MMEL1

Summary

MMEL1 (membrane metalloendopeptidase like 1, HGNC:14668) is a protein-coding gene on chromosome 1p36.32, encoding Membrane metallo-endopeptidase-like 1 (Q495T6). Metalloprotease involved in sperm function, possibly by modulating the processes of fertilization and early embryonic development.

The protein encoded by this gene is a member of the neutral endopeptidase (NEP) or membrane metallo-endopeptidase (MME) family. Family members play important roles in pain perception, arterial pressure regulation, phosphate metabolism and homeostasis. This protein is a type II transmembrane protein and is thought to be expressed as a secreted protein. This gene is expressed mainly in testis with weak expression in the brain, kidney, and heart.

Source: NCBI Gene 79258 — RefSeq curated summary.

At a glance

• GWAS associations: 29
• Clinical variants (ClinVar): 164 total
• Phenotypes (HPO): 41
• Druggable target: yes
• MANE Select transcript: NM_033467

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14668
Approved symbol	MMEL1
Name	membrane metalloendopeptidase like 1
Location	1p36.32
Locus type	gene with protein product
Status	Approved
Aliases	SEP, NL1, NL2, NEPII
Ensembl gene	ENSG00000142606
Ensembl biotype	protein_coding
OMIM	618104
Entrez	79258

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 retained_intron, 3 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000378412, ENST00000464195, ENST00000469962, ENST00000471840, ENST00000491941, ENST00000502556, ENST00000504800, ENST00000509374, ENST00000511099

RefSeq mRNA: 1 — MANE Select: NM_033467 NM_033467

CCDS: CCDS30569

Canonical transcript exons

ENST00000378412 — 24 exons

Exon	Start	End
ENSE00000955117	2606248	2606366
ENSE00000955118	2605558	2605623
ENSE00001035353	2594790	2594893
ENSE00001035383	2596561	2596689
ENSE00001035401	2594385	2594443
ENSE00001035410	2598654	2598790
ENSE00001035412	2603884	2603973
ENSE00001035416	2595276	2595359
ENSE00001035434	2604147	2604281
ENSE00001035437	2593814	2593933
ENSE00001035440	2596009	2596107
ENSE00001035444	2598207	2598300
ENSE00001066588	2611281	2611340
ENSE00001301908	2612127	2612204
ENSE00001428123	2632866	2633016
ENSE00001477450	2629331	2629521
ENSE00001957118	2590639	2591089
ENSE00003481724	2592655	2592720
ENSE00003508760	2609339	2609419
ENSE00003532852	2606974	2607069
ENSE00003541874	2609670	2609831
ENSE00003599396	2591932	2592027
ENSE00003641328	2592833	2592966
ENSE00003649471	2591557	2591633

Expression profiles

Bgee: expression breadth ubiquitous, 131 present calls, max score 91.01.

FANTOM5 (CAGE): breadth broad, TPM avg 0.3750 / max 29.3205, expressed in 196 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9925	0.2282	129
9924	0.1200	78
9926	0.0170	4
9927	0.0098	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.01	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.65	gold quality
left testis	UBERON:0004533	85.88	gold quality
right testis	UBERON:0004534	85.61	gold quality
testis	UBERON:0000473	85.26	gold quality
mucosa of transverse colon	UBERON:0004991	85.03	gold quality
right uterine tube	UBERON:0001302	84.72	gold quality
lower esophagus mucosa	UBERON:0035834	84.70	gold quality
body of stomach	UBERON:0001161	79.77	gold quality
cortical plate	UBERON:0005343	77.35	gold quality
duodenum	UBERON:0002114	76.89	gold quality
right lung	UBERON:0002167	76.30	gold quality
stomach	UBERON:0000945	75.94	gold quality
fundus of stomach	UBERON:0001160	75.74	gold quality
prostate gland	UBERON:0002367	74.93	gold quality
transverse colon	UBERON:0001157	73.29	gold quality
omental fat pad	UBERON:0010414	72.95	gold quality
upper lobe of left lung	UBERON:0008952	72.69	gold quality
gall bladder	UBERON:0002110	72.66	gold quality
small intestine Peyer’s patch	UBERON:0003454	72.36	gold quality
small intestine	UBERON:0002108	72.14	gold quality
fallopian tube	UBERON:0003889	71.82	gold quality
thoracic mammary gland	UBERON:0005200	71.53	gold quality
ganglionic eminence	UBERON:0004023	71.09	gold quality
esophagus mucosa	UBERON:0002469	71.01	gold quality
adipose tissue	UBERON:0001013	70.87	gold quality
lung	UBERON:0002048	70.39	gold quality
hypothalamus	UBERON:0001898	69.71	gold quality
spleen	UBERON:0002106	69.69	gold quality
subcutaneous adipose tissue	UBERON:0002190	69.21	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.57

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

22 targeting MMEL1, 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-4692	100.00	67.32	2066
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-6818-3P	98.56	68.23	1307
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-374C-3P	98.47	67.93	451
HSA-MIR-7843-3P	98.31	67.94	803
HSA-MIR-127-5P	97.78	67.64	869
HSA-MIR-500A-3P	97.60	67.48	595
HSA-MIR-6515-5P	97.08	65.48	1219
HSA-MIR-6854-5P	96.77	65.96	848
HSA-MIR-549A-5P	96.35	68.08	587
HSA-MIR-3935	96.33	66.79	797
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280
HSA-MIR-3622B-5P	94.62	64.58	835

Literature-anchored findings (GeneRIF, showing 8)

• NEP2 substrate specificity and inhibitor binding was distinct from that of human NEP, suggesting that NEP and NEP2 play distinct physiological roles in humans. (PMID:18539150)
• A combined analysis of the nsSNP screen and replication data provides evidence implicating a novel additional locus, rs3748816 in membrane metalloendopeptidase-like 1 in multiple sclerosis susceptibility. (PMID:20574445)
• This study identifies MMEL1 and CTLA4 as RA susceptibility genes, in Han Chinese popilation. (PMID:21784728)
• The NEP2 expression and activity are altered in MCI is significant as these changes may potentially serve as preclinical markers for AD and reduced NEP2 activity may be associated with the development of Alzheimer’s disease. (PMID:22008264)
• Te results of this study suggested taht genetic variations in MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9 genes do not play major role among the Finnish AD patient cohort. (PMID:22027013)
• MMEL1 518 Met/Thr polymorphism contributes to celiac disease risk among Saudi Arabians, both in single and also in synergistic cooperation with SH2B3 gene marker. (PMID:26843707)
• the dynamic behavior of human NEP and NEP2 proteins was monitored by conducting molecular dynamics (MD) simulations. (PMID:26846903)
• Investigating the association of polymorphisms of ANKRD55 and MMEL1 with susceptibility to multiple sclerosis in Iranian population. (PMID:33491520)

Cross-species orthologs

25 orthologs

Organism	Symbol	Gene ID
danio_rerio	mmel1	ENSDARG00000105389
mus_musculus	Mmel1	ENSMUSG00000058183
rattus_norvegicus	Mmel1	ENSRNOG00000012593
drosophila_melanogaster	Nepl21	FBGN0027578
drosophila_melanogaster	Nep3	FBGN0031081
drosophila_melanogaster	Nepl3	FBGN0031678
drosophila_melanogaster	Nepl12	FBGN0037727
drosophila_melanogaster	Nep4	FBGN0038818
drosophila_melanogaster	Nepl15	FBGN0039024
drosophila_melanogaster	Nep7	FBGN0039564
drosophila_melanogaster	Nepl18	FBGN0039611
drosophila_melanogaster	Nepl19	FBGN0039612
drosophila_melanogaster	Nepl20	FBGN0039613
caenorhabditis_elegans		WBGENE00013785
caenorhabditis_elegans		WBGENE00013786
caenorhabditis_elegans		WBGENE00013926
caenorhabditis_elegans		WBGENE00016778
caenorhabditis_elegans		WBGENE00016896
caenorhabditis_elegans		WBGENE00017550
caenorhabditis_elegans		WBGENE00017553
caenorhabditis_elegans		WBGENE00017554
caenorhabditis_elegans		WBGENE00017555
caenorhabditis_elegans		WBGENE00018196
caenorhabditis_elegans		WBGENE00018227
caenorhabditis_elegans		WBGENE00020293

Paralogs (6): PHEX (ENSG00000102174), ECE1 (ENSG00000117298), ECE2 (ENSG00000145194), ECEL1 (ENSG00000171551), MME (ENSG00000196549), KEL (ENSG00000197993)

Protein

Protein identifiers

Membrane metallo-endopeptidase-like 1 — Q495T6 (reviewed: Q495T6)

Alternative names: Membrane metallo-endopeptidase-like 2, NEP2(m), Neprilysin II, Neprilysin-2

All UniProt accessions (2): Q495T6, J3KRD2

UniProt curated annotations — full annotation on UniProt →

Function. Metalloprotease involved in sperm function, possibly by modulating the processes of fertilization and early embryonic development. Degrades a broad variety of small peptides with a preference for peptides shorter than 3 kDa containing neutral bulky aliphatic or aromatic amino acid residues. Shares the same substrate specificity with MME and cleaves peptides at the same amide bond.

Subcellular location. Membrane. Secreted.

Tissue specificity. Predominantly expressed in testis. Weakly expressed in brain, kidney and heart.

Post-translational modifications. N-glycosylated.

Activity regulation. Inhibited by thiorphan and phosphoramidon.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the peptidase M13 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q495T6-1	1	yes
Q495T6-2	2
Q495T6-3	3

RefSeq proteins (1): NP_258428* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000718	Peptidase_M13	Family
IPR008753	Peptidase_M13_N	Domain
IPR018497	Peptidase_M13_C	Domain
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR042089	Peptidase_M13_dom_2	Homologous_superfamily

Pfam: PF01431, PF05649

Enzyme classification (BRENDA):

• EC 3.4.24.B14 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (30 total): glycosylation site 5, disulfide bond 5, binding site 4, splice variant 3, chain 2, topological domain 2, sequence conflict 2, active site 2, site 1, sequence variant 1, transmembrane region 1, domain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q495T6-F1	90.34	0.84

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 (3): 73–74 (cleavage); 614; 680 (proton donor)

Ligand- & substrate-binding residues (4): 613; 617; 676; 135

Disulfide bonds (5): 89–94, 112–764, 120–724, 175–439, 650–776

Glycosylation sites (5): 177, 207, 350, 530, 657

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 149 (showing top): GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_PROTEIN_MATURATION, GATA1_01, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, GOBP_PROTEOLYSIS, ER_Q6_02, GOMF_PEPTIDASE_ACTIVITY, MATZUK_SPERMATOZOA, GSE13522_WT_VS_IFNG_KO_SKIN_DN, DODD_NASOPHARYNGEAL_CARCINOMA_DN, chr1p36, MIKKELSEN_MCV6_LCP_WITH_H3K27ME3, MIKKELSEN_MEF_LCP_WITH_H3K27ME3, MARTENS_TRETINOIN_RESPONSE_UP, GOBP_PROTEIN_PROCESSING

GO Biological Process (2): proteolysis (GO:0006508), protein processing (GO:0016485)

GO Molecular Function (6): endopeptidase activity (GO:0004175), metalloendopeptidase activity (GO:0004222), metal ion binding (GO:0046872), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), membrane (GO:0016020), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidase activity	2
cellular anatomical structure	2
protein metabolic process	1
proteolysis	1
protein maturation	1
endopeptidase activity	1
metallopeptidase activity	1
cation binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1190 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MMEL1	IDE	P14735	949
MMEL1	APP	P05067	889
MMEL1	ACE	P12821	889
MMEL1	BACE1	P56817	861
MMEL1	NR3C2	P08235	840
MMEL1	REN	P00797	791
MMEL1	PSEN1	P49768	789
MMEL1	NCSTN	Q92542	767
MMEL1	AGT	P01019	766
MMEL1	PSEN2	P49810	729
MMEL1	APH1A	Q96BI3	724
MMEL1	NPPA	P01160	708
MMEL1	LRP1	Q07954	704
MMEL1	SLC5A2	P31639	697
MMEL1	NPPB	P16860	697

IntAct

2 interactions, top by confidence:

A	B	Type	Score
MMEL1	NUMA1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (6): MMEL1 (Proximity Label-MS), MMEL1 (Cross-Linking-MS (XL-MS)), MMEL1 (Cross-Linking-MS (XL-MS)), MMEL1 (Cross-Linking-MS (XL-MS)), MMEL1 (Cross-Linking-MS (XL-MS)), MMEL1 (Protein-RNA)

ESM2 similar proteins: A0A0B4K692, A5HUI5, B2RQR8, D3UW23, F1N476, O16796, O44857, O95672, P07861, P08049, P08473, P0C1T0, P0DPD6, P0DPD9, P15144, P15145, P15684, P16406, P42891, P42892, P42893, P50123, P97739, Q07075, Q10715, Q10751, Q18673, Q22523, Q32LQ0, Q495T6, Q4PZA2, Q56H28, Q56NL1, Q58DD0, Q5EGZ1, Q5RE69, Q5RFN1, Q61391, Q6Q4G4, Q8IS64

Diamond homologs: A0A0B4K692, B2RQR8, F1N476, O16796, O44857, O95672, P07861, P08049, P08473, P0C1T0, P0DPD6, P0DPD8, P0DPD9, P0DPE2, P42891, P42892, P42893, P70669, P78562, P97739, Q18673, Q22523, Q495T6, Q4PZA2, Q5RE69, Q61391, Q8IS64, Q8T062, Q9JHL3, Q9JLI3, Q9JMI0, Q9W436, Q9W5Y0, W4VS99, P23276, Q9EQF2, P19621, A5PK19, A5WVX1, P0DPD7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	132
Likely benign	13
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

4710 predictions. Top by Δscore:

Variant	Effect	Δscore
1:2592651:CCACC:C	donor_loss	1.0000
1:2592652:CA:C	donor_loss	1.0000
1:2592653:A:AT	donor_loss	1.0000
1:2592654:C:CA	donor_loss	1.0000
1:2592801:C:CA	donor_gain	1.0000
1:2592806:AG:A	donor_gain	1.0000
1:2592831:A:AC	donor_gain	1.0000
1:2592832:C:CC	donor_gain	1.0000
1:2592832:CGTT:C	donor_gain	1.0000
1:2593929:GAATA:G	acceptor_gain	1.0000
1:2593930:AATA:A	acceptor_gain	1.0000
1:2593931:ATA:A	acceptor_gain	1.0000
1:2593932:TA:T	acceptor_gain	1.0000
1:2593933:ACT:A	acceptor_loss	1.0000
1:2593934:C:CC	acceptor_gain	1.0000
1:2593941:C:CT	acceptor_gain	1.0000
1:2593941:C:T	acceptor_gain	1.0000
1:2593942:A:T	acceptor_gain	1.0000
1:2593947:C:CT	acceptor_gain	1.0000
1:2593948:G:T	acceptor_gain	1.0000
1:2594788:A:AC	donor_gain	1.0000
1:2594789:C:CG	donor_gain	1.0000
1:2594789:CA:C	donor_gain	1.0000
1:2594789:CAG:C	donor_gain	1.0000
1:2594789:CAGA:C	donor_gain	1.0000
1:2594789:CAGAT:C	donor_gain	1.0000
1:2594818:T:TA	donor_gain	1.0000
1:2594891:CAG:C	acceptor_gain	1.0000
1:2594894:C:CC	acceptor_gain	1.0000
1:2595274:A:AC	donor_gain	1.0000

AlphaMissense

5132 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:2591557:C:A	R747M	0.999
1:2591571:A:C	S742R	0.999
1:2591571:A:T	S742R	0.999
1:2591573:T:G	S742R	0.999
1:2592691:G:C	N677K	0.999
1:2592691:G:T	N677K	0.999
1:2591557:C:G	R747T	0.998
1:2591576:G:C	H741D	0.998
1:2591625:G:C	C724W	0.998
1:2592683:T:A	D680V	0.998
1:2592684:C:G	D680H	0.998
1:2592695:T:A	E676V	0.998
1:2594410:G:C	F574L	0.998
1:2594410:G:T	F574L	0.998
1:2594412:A:G	F574L	0.998
1:2591089:C:A	R747S	0.997
1:2591089:C:G	R747S	0.997
1:2591626:C:T	C724Y	0.997
1:2592683:T:G	D680A	0.997
1:2592686:G:T	A679D	0.997
1:2593824:A:C	F619L	0.997
1:2593824:A:T	F619L	0.997
1:2593826:A:G	F619L	0.997
1:2593839:C:A	E614D	0.997
1:2593839:C:G	E614D	0.997
1:2593840:T:A	E614V	0.997
1:2593843:T:G	H613P	0.997
1:2596047:A:G	W488R	0.997
1:2596047:A:T	W488R	0.997
1:2596654:C:A	W436C	0.997

dbSNP variants (sampled 300 via entrez): RS1000029704 (1:2619200 A>G), RS1000072045 (1:2610955 G>A,T), RS1000126119 (1:2626867 C>T), RS1000214335 (1:2612817 G>A,C), RS1000287885 (1:2596205 G>A,C), RS1000320097 (1:2631703 C>A,G,T), RS1000468710 (1:2601737 T>C), RS1000486043 (1:2619413 T>A), RS1000507111 (1:2610697 C>T), RS1000508136 (1:2593439 T>G), RS1000610852 (1:2633613 T>C), RS1000663106 (1:2633952 G>C), RS1000670673 (1:2631887 G>A), RS1000735599 (1:2608193 G>A,C), RS1000743144 (1:2627241 T>C)

Disease associations

OMIM: gene MIM:618104 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000820	Abnormality of the thyroid gland
HP:0000939	Osteoporosis
HP:0000952	Jaundice
HP:0000953	Hyperpigmentation of the skin
HP:0000989	Pruritus
HP:0001114	Xanthelasma
HP:0001262	Excessive daytime somnolence
HP:0001278	Orthostatic hypotension
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001399	Hepatic failure
HP:0001402	Hepatocellular carcinoma
HP:0001409	Portal hypertension
HP:0001541	Ascites
HP:0001744	Splenomegaly
HP:0002040	Esophageal varix
HP:0002240	Hepatomegaly
HP:0002360	Sleep disturbance
HP:0002480	Hepatic encephalopathy
HP:0002570	Steatorrhea
HP:0002608	Celiac disease
HP:0002613	Biliary cirrhosis
HP:0002841	Recurrent fungal infections
HP:0002908	Conjugated hyperbilirubinemia
HP:0002960	Autoimmunity
HP:0003073	Hypoalbuminemia
HP:0003119	Abnormal circulating lipid concentration
HP:0003124	Hypercholesterolemia
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003261	Increased circulating IgA concentration

GWAS associations

29 associations (top):

Study	Trait	p-value
GCST000232_1	Rheumatoid arthritis	1.000000e-07
GCST000612_12	Celiac disease	3.000000e-09
GCST000964_38	Ulcerative colitis	3.000000e-09
GCST001198_58	Multiple sclerosis	1.000000e-14
GCST001362_2	Non-obstructive azoospermia	6.000000e-12
GCST001728_20	Ulcerative colitis	3.000000e-12
GCST002318_126	Rheumatoid arthritis	8.000000e-14
GCST002318_127	Rheumatoid arthritis	5.000000e-09
GCST002318_33	Rheumatoid arthritis	8.000000e-07
GCST003566_6	Multiple sclerosis	2.000000e-10
GCST004030_1	Primary sclerosing cholangitis	5.000000e-13
GCST004131_113	Inflammatory bowel disease	8.000000e-07
GCST004133_54	Ulcerative colitis	1.000000e-10
GCST005523_1	Celiac disease	5.000000e-12
GCST005524_1	Autoimmune thyroid diseases (Graves disease or Hashimoto’s thyroiditis)	6.000000e-06
GCST005526_1	Graves’ disease	8.000000e-07
GCST005531_24	Multiple sclerosis	1.000000e-26
GCST005568_26	Rheumatoid arthritis (ACPA-positive)	7.000000e-10
GCST005569_1	Rheumatoid arthritis	4.000000e-08
GCST005951_35	Body mass index	4.000000e-08
GCST006048_34	Rheumatoid arthritis (ACPA-positive)	7.000000e-12
GCST006670_4	Primary sclerosing cholangitis	7.000000e-12
GCST006959_144	Rheumatoid arthritis	4.000000e-14
GCST006959_62	Rheumatoid arthritis	2.000000e-10
GCST008644_5	Celiac disease and Rheumatoid arthritis	2.000000e-13
GCST008725_1	Diffuse large B-cell lymphoma or rheumatoid arthritis	2.000000e-08
GCST009873_1	Autoimmune traits (pleiotropy)	3.000000e-10
GCST009874_29	Celiac disease	1.000000e-08
GCST009877_14	Rheumatoid arthritis	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3638356 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

44 measured of 44 human assays (44 total across all organisms); most potent 44 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2R,4S)-5-[4-(3-chlorophenyl)phenyl]-2-methyl-4-[(3-oxo-1,2-oxazole-5-carbonyl)amino]pentanoic acid	IC50	0.03 nM	US-8993631: Method of treating contrast-induced nephropathy
(3R)-4-[4-(3-chlorophenyl)phenyl]-3-[(3-oxo-1,2-oxazole-5-carbonyl)amino]butanoic acid	IC50	0.07 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
(3R)-3-[[(Z)-4-amino-2-hydroxy-4-oxobut-2-enoyl]amino]-4-[4-(3-chlorophenyl)phenyl]butanoic acid	IC50	0.07 nM	US-8993631: Method of treating contrast-induced nephropathy
(2S)-2-[[(2S)-3-[4-(3-chlorophenyl)phenyl]-1-oxo-1-(2H-tetrazol-5-ylamino)propan-2-yl]amino]propanoic acid	IC50	0.09 nM	US-8993631: Method of treating contrast-induced nephropathy
4-[[(2R)-1-carboxy-3-[4-(3-chlorophenyl)phenyl]propan-2-yl]amino]-4-oxobutanoic acid	IC50	0.2 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
4-[[(2R)-1-carboxy-3-[4-(2,5-dichlorophenyl)phenyl]propan-2-yl]amino]-4-oxobutanoic acid	IC50	0.2 nM	US-8993631: Method of treating contrast-induced nephropathy
(2S)-2-[[(2S)-3-[4-(3-chlorophenyl)phenyl]-1-oxo-1-(2H-tetrazol-5-ylamino)propan-2-yl]amino]-4-phenylbutanoic acid	IC50	0.2 nM	US-8993631: Method of treating contrast-induced nephropathy
(2S)-2-[[(2S)-3-[4-(3-chlorophenyl)phenyl]-1-oxo-1-(2H-tetrazol-5-ylamino)propan-2-yl]amino]butanoic acid	IC50	0.2 nM	US-8993631: Method of treating contrast-induced nephropathy
(2S,4S)-5-[4-(3-chlorophenyl)phenyl]-2-methyl-4-[(3-oxo-1,2-oxazole-5-carbonyl)amino]pentanoic acid	IC50	0.3 nM	US-8993631: Method of treating contrast-induced nephropathy
(2S)-2-[[(2S)-3-[4-(2,5-dichlorophenyl)phenyl]-1-oxo-1-(2H-tetrazol-5-ylamino)propan-2-yl]amino]propanoic acid	IC50	0.3 nM	US-8993631: Method of treating contrast-induced nephropathy
(2R,4S)-4-(3-carboxypropanoylamino)-5-[4-(3-chlorophenyl)phenyl]-2-methylpentanoic acid	IC50	0.3 nM	US-8993631: Method of treating contrast-induced nephropathy
(3R)-4-[4-(5-chloro-2-fluorophenyl)phenyl]-3-[(2-ethyl-1,3-oxazole-5-carbonyl)amino]butanoic acid	IC50	0.4 nM	US-8993631: Method of treating contrast-induced nephropathy
(3R)-4-[4-(3-chlorophenyl)phenyl]-3-[(2-oxo-3H-1,3,4-oxadiazole-5-carbonyl)amino]butanoic acid	IC50	0.5 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
4-[[(2R)-1-carboxy-3-[4-(3-chlorophenyl)phenyl]propan-2-yl]amino]-2,2,3,3-tetrafluoro-4-oxobutanoic acid	IC50	0.5 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
4-[[(2R)-1-carboxy-3-[4-(5-chloro-2-methoxyphenyl)phenyl]propan-2-yl]amino]-4-oxobutanoic acid	IC50	0.7 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
(3R)-4-[4-(5-fluoro-2-methoxyphenyl)phenyl]-3-[(3-oxo-1,2-oxazole-5-carbonyl)amino]butanoic acid	IC50	0.7 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
(3R)-3-(carboxymethylcarbamoylamino)-4-[4-(3-chlorophenyl)phenyl]butanoic acid	IC50	0.8 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
6-[[(2S,4R)-4-carboxy-1-(4-phenylphenyl)pentan-2-yl]carbamoyl]pyrimidine-4-carboxylic acid	IC50	1 nM	US-8993631: Method of treating contrast-induced nephropathy
(3R)-4-[4-(3-chlorophenyl)phenyl]-3-(2H-tetrazole-5-carbonylamino)butanoic acid	IC50	1.2 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
4-[[(2R)-1-carboxy-3-[4-(5-fluoro-2-methoxyphenyl)phenyl]propan-2-yl]amino]-4-oxobutanoic acid	IC50	2.3 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
(2S)-2-[[(2S)-3-[4-(3-chlorophenyl)phenyl]-1-oxo-1-[(3-oxo-1,2-oxazol-5-yl)amino]propan-2-yl]amino]propanoic acid	IC50	2.4 nM	US-8993631: Method of treating contrast-induced nephropathy
(3R)-4-[4-(3-chlorophenyl)phenyl]-3-[(2-ethyl-1,3-oxazole-5-carbonyl)amino]butanoic acid	IC50	2.7 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
(3R)-3-[(2-oxo-1H-pyrimidine-5-carbonyl)amino]-4-(4-phenylphenyl)butanoic acid	IC50	3 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
4-[[(2R)-1-carboxy-3-[4-(2-methoxyphenyl)phenyl]propan-2-yl]amino]-4-oxobutanoic acid	IC50	4 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
4-[[(2R)-1-carboxy-3-[4-(3-fluorophenyl)phenyl]propan-2-yl]amino]-4-oxobutanoic acid	IC50	7 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
5-[[(2S,4R)-4-carboxy-1-(4-phenylphenyl)pentan-2-yl]carbamoyl]-1H-imidazole-2-carboxylic acid	IC50	7.3 nM	US-8993631: Method of treating contrast-induced nephropathy
(2S)-2-[[(2S)-1-oxo-3-(4-phenylphenyl)-1-(2H-tetrazol-5-ylamino)propan-2-yl]amino]propanoic acid	IC50	11 nM	US-8993631: Method of treating contrast-induced nephropathy
(2R,4S)-2-methyl-5-(4-phenylphenyl)-4-(2H-tetrazole-5-carbonylamino)pentanoic acid	IC50	14 nM	US-8993631: Method of treating contrast-induced nephropathy
(3R)-3-[(4-butoxy-4-oxobutanoyl)amino]-4-[4-(3-chlorophenyl)phenyl]butanoic acid	IC50	15 nM	US-8993631: Method of treating contrast-induced nephropathy
(3R)-4-[4-(3-chlorophenyl)phenyl]-3-[(5-ethoxy-5-oxopentanoyl)amino]butanoic acid	IC50	15 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
4-[4-(3-chlorophenyl)phenyl]-3-[[4-(2,3-dihydro-1H-inden-5-yloxy)-4-oxobutanoyl]amino]butanoic acid	IC50	15 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
benzyl 1-[2-[[(2R)-4-ethoxy-4-oxo-1-(4-phenylphenyl)butan-2-yl]amino]-2-oxoethyl]pyrrolidine-2-carboxylate	IC50	18 nM	US-8993631: Method of treating contrast-induced nephropathy
4-[[(2R)-1-carboxy-3-(4-phenylphenyl)propan-2-yl]amino]-4-oxobutanoic acid	IC50	38 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
(3R)-4-(4-phenylphenyl)-3-(2H-tetrazole-5-carbonylamino)butanoic acid	IC50	56 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
6-[[(2R)-1-carboxy-3-(4-phenylphenyl)propan-2-yl]carbamoyl]pyrimidine-4-carboxylic acid	IC50	67 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
(3R)-4-(2-carboxyethylamino)-4-oxo-3-[(4-phenylphenyl)methyl]butanoic acid	IC50	75 nM	US-8822534: Substituted aminopropionic derivatives as neprilysin inhibitors
(2S)-2-[[(2S)-3-[4-(3-chlorophenyl)phenyl]-1-[(1-methyltetrazol-5-yl)amino]-1-oxopropan-2-yl]amino]propanoic acid	IC50	91 nM	US-8993631: Method of treating contrast-induced nephropathy
(2R,4S)-4-(carboxymethylcarbamoylamino)-2-methyl-5-(4-phenylphenyl)pentanoic acid	IC50	93 nM	US-8993631: Method of treating contrast-induced nephropathy
1-[[(2S,4R)-4-carboxy-1-(4-phenylphenyl)pentan-2-yl]carbamoyl]pyrazole-3-carboxylic acid	IC50	142 nM	US-8993631: Method of treating contrast-induced nephropathy
(2R,4S)-2-methyl-4-[4-(2-methyl-1,3-benzothiazol-6-yl)butanoylamino]-5-(4-phenylphenyl)pentanoic acid	IC50	250 nM	US-8993631: Method of treating contrast-induced nephropathy
(2R,4S)-4-[(3-carboxy-3-methylbutanoyl)amino]-2-methyl-5-(4-phenylphenyl)pentanoic acid	IC50	267 nM	US-8993631: Method of treating contrast-induced nephropathy
3-[[(2S,4R)-4-carboxy-1-(4-phenylphenyl)pentan-2-yl]carbamoyl]benzoic acid	IC50	283 nM	US-8993631: Method of treating contrast-induced nephropathy
6-[[(2S,4R)-4-carboxy-1-(4-phenylphenyl)pentan-2-yl]carbamoyl]-4-oxopyran-2-carboxylic acid	IC50	350 nM	US-8993631: Method of treating contrast-induced nephropathy
(2S)-1-[[(2S,4R)-4-carboxy-1-(4-phenylphenyl)pentan-2-yl]carbamoyl]pyrrolidine-2-carboxylic acid	IC50	450 nM	US-8993631: Method of treating contrast-induced nephropathy

ChEMBL bioactivities

65 potent at pChembl≥5 of 65 total, top 48 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.52	IC50	0.03	nM	CHEMBL3703477
10.40	IC50	0.04	nM	CHEMBL3703477
10.15	IC50	0.07	nM	CHEMBL3676152
10.15	IC50	0.07	nM	CHEMBL3703472
10.05	IC50	0.09	nM	CHEMBL3703478
9.70	IC50	0.2	nM	CHEMBL3676150
9.70	IC50	0.2	nM	CHEMBL3703475
9.70	IC50	0.2	nM	CHEMBL3703482
9.70	IC50	0.2	nM	CHEMBL3703483
9.52	IC50	0.3	nM	CHEMBL3677671
9.52	IC50	0.3	nM	CHEMBL3703479
9.52	IC50	0.3	nM	CHEMBL3703484
9.40	IC50	0.4	nM	CHEMBL3703473
9.30	IC50	0.5	nM	CHEMBL3676145
9.30	IC50	0.5	nM	CHEMBL3676151
9.15	IC50	0.7	nM	CHEMBL3676144
9.15	IC50	0.7	nM	CHEMBL3676147
9.10	IC50	0.8	nM	CHEMBL3676153
9.00	IC50	1	nM	CHEMBL3677663
8.96	IC50	1.1	nM	CHEMBL3676150
8.92	IC50	1.2	nM	CHEMBL3676154
8.64	IC50	2.3	nM	CHEMBL3676143
8.62	IC50	2.4	nM	CHEMBL3695451
8.57	IC50	2.7	nM	CHEMBL3676146
8.52	IC50	3	nM	CHEMBL3639750
8.40	IC50	4	nM	CHEMBL3676141
8.15	IC50	7	nM	CHEMBL3676140
8.14	IC50	7.3	nM	CHEMBL3902042
7.96	IC50	11	nM	CHEMBL3703480
7.85	IC50	14	nM	CHEMBL3703476
7.82	IC50	15	nM	CHEMBL3676138
7.82	IC50	15	nM	CHEMBL3676139
7.82	IC50	15	nM	CHEMBL3676137
7.75	IC50	18	nM	CHEMBL3676137
7.75	IC50	18	nM	CHEMBL3703474
7.42	IC50	38	nM	CHEMBL3676155
7.38	IC50	42	nM	CHEMBL3676155
7.25	IC50	56	nM	CHEMBL3676149
7.17	IC50	67	nM	CHEMBL3676142
7.12	IC50	75	nM	CHEMBL3676148
7.04	IC50	91	nM	CHEMBL3703481
7.03	IC50	93	nM	CHEMBL3677669
6.85	IC50	142	nM	CHEMBL3677670
6.60	IC50	250	nM	CHEMBL3677662
6.57	IC50	267	nM	CHEMBL3677666
6.55	IC50	283	nM	CHEMBL3677665
6.46	IC50	350	nM	CHEMBL3677667
6.35	IC50	450	nM	CHEMBL3677668

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation	2
propionaldehyde	decreases expression	1
bisphenol A	decreases expression	1
dimethylselenide	increases oxidation, decreases expression, increases expression	1
sodium arsenite	increases expression	1
candoxatrilat	decreases activity	1
omapatrilat	decreases activity	1
jinfukang	increases expression	1
Zoledronic Acid	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Smoke	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Hydroxyl Radical	increases expression, increases oxidation, decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3706013	Binding	Inhibition Assay: Recombinant human neutral endopeptidase (expressed in insect cells and purified using standard methods, final concentration 7 μM) is pre-incubated with test compounds at various concentrations for 1 hour at room temperatur	Substituted aminopropionic derivatives as neprilysin inhibitors

Clinical trials (associated diseases)

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