,38,41,47,50-tetradecazapentacyclo[29.20.4.07,11.013,17.043,47]pentapentacontan-40-yl]acetic acid	1574053: Inhibition of human plasmin using Ac-RM(O2)YR-pNA as substrate after 30 mins	ki	0.0007	uM
2-[(1R,4S,7S,13S,19S,22S,25S,28S,31R,34S,40S,43S,49S)-19,25-bis(4-aminobutyl)-4-(2-amino-2-oxoethyl)-49-benzyl-34-[3-(diaminomethylideneamino)propyl]-22-(hydroxymethyl)-28-[(4-hydroxyphenyl)methyl]-3,6,12,18,21,24,27,30,33,36,39,42,48,51-tetradecaoxo-53,54-dithia-2,5,11,17,20,23,26,29,32,35,38,41,47,50-tetradecazapentacyclo[29.20.4.07,11.013,17.043,47]pentapentacontan-40-yl]acetic acid	1574053: Inhibition of human plasmin using Ac-RM(O2)YR-pNA as substrate after 30 mins	ki	0.0007	uM
2-[4-benzyl-2-[(4-carbamimidoylphenyl)carbamoyl]phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0007	uM
2-[4-[(Z)-but-2-enyl]-2-[(4-carbamimidoylphenyl)carbamoyl]phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0007	uM
(17S,20R)-20-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,10,19-trioxo-2,5,8,11,18-pentazatetracyclo[20.2.2.25,8.212,15]triaconta-1(25),12,14,22(26),23,27-hexaene-17-carboxamide;2,2,2-trifluoroacetic acid	724901: Inhibition of human plasmin protease domain using Tos-Gly-Pro-Lys-pNA as substrate by micro plate reader analysis	ki	0.0007	uM
5-[4-[(2S)-2-[[4-(aminomethyl)cyclohexanecarbonyl]amino]-3-[(7-chloro-2-oxo-3H-1,3-benzoxazol-5-yl)amino]-3-oxopropyl]phenyl]-6-methyl-N-propan-2-ylpyridine-2-carboxamide	1558626: Inhibition of human plasmin preincubated for 15 mins followed by MeOSuc-Ala-Phe-Lys-AMC substrate addition and measured after 30 mins by fluorescence method	ic50	0.0008	uM
methyl N-[(19S,22R)-19-[(4-carbamimidoylphenyl)methylcarbamoyl]-3,12,21-trioxo-2,6,9,13,20-pentazatetracyclo[22.2.2.26,9.214,17]dotriaconta-1(27),14(30),15,17(29),24(28),25-hexaen-22-yl]carbamate;tris(2,2,2-trifluoroacetic acid)	1626133: Binding affinity to human plasmin assessed as slow binding constant in presence of Mes-DArg-Phe-Arg-AMC after 20 mins by Dixon plot analysis	ki	0.0008	uM
benzyl N-[(19S,22R)-19-[(4-carbamimidoylphenyl)methylcarbamoyl]-3,12,21-trioxo-2,6,9,13,20-pentazatetracyclo[22.2.2.26,9.214,17]dotriaconta-1(27),14(30),15,17(29),24(28),25-hexaen-22-yl]carbamate;tris(2,2,2-trifluoroacetic acid)	1626135: Inhibition of human plasmin using Mes-DSer(Bzl)-Phe-Arg-AMC as substrate by Dixon plot analysis	ki	0.0008	uM
3-[[(2R)-1-[[(2S)-3-(3-carbamimidoylphenyl)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxopropan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoic acid	2064597: Binding affinity to plasmin (unknown origin) assessed as inhibition constant	ki	0.0008	uM
2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-(3-hydroxyprop-1-en-2-yl)phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid	397860: Inhibition of plasmin	ic50	0.0008	uM
(8S,11R)-11-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-10-oxo-3,4,5,9,14,15,16-heptazatetracyclo[16.3.1.13,6.113,16]tetracosa-1(21),4,6(24),13(23),14,18(22),19-heptaene-8-carboxamide	656100: Inhibition of plasmin by dixon plot method	ki	0.0008	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Ethinyl Estradiol	affects binding, increases expression, affects cotreatment, increases activity	5
Benzo(a)pyrene	decreases expression, increases methylation	3
Contraceptives, Oral	increases expression	3
Gestodene	affects cotreatment, increases activity, increases expression	2
ethinyl estradiol-desogestrel combination	increases activity, increases expression	2
Acetaminophen	decreases expression	2
Estradiol	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Aflatoxin B1	affects expression, decreases expression, decreases methylation	2
Levonorgestrel	affects cotreatment, increases expression	2
ginger extract	decreases expression, increases abundance	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
norgestimate	increases expression, affects cotreatment	1
sodium arsenite	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	affects expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	increases methylation	1
perfluoro-n-nonanoic acid	decreases expression	1
corosolic acid	increases expression	1
entinostat	decreases expression	1
belinostat	decreases expression	1
(R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine	decreases activity, decreases reaction, increases activity, increases secretion, affects reaction	1
NuvaRing	increases expression	1
(+)-JQ1 compound	decreases expression	1
waixenicin A	increases activity, increases secretion	1
Arsenic Trioxide	decreases activity	1
Vorinostat	decreases expression	1
Amiloride	decreases reaction, increases degradation	1
Arsenic	decreases reaction, increases reaction, decreases activity	1

ChEMBL screening assays

480 unique, capped per target: 467 binding, 7 admet, 6 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003517	Binding	Inhibition of plasmin after 30 mins by microtiter plate method	Micropeptins 478-A and -B, Plasmin Inhibitors from the Cyanobacterium Microcystis aeruginosa — J Nat Prod
CHEMBL3739099	ADMET	Stability of the compound assessed as Plasmin (unknown origin)-mediated drug degradation after 1 hr	Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor. — J Med Chem
CHEMBL762810	Functional	Time to reach maximum percent inhibition by the compound was determined against plasmin(625 nM)	Guanidinophenyl-substituted enol lactones as selective, mechanism-based inhibitors of trypsin-like serine proteases. — J Med Chem

Clinical trials (associated diseases)

294 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00914966	PHASE4	COMPLETED	A Study to Evaluate the Safety and Effect of Escalating Doses of CINRYZE
NCT01151735	PHASE4	WITHDRAWN	C1-INH Compared to Placebo at the Time of Prodromal Symptoms for Hereditary Angioedema (HAE) Exacerbation
NCT01457430	PHASE4	COMPLETED	Efficacy, Safety and Tolerability of Icatibant for the Treatment of HAE
NCT01679912	PHASE4	COMPLETED	A Call Center During HAE Attacks (SOS HAE)
NCT06690047	PHASE4	COMPLETED	Treatment of Hereditary Angioedema Prodrome with Recombinant C1-esterase Inhibitor (Ruconest)
NCT06806657	PHASE4	ACTIVE_NOT_RECRUITING	Safety Study in Subjects ≥ 12 Years of Age With Hereditary Angioedema Switching to Garadacimab
NCT07290855	PHASE4	COMPLETED	A Study to Evaluate the Safety and Efficacy of Icatibant in Patients With Bradykinin Induced Angioedema
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT06343779	PHASE3	COMPLETED	Study of Oral Deucrictibant Soft Capsule for On-Demand Treatment of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema
NCT06960213	PHASE3	RECRUITING	STOP-HAE: A Phase 3 Study of ADX-324 in HAE
NCT07428499	PHASE3	RECRUITING	Phase 3 Extension Study of ADX-324 in Participants With Hereditary Angioedema (HAE)
NCT00262080	PHASE3	COMPLETED	Efficacy and Safety Study of DX-88 to Treat Acute Attacks of Hereditary Angioedema (HAE)
NCT00262301	PHASE3	COMPLETED	Recombinant Human C1 Inhibitor for the Treatment of Acute Attacks in Patients With Hereditary Angioedema
NCT00289211	PHASE3	COMPLETED	C1 Esterase Inhibitor (C1INH-nf) for the Treatment of Acute Hereditary Angioedema (HAE) Attacks
NCT00292981	PHASE3	COMPLETED	C1 Esterase Inhibitor in Hereditary Angioedema (HAE)(Extension Study)
NCT00438815	PHASE3	COMPLETED	Open-Label C1 Esterase Inhibitor (C1INH-nf) for the Treatment of Acute Hereditary Angioedema (HAE) Attacks
NCT00456508	PHASE3	COMPLETED	Safety and Efficacy Study of Repeated Doses of DX-88 (Ecallantide) to Treat Attacks of Hereditary Angioedema (HAE)
NCT00457015	PHASE3	COMPLETED	Efficacy Study of DX-88 (Ecallantide) to Treat Acute Attacks of Hereditary Angioedema (HAE)
NCT00462709	PHASE3	COMPLETED	Open-Label C1 Esterase Inhibitor (C1INH-nf) for the Prevention of Acute Hereditary Angioedema (HAE) Attacks
NCT00500656	PHASE3	COMPLETED	Subcutaneous Treatment With Icatibant for Acute Attacks of Hereditary Angioedema (HAE)
NCT00748202	PHASE3	COMPLETED	Berinert P Study of Subcutaneous Versus Intravenous Administration
NCT00912093	PHASE3	COMPLETED	A Study of Icatibant in Patients With Acute Attacks of Hereditary Angioedema (FAST-3)
NCT00997204	PHASE3	COMPLETED	EASSI - Evaluation of the Safety of Self-Administration With Icatibant
NCT01005888	PHASE3	COMPLETED	C1 Esterase Inhibitor (C1INH-nf) for the Prevention of Acute Hereditary Angioedema (HAE) Attacks
NCT01188564	PHASE3	COMPLETED	Efficacy, Safety and Immunogenicity Study of Recombinant Human C1 Inhibitor for the Treatment of Acute HAE Attacks
NCT01386658	PHASE3	COMPLETED	A Pharmacokinetic, Tolerability and Safety Study of Icatibant in Children and Adolescents With Hereditary Angioedema
NCT02052141	PHASE3	COMPLETED	Safety and Efficacy Study of CINRYZE for Prevention of Angioedema Attacks in Children Ages 6-11 With Hereditary Angioedema