PADI4

Summary

PADI4 (peptidyl arginine deiminase 4, HGNC:18368) is a protein-coding gene on chromosome 1p36.13, encoding Protein-arginine deiminase type-4 (Q9UM07). Catalyzes the citrullination/deimination of arginine residues of proteins such as histones, thereby playing a key role in histone code and regulation of stem cell maintenance.

This gene is a member of a gene family which encodes enzymes responsible for the conversion of arginine residues to citrulline residues. This gene may play a role in granulocyte and macrophage development leading to inflammation and immune response.

Source: NCBI Gene 23569 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 134 total
• Phenotypes (HPO): 1
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_012387

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18368
Approved symbol	PADI4
Name	peptidyl arginine deiminase 4
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Aliases	PAD, PDI5, PDI4
Ensembl gene	ENSG00000159339
Ensembl biotype	protein_coding
OMIM	605347
Entrez	23569

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000375448, ENST00000375453, ENST00000467001, ENST00000468945, ENST00000487048

RefSeq mRNA: 1 — MANE Select: NM_012387 NM_012387

CCDS: CCDS180

Canonical transcript exons

ENST00000375448 — 16 exons

Exon	Start	End
ENSE00001044963	17359280	17359408
ENSE00001044965	17333943	17334009
ENSE00001044969	17346028	17346139
ENSE00001044973	17358838	17358908
ENSE00001044974	17342299	17342402
ENSE00001044980	17347941	17348048
ENSE00001044981	17338038	17338155
ENSE00001044983	17336159	17336226
ENSE00001044989	17339688	17339813
ENSE00001268541	17341943	17342121
ENSE00001268578	17330969	17331149
ENSE00001467124	17363522	17364004
ENSE00001883200	17308197	17308314
ENSE00003537690	17354533	17354687
ENSE00003660940	17355983	17356127
ENSE00003683785	17356357	17356459

Expression profiles

Bgee: expression breadth ubiquitous, 123 present calls, max score 98.35.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 5.6917 / max 2263.4820, expressed in 173 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
991	5.6917	173

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	98.35	gold quality
bone marrow	UBERON:0002371	97.53	gold quality
bone marrow cell	CL:0002092	96.77	gold quality
monocyte	CL:0000576	96.64	gold quality
leukocyte	CL:0000738	96.40	gold quality
granulocyte	CL:0000094	93.49	gold quality
spleen	UBERON:0002106	91.22	gold quality
upper lobe of left lung	UBERON:0008952	81.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.41	gold quality
right lung	UBERON:0002167	77.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.75	gold quality
lung	UBERON:0002048	74.39	gold quality
right lobe of liver	UBERON:0001114	69.66	gold quality
gall bladder	UBERON:0002110	67.72	gold quality
smooth muscle tissue	UBERON:0001135	66.77	gold quality
vermiform appendix	UBERON:0001154	66.45	gold quality
placenta	UBERON:0001987	66.10	gold quality
omental fat pad	UBERON:0010414	65.32	gold quality
superior frontal gyrus	UBERON:0002661	64.78	gold quality
hindlimb stylopod muscle	UBERON:0004252	64.00	gold quality
liver	UBERON:0002107	63.99	gold quality
apex of heart	UBERON:0002098	63.05	gold quality
right frontal lobe	UBERON:0002810	62.75	gold quality
left uterine tube	UBERON:0001303	62.48	gold quality
heart left ventricle	UBERON:0002084	62.31	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	60.85	gold quality
frontal cortex	UBERON:0001870	60.77	gold quality
lymph node	UBERON:0000029	60.60	gold quality
Brodmann (1909) area 9	UBERON:0013540	60.59	gold quality
adipose tissue	UBERON:0001013	59.59	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	2131.99
E-ANND-3	yes	14.60
E-MTAB-9067	yes	11.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, FOS, NFKB1, NFKB, RELA, SP1, SP3, TP53

miRNA regulators (miRDB)

34 targeting PADI4, 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-513A-5P	100.00	69.77	2465
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-3164	99.02	68.39	1071
HSA-MIR-6820-3P	99.02	68.50	1035
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-1301-3P	98.64	68.27	1071
HSA-MIR-5047	98.64	68.62	1035
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-4468	98.01	66.85	1187

Literature-anchored findings (GeneRIF, showing 40)

• PAD V is localized in the nucleus in Hela cells (PMID:12393868)
• identified a haplotype of PADI4 associated with susceptibility to rheumatoid arthritis that affected stability of transcripts and was associated with levels of antibody to citrullinated peptide in sera from individuals with rheumatoid arthritis (PMID:12833157)
• A PADI4 susceptibility haplotype associated with RA in a Japanese population is not associated with RA in a UK population but other genes involved in the citrullinating pathway remain strong candidate (PMID:15077293)
• Ca(2+)-induces activation of human PAD4 (PMID:15247907)
• peptidylarginine deiminase 4 regulates histone Arg methylation by converting methyl-Arg to citrulline and releasing methylamine; data suggest that PAD4 mediates gene expression by regulating Arg methylation and citrullination in histones (PMID:15345777)
• hPADI2 and hPADI4 have different roles under physiological and pathological conditions (PMID:15629448)
• Recombinant protein arginine deiminase 4 catalyzes the hydrolytic deimination of arginine residues to produce citrulline and ammonia. (PMID:16060666)
• Replication of association in individual samples strongly suggests that PADI4 is a true susceptibility gene for rheumatoid arthritis. (PMID:16200584)
• PAD4 is expressed in CD34(+) cells of bone marrow and distributed in derives of the multi-potent progenitor cells in diverse tissues. The development of tumor cells expressing PAD4 is possibly associated with abnormal proliferation of CD34(+) stem cells. (PMID:16355400)
• There is strong support for an association of PADI4 with the development of rheumatoid arthritis, but only in the North American Rheumatoid Athritis Consortium cohort. (PMID:16380915)
• Variability of the PADI4 gene may influence susceptibility to rheumatoid arthritis in the German population. (PMID:16469113)
• PADI4 induces apoptosis mainly through cell cycle arrest and mitochondria-mediated pathway. (PMID:16502257)
• observations provide structural insights into target protein recognition by histone modification enzymes and illustrate how PAD4 can target multiple arginine sites in the histone N-terminal tails (PMID:16567635)
• These results do not support a major role of the PADI4 gene, but further studies may contribute to clarify the genetic factors that regulate deimination. (PMID:16828881)
• Data show that the functional haplotype of peptidylarginine deiminase IV, associated with susceptibility to rheumatoid arthritis, dominates apoptosis of acute T leukemia Jurkat cells. (PMID:17216583)
• The PADI4 rheumatoid arthritis (RA) risk haplotype is associated with increased anti-cyclic citrullinated peptide levels in RA patients with disease of short duration, and PADI4 may play a role in early RA. (PMID:17469103)
• Polymorphisms of the PADI4 gene are not associated with rheumatoid arthritis and are unlikely to be responsible for the presence of anti-CCP autoantibodies in a white Hungarian population. (PMID:17911417)
• PAD-2 & PAD-4 are only isotypes expressed in synovial tissue in rheumatoid arthritis & other arthritides; inflammatory cells are major source, but PAD-4 also comes from hyperplastic synoviocytes; both isotypes probably involved in citrullination of fibrin (PMID:17968929)
• results indicate that haplotype 1 of PADI4 is associated with non-susceptibility to UC (ulcerative colitis), whereas haplotype 2 is susceptible to UC. Thus, it is likely that PADI4 is one of genetic determinants of UC in the Japanese population. (PMID:17980669)
• PADI4 gene single nucleotide polymorphism was associated with rheumatoid arthritis (PMID:18087673)
• it was concluded that PADI4 is not a predictor of aggravation of functional impairment of rheumatoid arthritis in a Japanese population (PMID:18292109)
• The presence of anti-PAD4 (anti-peptidyl arginine deiminase type IV) in rheumatoid arthritis (RA) indicates that PAD4 may act as an autoantigen that may play a role in the pathogenesis of RA (PMID:18398945)
• The PADI-4 genotype is not associated with risk for rheumatoid arthritis in the Nurses’ Health Study (NHS) and NHSII cohorts in any model. (PMID:18462498)
• These results suggest a role of PAD4 in the regulation of p53 target gene expression. (PMID:18505818)
• Polymorphisms in the PADI4 gene influence the immune response to the PAD-4 protein, potentially contributing to disease propagation (PMID:18576335)
• PADI4 genotype in combination with anti-CCPs and SE modulates clinical and serological characteristics of RA. (PMID:18633125)
• The citrullinating enzyme PAD-4 was detected in synovial fluid from patients with rheumatoid arthritis, spondylarthritides, and osteoarthritis. (PMID:18668562)
• PADI4 SNPs, functional haplotype and PADI4 expression may contribute to an inherited predisposition to Rheumatoid arthritis in a Chinese population. (PMID:18764812)
• The transcriptional regulation of three human PADI type genes (PADI1, PADI2 and PADI3) in the epidermis have been carried out. (PMID:19004619)
• Quantitative PCR measured higher transcription of PADI4 in the synovial membrane of rheumatoid arthritis than in the samples of osteoarthritis and ankylosing spondylitis. (PMID:19199100)
• The PADI4 SNPs and haplotypes are associated with RA susceptibility in Chinese. HLA-DRB1 shared epitope is also an important risky factor for RA. (PMID:19199253)
• PADI4 may be a new susceptibility gene independent of HLA-DRB1 for rheumatoid arthritis in Caucasian populations. (PMID:19332633)
• In the largest study performed to date, the PADI4 genotype was not a significant risk factor for rheumatoid arthritis in people of European ancestry, in contrast to Asian populations. (PMID:19470526)
• DNA damage induces the citrullination of various proteins in a p53/PADI4-dependent manner (PMID:19843866)
• Autoantibodies to PAD-4 inhibit in vitro citrullination of fibrinogen by PAD-4. (PMID:20039406)
• Combination of PAD4 and HDAC2 inhibitors may be a potential strategy for cancer treatment. (PMID:20190809)
• Autoimmunity to peptidyl arginine deiminase type 4 precedes clinical onset of rheumatoid arthritis. (PMID:20496417)
• A haplotype of nonsynonymous single-nucleotide polymorphisms in PADI4 contributes to development of rheumatoid arthritis regardless of anti-cyclic citrullinated peptide or erosive joint status. (PMID:20537173)
• These data indicated that PADI4 polymorphisms were unlikely to play an important role in the susceptibility to rheumatoid arthritis in Chinese Han population. (PMID:20563870)
• HLA-DR4, PAD4 and STAT4 are overexpressed in rheumatoid arthritis and may be involved in the pathogenesis of RA. (PMID:20584675)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	padi2	ENSDARG00000044167
mus_musculus	Padi4	ENSMUSG00000025330
rattus_norvegicus	Padi4	ENSRNOG00000006855

Paralogs (4): PADI2 (ENSG00000117115), PADI3 (ENSG00000142619), PADI1 (ENSG00000142623), PADI6 (ENSG00000276747)

Protein

Protein identifiers

Protein-arginine deiminase type-4 — Q9UM07 (reviewed: Q9UM07)

Alternative names: HL-60 PAD, Peptidylarginine deiminase IV, Protein-arginine deiminase type IV

All UniProt accessions (2): Q9UM07, B1AQ67

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the citrullination/deimination of arginine residues of proteins such as histones, thereby playing a key role in histone code and regulation of stem cell maintenance. Citrullinates histone H1 at ‘Arg-54’ (to form H1R54ci), histone H3 at ‘Arg-2’, ‘Arg-8’, ‘Arg-17’ and/or ‘Arg-26’ (to form H3R2ci, H3R8ci, H3R17ci, H3R26ci, respectively) and histone H4 at ‘Arg-3’ (to form H4R3ci). Acts as a key regulator of stem cell maintenance by mediating citrullination of histone H1: citrullination of ‘Arg-54’ of histone H1 (H1R54ci) results in H1 displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance. Promotes profound chromatin decondensation during the innate immune response to infection in neutrophils by mediating formation of H1R54ci. Required for the formation of neutrophil extracellular traps (NETs); NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation. Citrullination of histone H3 prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription. Citrullinates EP300/P300 at ‘Arg-2142’, which favors its interaction with NCOA2/GRIP1.

Subcellular location. Cytoplasm. Nucleus. Cytoplasmic granule.

Tissue specificity. Expressed in eosinophils and neutrophils, not expressed in peripheral monocytes or lymphocytes.

Post-translational modifications. Autocitrullination at Arg-372 and Arg-374 inactivates the enzyme.

Disease relevance. Rheumatoid arthritis (RA) [MIM:180300] An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. The gene represented in this entry may be involved in disease pathogenesis. The association to rheumatoid arthritis was initially thought to result from increased citrullination of target proteins. However, variants that have been associated to rheumatoid arthritis (Ser-55, Ala-82 and Ala-112) do not affect the catalytic activity or the citrullination activity of PADI4, suggesting that these variants may affect the mRNA stability rather than the protein.

Activity regulation. Strongly Inhibited by F-amidine and N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine). These inhibitors are however not specific to PADI4 and also inhibit other members of the family. Incorporation of a carboxylate ortho to the backbone amide of Cl-amidine results in inhibitors with increased specificity for PADI4: N-alpha-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-L-ornithine amide (o-F-amidine) and N-alpha-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-L-ornithine amide (o-Cl-amidine). Strongly and specifically inhibited by Thr-Asp-F-amidine (TDFA); other members of the family are not inhibited.

Cofactor. Binds 5 Ca(2+) ions per subunit.

Similarity. Belongs to the protein arginine deiminase family.

RefSeq proteins (1): NP_036519* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004303	PAD	Family
IPR008972	Cupredoxin	Homologous_superfamily
IPR013530	PAD_C	Domain
IPR013732	PAD_N	Domain
IPR013733	Prot_Arg_deaminase_cen_dom	Domain
IPR036556	PAD_central_sf	Homologous_superfamily
IPR038685	PAD_N_sf	Homologous_superfamily

Pfam: PF03068, PF08526, PF08527

Enzyme classification (BRENDA):

• EC 3.5.3.15 — protein-arginine deiminase (BRENDA: 14 organisms, 435 substrates, 132 inhibitors, 239 Km, 204 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
N-ALPHA-BENZOYL-L-ARGININE ETHYL ESTER	0.1–30	62
NALPHA-BENZOYL-L-ARGININE ETHYL ESTER	0.27–2.77	21
NALPHA-BENZOYL L-ARGININE ETHYL ESTER	0.44–1.7	20
[HISTONE H4]-L-ARG	0.088–0.35	17
BENZOYL-L-ARG	0.0029–33.6	6
ACETYL-L-ARG METHYL ESTER	1.19–66.3	5
BENZOYL-ARG ETHYL ESTER	0.33–0.78	4
BENZOYL-L-ARG ETHYL ESTER	0.35–7.5	4
N-ALPHA-BENZOYL-L-ARGININE AMIDE	0.16–17.5	4
AC-SER-GLY-ARG-GLY-ACETYL-LYS-GLY-GLY-ACETYL-LYS	0.15–1.07	3
AC-SER-GLY-ARG-GLY-LYS-GLY-GLY-LYS-GLY-LEU-GLY-L	0.15–0.59	3
AC-SER-GLY-ARG-GLY-LYS-GLY-GLY-LYS-GLY-LEU-GLY-L	0.22–1.95	3
AC-SER-GLY-ARG-GLY-LYS-GLY-GLY-LYS-GLY-LEU-GLY-L	0.21–0.64	3
AC-SER-GLY-ARG-GLY-LYS-GLY-GLY-LYS-GLY-LEU-GLY-L	0.48–3.27	3
ACETYL-L-ARG	0.91–11.3	3

Catalyzed reactions (Rhea), 1 shown:

• L-arginyl-[protein] + H2O = L-citrullyl-[protein] + NH4(+) (RHEA:18089)

UniProt features (133 total): strand 48, binding site 24, helix 22, sequence variant 11, turn 9, modified residue 6, mutagenesis site 5, active site 4, sequence conflict 3, chain 1

Structure

Experimental structures (PDB)

28 structures.

PDB	Method	Resolution (Å)
2DEW	X-RAY DIFFRACTION	2.1
2DEX	X-RAY DIFFRACTION	2.1
3B1U	X-RAY DIFFRACTION	2.1
5N0M	X-RAY DIFFRACTION	2.18
5N0Y	X-RAY DIFFRACTION	2.23
2DEY	X-RAY DIFFRACTION	2.25
1WDA	X-RAY DIFFRACTION	2.3
2DW5	X-RAY DIFFRACTION	2.3
9DPZ	X-RAY DIFFRACTION	2.41
9DOP	X-RAY DIFFRACTION	2.44
3APM	X-RAY DIFFRACTION	2.5
3B1T	X-RAY DIFFRACTION	2.5
5N0Z	X-RAY DIFFRACTION	2.52
1WD9	X-RAY DIFFRACTION	2.6
3APN	X-RAY DIFFRACTION	2.7
1WD8	X-RAY DIFFRACTION	2.8
8GOD	X-RAY DIFFRACTION	2.88
5N1B	X-RAY DIFFRACTION	2.9
9HUH	ELECTRON MICROSCOPY	2.96
4DKT	X-RAY DIFFRACTION	2.98
4X8C	X-RAY DIFFRACTION	3.1
8R8U	ELECTRON MICROSCOPY	3.1
4X8G	X-RAY DIFFRACTION	3.29
8SML	ELECTRON MICROSCOPY	3.3
8SMK	ELECTRON MICROSCOPY	3.5
9HUJ	ELECTRON MICROSCOPY	3.57
8R8V	ELECTRON MICROSCOPY	3.6
9HUI	ELECTRON MICROSCOPY	3.73

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UM07-F1	94.58	0.89

Antibody-complex structures (SAbDab): 2 — 8SMK, 8SML

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 (4): 350; 471; 473; 645

Ligand- & substrate-binding residues (24): 165; 165; 168; 170; 176; 179; 179; 349; 351; 353; 369; 370 …

Post-translational modifications (6): 205, 212, 218, 372, 374, 383

Mutagenesis-validated functional residues (5):

Position	Phenotype
346	impaired binding of tdfa inhibitor.
374	strongly reduces enzymatic activity.
374	impaired binding of tdfa inhibitor.
639	impaired binding of tdfa inhibitor.
645	abolishes enzymatic activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3247509	Chromatin modifying enzymes

MSigDB gene sets: 170 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE45365_NK_CELL_VS_CD11B_DC_DN, AP1_01, AP1_Q4_01, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, MYOD_01, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, TGCTGAY_UNKNOWN, BACH2_01, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GOBP_MAINTENANCE_OF_CELL_NUMBER, TGANTCA_AP1_C, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, LEE_LIVER_CANCER_DENA_DN, COATES_MACROPHAGE_M1_VS_M2_DN

GO Biological Process (8): chromatin organization (GO:0006325), nucleosome assembly (GO:0006334), chromatin remodeling (GO:0006338), stem cell population maintenance (GO:0019827), protein modification process (GO:0036211), post-translational protein modification (GO:0043687), innate immune response (GO:0045087), immune system process (GO:0002376)

GO Molecular Function (11): protein-arginine deiminase activity (GO:0004668), calcium ion binding (GO:0005509), identical protein binding (GO:0042802), histone arginine deiminase activity (GO:0140794), histone H3R2 arginine deiminase activity (GO:0140795), histone H3R8 arginine deiminase activity (GO:0140796), histone H3R17 arginine deiminase activity (GO:0140797), histone H3R26 arginine deiminase activity (GO:0140798), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Chromatin organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
histone H3 arginine deiminase activity	4
cellular anatomical structure	3
chromatin organization	2
cellular component organization	1
nucleosome organization	1
protein-DNA complex assembly	1
multicellular organismal process	1
maintenance of cell number	1
protein metabolic process	1
macromolecule modification	1
protein modification process	1
immune response	1
defense response to symbiont	1
biological_process	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amidines	1
metal ion binding	1
protein binding	1
protein-arginine deiminase activity	1
histone modifying activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
cellular_component	1

Protein interactions and networks

STRING

944 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PADI4	H3C14	Q71DI3	906
PADI4	H3-3A	P06351	905
PADI4	H3-5	Q6NXT2	905
PADI4	H3C1	P02295	905
PADI4	H3-4	Q16695	905
PADI4	H3-7	Q5TEC6	905
PADI4	PTPN22	Q9Y2R2	864
PADI4	ELANE	P08246	860
PADI4	PRTN3	P15637	852
PADI4	MPO	P05164	822
PADI4	SLC22A4	Q9H015	772
PADI4	TRAF1	Q13077	754
PADI4	CTSG	P08311	736
PADI4	TP53	P04637	729
PADI4	PIP4K2C	Q8TBX8	658

IntAct

32 interactions, top by confidence:

A	B	Type	Score
PADI4	ANXA4	psi-mi:“MI:0915”(physical association)	0.720
ANXA4	PADI4	psi-mi:“MI:0915”(physical association)	0.720
PADI4		psi-mi:“MI:0407”(direct interaction)	0.560
PADI4		psi-mi:“MI:0985”(deamination reaction)	0.560
POU6F2	PADI4	psi-mi:“MI:0915”(physical association)	0.560
TRIB3	PADI4	psi-mi:“MI:0915”(physical association)	0.560
PADI4	PADI4	psi-mi:“MI:0407”(direct interaction)	0.440
LRRK2	PADI4	psi-mi:“MI:0407”(direct interaction)	0.440
ELP2	PADI4	psi-mi:“MI:0915”(physical association)	0.400
PADI4	RPS4Y1	psi-mi:“MI:0915”(physical association)	0.400
PADI3	NFKB1	psi-mi:“MI:0914”(association)	0.350
PADI4	CCT8	psi-mi:“MI:0914”(association)	0.350
GNG8	POTEF	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350
PADI4	CAMK2B	psi-mi:“MI:0914”(association)	0.350
DNPEP	PADI4	psi-mi:“MI:0915”(physical association)	0.000
PADI4	POU6F2	psi-mi:“MI:0915”(physical association)	0.000
ANXA4	PADI4	psi-mi:“MI:0915”(physical association)	0.000
PADI4	TRIB3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (52): PADI4 (Two-hybrid), PADI4 (Biochemical Activity), PADI4 (Affinity Capture-MS), PADI4 (Reconstituted Complex), PADI4 (Two-hybrid), PADI4 (Two-hybrid), ANXA4 (Two-hybrid), GMPPA (Affinity Capture-MS), PADI4 (Affinity Capture-MS), PADI4 (Affinity Capture-MS), CCT8 (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPS31 (Affinity Capture-MS), PADI4 (Affinity Capture-RNA), PADI4 (Affinity Capture-MS)

ESM2 similar proteins: A0A0M5K865, A2ARP1, A7Z050, O02849, O75339, O88806, O88807, P09543, P0C644, P13834, P16330, P20717, P70708, Q01433, Q02356, Q08642, Q0P4Y1, Q2NL29, Q2Y8M6, Q4R6E3, Q5RDF1, Q5RFD0, Q5SW19, Q66K08, Q6AYK3, Q6PFW1, Q6TGC4, Q75EG6, Q7SZF1, Q8BGC1, Q8BH86, Q8BJK1, Q8CIG3, Q8K3V4, Q8VHT6, Q91WU5, Q99279, Q9DBT5, Q9JHU9, Q9NPH2

Diamond homologs: O02849, O88806, O88807, P20717, P70708, Q08642, Q6TGC4, Q8K3V4, Q9ULC6, Q9ULW8, Q9UM07, Q9Y2J8, Q9Z183, Q9Z184, Q9Z185

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SMURF1	unknown	PADI4	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	95
Likely benign	15
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

3365 predictions. Top by Δscore:

Variant	Effect	Δscore
1:17330967:A:AG	acceptor_gain	1.0000
1:17330968:G:GA	acceptor_gain	1.0000
1:17330968:GCTCT:G	acceptor_gain	1.0000
1:17331146:GAAG:G	donor_gain	1.0000
1:17331150:G:C	donor_loss	1.0000
1:17336148:T:TA	acceptor_gain	1.0000
1:17336149:G:A	acceptor_gain	1.0000
1:17336333:C:CC	acceptor_gain	1.0000
1:17338028:T:A	acceptor_gain	1.0000
1:17339686:A:AG	acceptor_gain	1.0000
1:17339687:G:GT	acceptor_gain	1.0000
1:17339687:GA:G	acceptor_gain	1.0000
1:17339687:GAC:G	acceptor_gain	1.0000
1:17339687:GACCT:G	acceptor_gain	1.0000
1:17339814:G:GG	donor_gain	1.0000
1:17341938:CCTAG:C	acceptor_loss	1.0000
1:17341939:CTAGG:C	acceptor_loss	1.0000
1:17341940:TAG:T	acceptor_loss	1.0000
1:17341941:AGG:A	acceptor_gain	1.0000
1:17341942:GGG:G	acceptor_gain	1.0000
1:17342295:GCA:G	acceptor_loss	1.0000
1:17342298:G:GA	acceptor_loss	1.0000
1:17342298:G:GT	acceptor_gain	1.0000
1:17342298:GGA:G	acceptor_gain	1.0000
1:17342386:G:GT	donor_gain	1.0000
1:17342400:CAGGT:C	donor_loss	1.0000
1:17342402:GGT:G	donor_loss	1.0000
1:17342403:GT:G	donor_loss	1.0000
1:17342404:T:A	donor_loss	1.0000
1:17346024:CTA:C	acceptor_loss	1.0000

AlphaMissense

4396 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:17354614:A:C	S413R	0.999
1:17354616:C:A	S413R	0.999
1:17354616:C:G	S413R	0.999
1:17342353:T:A	W296R	0.995
1:17342353:T:C	W296R	0.995
1:17356068:T:A	W466R	0.994
1:17356068:T:C	W466R	0.994
1:17346131:T:A	W347R	0.993
1:17346131:T:C	W347R	0.993
1:17356360:T:C	F487L	0.992
1:17356362:C:A	F487L	0.992
1:17356362:C:G	F487L	0.992
1:17363698:C:G	C645W	0.990
1:17363716:A:C	R651S	0.990
1:17363716:A:T	R651S	0.990
1:17347941:G:C	D350H	0.989
1:17347942:A:T	D350V	0.989
1:17354600:G:T	G408V	0.989
1:17354606:T:C	L410P	0.988
1:17347942:A:C	D350A	0.987
1:17356072:T:C	L467P	0.987
1:17358896:T:A	N539K	0.987
1:17358896:T:G	N539K	0.987
1:17359299:G:C	R550P	0.987
1:17346133:G:C	W347C	0.986
1:17346133:G:T	W347C	0.986
1:17363735:T:A	W658R	0.986
1:17363735:T:C	W658R	0.986
1:17354600:G:A	G408E	0.985
1:17356090:A:T	D473V	0.985

dbSNP variants (sampled 300 via entrez): RS1000142498 (1:17337903 G>A), RS1000159473 (1:17355237 G>A), RS1000178880 (1:17338107 G>A), RS1000251214 (1:17336584 A>T), RS1000279640 (1:17324580 C>G,T), RS1000287182 (1:17332730 C>T), RS1000329874 (1:17346834 C>A), RS1000420475 (1:17341398 C>G), RS1000504467 (1:17352199 T>C), RS1000511504 (1:17339308 C>T), RS1000604070 (1:17309645 G>A,C), RS1000619313 (1:17320649 T>A,C), RS1000620734 (1:17309383 A>T), RS1000662135 (1:17332478 G>A,C), RS1000704820 (1:17336382 T>C)

Disease associations

OMIM: gene MIM:605347 | disease phenotypes: MIM:180300

GenCC curated gene-disease

Mondo (2): rheumatoid arthritis (MONDO:0008383), interstitial lung disease (MONDO:0015925)

Orphanet (2): Interstitial lung disease (Orphanet:182095), NON RARE IN EUROPE: Rheumatoid arthritis (Orphanet:284130)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0001370	Rheumatoid arthritis

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000249_1	Basal cell carcinoma	4.000000e-12
GCST001022_5	Rheumatoid arthritis	2.000000e-08
GCST001042_2	Rheumatoid arthritis	2.000000e-08
GCST002318_38	Rheumatoid arthritis	1.000000e-18
GCST002318_85	Rheumatoid arthritis	8.000000e-13
GCST002318_86	Rheumatoid arthritis	6.000000e-09
GCST002655_13	IgA nephropathy	2.000000e-06
GCST005568_43	Rheumatoid arthritis (ACPA-positive)	1.000000e-10
GCST005568_56	Rheumatoid arthritis (ACPA-positive)	6.000000e-09
GCST005569_17	Rheumatoid arthritis	3.000000e-10
GCST005569_50	Rheumatoid arthritis	4.000000e-08
GCST006048_35	Rheumatoid arthritis (ACPA-positive)	5.000000e-21
GCST006959_134	Rheumatoid arthritis	6.000000e-19
GCST006959_23	Rheumatoid arthritis	6.000000e-09
GCST006959_4	Rheumatoid arthritis	9.000000e-13
GCST009873_23	Autoimmune traits (pleiotropy)	4.000000e-08
GCST009877_12	Rheumatoid arthritis	2.000000e-09
GCST011389_8	Rheumatoid arthritis	7.000000e-16
GCST011781_1	IgA nephropathy	8.000000e-08
GCST90002379_1	Basophil count	2.000000e-14
GCST90002380_75	Basophil percentage of white cells	3.000000e-16

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005090	basophil count
EFO:0007992	basophil percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001172	Arthritis, Rheumatoid	C05.550.114.154; C05.799.114; C17.300.775.099; C20.111.199
D017563	Lung Diseases, Interstitial	C08.381.483

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6111 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 74,968 (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
CHEMBL404520	CHLORTETRACYCLINE	4	27,546
CHEMBL11417	STREPTONIGRIN	2	43,337
CHEMBL98123	PAPAVERINE HYDROCHLORIDE	2	4,085

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2240340	PADI4		0.00	0
rs2477134	PADI4		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 3.5.3.15 Peptidyl arginine deiminases (PADI)

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
JBI-589	Inhibition	6.91	pIC50
o-F-amidine	Irreversible inhibition	5.72	pIC50
streptonigrin	Inhibition	5.6	pIC50

Binding affinities (BindingDB)

1373 measured of 1439 human assays (1440 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[4-[2-[6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)indol-7-yl]piperidin-1-yl]-(3-hydroxycyclobutyl)methanone	IC50	3 nM	US-12473304: Heterocyclic PAD4 inhibitors
(2R)-1-[4-[2-[6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)indol-7-yl]piperidin-1-yl]-2-hydroxypropan-1-one	IC50	3 nM	US-12473304: Heterocyclic PAD4 inhibitors
((3R,5R)-3-amino-5- fluoropiperidin-1-yl)(27- methoxy-11H, 21H-1,2(2,1)- dipyrrolo[2,3-b]pyridina- 4(3,5)-pyridina-5(1,2)- benzenacyclononaphane-25- yl)methanone	IC50	4 nM	US-12492202: Macrocyclic PAD4 inhibitors useful as immunosuppressant
((7R)-7-amino-2- azabicyclo[2.2.1]heptan-2- yl)((E)-27-methoxy-11H,21H,41H- 6-oxa-2(2,1)-benzo[d]imidazola- 1(2,1)-indola-4(3,1)-pyrazola- 5(1,2)-benzenacyclononaphane- 25-yl)methanone	IC50	5 nM	US-12492202: Macrocyclic PAD4 inhibitors useful as immunosuppressant
[4-[2-[6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)indol-7-yl]piperidin-1-yl]-(3-hydroxycyclobutyl)methanone	IC50	5 nM	US-12473304: Heterocyclic PAD4 inhibitors
7-[2-[5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione	IC50	6 nM	US-11524959: Indole and azaindole inhibitors of pad enzymes
((1R,4R,7R)-7-amino-2- azabicyclo[2.2.1]heptan-2- yl)(27-methoxy-11H,21H-6- oxa-1,2(2,1)-dipyrrolo[2,3- b]pyridina-4(3,5)-pyridina- 5(1,2)- benzenacyclononaphane-25- yl)methanone	IC50	7 nM	US-12492202: Macrocyclic PAD4 inhibitors useful as immunosuppressant
((3R,5R)-3-Amino-5-fluoropiperidin-1-yl)(16-(2-hydroxypropan-2-yl)-27-methoxy-11H,21H-1,2(2,1)-dipyrrolo[2,3-b]pyridina-4(3,5)-pyridina-5(1,2)-benzenacyclononaphane-25-yl)methanone	IC50	8 nM	US-12492202: Macrocyclic PAD4 inhibitors useful as immunosuppressant
methyl 6-[2-[5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)indol-6-yl]quinoline-2-carboxylate	IC50	9 nM	US-11524959: Indole and azaindole inhibitors of pad enzymes
((3R,5R)-3-amino-5- fluoropiperidin-1-yl)((E)-27- methoxy-11H,21H,41H-6-oxa- 1,2(2,1)-dipyrrolo[2,3-b]pyridina- 4(3,1)-pyrazola-5(1,2)- benzenacyclononaphane-25- yl)methanone	IC50	9 nM	US-12492202: Macrocyclic PAD4 inhibitors useful as immunosuppressant
5-[2-[6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]-2,3-dihydroisoindol-1-one	IC50	9 nM	US-12473304: Heterocyclic PAD4 inhibitors
N-[3-[2-[5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]phenyl]ethenesulfonamide	IC50	10 nM	US-11524959: Indole and azaindole inhibitors of pad enzymes
((1R,4R,7R)-7-amino-2- azabicyclo[2.2.1]heptan-2- yl)(27-methoxy-11H,21H- 1,2(2,1)-dipyrrolo[2,3- b]pyridina-4(3,5)-pyridina- 5(1,2)- benzenacyclononaphane-25- yl)methanone	IC50	10 nM	US-12492202: Macrocyclic PAD4 inhibitors useful as immunosuppressant
5-[2-[6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]-N-methylpyridine-2-carboxamide	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
1-[4-[2-[6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]phenyl]pyrrolidin-2-one	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
[4-[2-[6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)indol-7-yl]piperidin-1-yl]-(4-hydroxycyclohexyl)methanone	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
[4-[2-[6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)indol-7-yl]piperidin-1-yl]-(oxolan-2-yl)methanone	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
1-[4-[2-[6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)indol-7-yl]piperidin-1-yl]ethanone	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
[4-[2-[6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)indol-7-yl]piperidin-1-yl]-(4-hydroxycyclohexyl)methanone	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
1-[4-[2-[6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)indol-7-yl]piperidin-1-yl]-2-methoxyethanone	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
methyl 4-[2-[6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)indol-7-yl]piperidine-1-carboxylate	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
1-(4-(2-(6-((3R,5R)-3-Amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperidin-1-yl)-2-methoxyethan-1-one	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
1-[3-[2-[6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)indol-7-yl]azetidin-1-yl]ethanone	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
[(3R,5R)-3-amino-5-fluoropiperidin-1-yl]-[2-[7-[2-(4-aminopyrazol-1-yl)ethoxy]-1-(cyclopropylmethyl)indol-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl]methanone	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
4-(((2-(6-((R)-3-Aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (isomer 1)	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
[(3R,5R)-3-amino-5-fluoropiperidin-1-yl]-[2-[1-(cyclopropylmethyl)-7-(2-imidazol-1-ylethoxy)pyrrolo[2,3-c]pyridin-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl]methanone	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
4-[[2-[6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-c]pyridin-7-yl]oxymethyl]pyrrolidin-2-one	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
[(3R)-3-aminopiperidin-1-yl]-[2-[1-(cyclopropylmethyl)-7-(2-imidazol-1-ylethoxy)pyrrolo[2,3-c]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridin-6-yl]methanone	IC50	10 nM	US-12473304: Heterocyclic PAD4 inhibitors
6-[2-[5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]-3H-quinazolin-4-one	IC50	11 nM	US-11524959: Indole and azaindole inhibitors of pad enzymes
4-[2-[5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)indol-6-yl]-2,6-difluorobenzamide	IC50	11 nM	US-11524959: Indole and azaindole inhibitors of pad enzymes
((7R)-7-amino-2- azabicyclo[2.2.1]heptan-2- yl)((Z)-27-methoxy-11H,21H,41H- 6-oxa-2(2,1)-benzo[d]imidazola- 1(2,1)-indola-4(4,1)-pyrazola- 5(1,2)-benzenacyclononaphane- 25-yl) methanone	IC50	11 nM	US-12492202: Macrocyclic PAD4 inhibitors useful as immunosuppressant
((7R)-7-amino-2- azabicyclo[2.2.1]heptan-2- yl)((E)-27-methoxy-11H,21H,41H- 6-oxa-1,2(2,1)-dipyrrolo[2,3- b]pyridina-4(3,1)-pyrazola- 5(1,2)-benzenacyclononaphane- 25-yl) methanone	IC50	11 nM	US-12492202: Macrocyclic PAD4 inhibitors useful as immunosuppressant
((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone	IC50	11 nM	US-12473304: Heterocyclic PAD4 inhibitors
6-[2-[5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]-4a,5,6,7,8,8a-hexahydro-1H-quinazoline-2,4-dione	IC50	12 nM	US-11524959: Indole and azaindole inhibitors of pad enzymes
6-[2-[5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)indol-6-yl]-1H-cinnolin-4-one	IC50	12 nM	US-11524959: Indole and azaindole inhibitors of pad enzymes
((1R,4R,7R)-7-amino-2- azabicyclo[2.2.1]heptan-2-yl)(2-(4- (cyclopropylmethyl)-3-(piperidin- 4-yl)-4H-thieno[3,2-b]pyrrol-5-yl)- 7-methoxy-1-methyl-1H- benzo[d]imidazol-5-yl)methanone	IC50	12 nM	US-11981680: Substituted thienopyrroles as PAD4 inhibitors
5-(2-(6-((7R)-7-Amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one	IC50	12 nM	US-12473304: Heterocyclic PAD4 inhibitors
((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone	IC50	12 nM	US-12473304: Heterocyclic PAD4 inhibitors
((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone	IC50	12 nM	US-12473304: Heterocyclic PAD4 inhibitors
6-[2-[5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]-2,3-dihydroisoindol-1-one	IC50	13 nM	US-11524959: Indole and azaindole inhibitors of pad enzymes
4-[2-[5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]-3-methoxybenzamide	IC50	13 nM	US-11524959: Indole and azaindole inhibitors of pad enzymes
6-[2-[5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]-8-fluoro-3,4-dihydro-1H-quinolin-2-one	IC50	13 nM	US-11524959: Indole and azaindole inhibitors of pad enzymes
4-[2-[5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]-2-hydroxybenzamide	IC50	13 nM	US-11524959: Indole and azaindole inhibitors of pad enzymes
6-[2-[5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]-1H-quinoxalin-2-one	IC50	13 nM	US-11524959: Indole and azaindole inhibitors of pad enzymes
N-[(1R)-1-[2-[5-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]ethyl]-1-methylpyrazole-4-carboxamide	IC50	13 nM	US-11878965: Inhibitors of peptidylarginine deiminases
((3R,5R)-3-amino-5- fluoropiperidin-1-yl)((E)-27- methoxy-11H,21H,41H-6-oxa- 2(2,1)-benzo[d]imidazola-l(2,1)- indola-4(3,1)-pyrazola-5(1,2)- benzenacyclononaphane-25- yl)methanone	IC50	13 nM	US-12492202: Macrocyclic PAD4 inhibitors useful as immunosuppressant
1-(4-(5-(5-((1R,4R,7R)-7-amino-2- azabicyclo[2.2.1]heptane-2- carbonyl)-7-methoxy-1-methyl- 1H-benzo[d]imidazol-2-yl)-4- (cyclopropylmethyl)-4H- thieno[3,2-b]pyrrol-3-yl)piperidin- 1-yl)ethan-1-one	IC50	14 nM	US-11981680: Substituted thienopyrroles as PAD4 inhibitors
((3R,5R)-3-amino-5- fluoropiperidin-1-yl)(27- methoxy-11H,21H-6-oxa- 1,2(2,1)-dipyrrolo[2,3- b]pyridina-4(3,5)-pyridina- 5(1,2)- benzenacyclononaphane-25- yl)methanone	IC50	14 nM	US-12492202: Macrocyclic PAD4 inhibitors useful as immunosuppressant
((1R,4R,7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(16-(2-hydroxypropan-2-yl)-27-methoxy-11H,21H-1,2(2,1)-dipyrrolo[2,3-b]pyridina-4(3,5)-pyridina-5(1,2)-benzenacyclononaphane-25-yl)methanone	IC50	14 nM	US-12492202: Macrocyclic PAD4 inhibitors useful as immunosuppressant

ChEMBL bioactivities

1322 potent at pChembl≥5 of 1476 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.30	IC50	5	nM	CHEMBL5070220
8.30	IC50	5	nM	CHEMBL5083901
8.30	IC50	5	nM	CHEMBL5070080
8.30	IC50	5	nM	CHEMBL5087104
8.30	IC50	5	nM	CHEMBL5942152
8.22	IC50	6	nM	CHEMBL5093574
8.22	IC50	6	nM	CHEMBL5080973
8.22	IC50	6	nM	CHEMBL5907683
8.22	IC50	6	nM	CHEMBL5880934
8.15	IC50	7	nM	CHEMBL5942957
8.05	IC50	9	nM	CHEMBL6021157
8.05	IC50	9	nM	CHEMBL5763580
8.00	IC50	10	nM	CHEMBL5845223
7.96	IC50	11	nM	CHEMBL5769453
7.96	IC50	11	nM	CHEMBL6059673
7.92	IC50	12	nM	CHEMBL5884943
7.92	IC50	12	nM	CHEMBL5943660
7.92	IC50	12	nM	CHEMBL5989283
7.92	IC50	12	nM	CHEMBL5999153
7.89	IC50	13	nM	CHEMBL5919259
7.89	IC50	13	nM	CHEMBL5867744
7.89	IC50	13	nM	CHEMBL5772473
7.89	IC50	13	nM	CHEMBL6025724
7.89	IC50	13	nM	CHEMBL5905041
7.89	IC50	13	nM	CHEMBL6047036
7.85	IC50	14.1	nM	CHEMBL5180282
7.85	IC50	14	nM	CHEMBL5911607
7.82	IC50	15	nM	CHEMBL5957198
7.82	IC50	15	nM	CHEMBL5891363
7.82	IC50	15	nM	CHEMBL5831184
7.82	IC50	15	nM	CHEMBL6054900
7.82	IC50	15	nM	CHEMBL6054466
7.80	IC50	16	nM	CHEMBL5925717
7.80	IC50	16	nM	CHEMBL5809902
7.80	IC50	16	nM	CHEMBL5819308
7.80	IC50	16	nM	CHEMBL6022855
7.80	IC50	16	nM	CHEMBL5740023
7.80	IC50	16	nM	CHEMBL5868937
7.77	IC50	17	nM	CHEMBL6026525
7.77	IC50	17	nM	CHEMBL5871838
7.77	IC50	17	nM	CHEMBL5969282
7.77	IC50	17	nM	CHEMBL5851015
7.76	IC50	17.4	nM	CHEMBL5187676
7.75	IC50	18	nM	CHEMBL5760781
7.75	IC50	18	nM	CHEMBL5938402
7.75	IC50	18	nM	CHEMBL5911236
7.75	IC50	18	nM	CHEMBL5953663
7.75	IC50	18	nM	CHEMBL5975068
7.75	IC50	18	nM	CHEMBL5912361
7.72	IC50	19.1	nM	CHEMBL5201255

PubChem BioAssay actives

94 with measured affinity, of 373 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
(5S,7S)-14-[5-[(2R,3R)-3-amino-2-methylpiperidine-1-carbonyl]-1-cyclopropyl-7-fluorobenzimidazol-2-yl]-7,11,11-trifluoro-2-methyl-3,13,19-triazatetracyclo[11.5.2.05,7.016,20]icosa-1(19),14,16(20),17-tetraen-4-one	1813806: Inhibition of human PAD4 using BAEE as substrate incubated for 30 mins by spectrophotometric based assay	ic50	0.0050	uM
17-[5-[(1S,4R,5R)-4-amino-3,3-dideuterio-2-azabicyclo[3.2.1]octane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-2-methyl-3,16,22-triazatetracyclo[14.5.2.05,10.019,23]tricosa-1(22),5,7,9,17,19(23),20-heptaen-4-one	1813806: Inhibition of human PAD4 using BAEE as substrate incubated for 30 mins by spectrophotometric based assay	ic50	0.0050	uM
(5R)-14-[5-[(1S,4R,5R)-4-amino-2-azabicyclo[3.2.1]octane-2-carbonyl]-7-methoxy-1-methylbenzimidazol-2-yl]-6,6-difluoro-2-methyl-3,13,19-triazatetracyclo[11.5.2.05,7.016,20]icosa-1(19),14,16(20),17-tetraen-4-one	1813806: Inhibition of human PAD4 using BAEE as substrate incubated for 30 mins by spectrophotometric based assay	ic50	0.0050	uM
20-[5-[(2R,3R)-3-amino-2-methylpiperidine-1-carbonyl]-1-cyclopropyl-7-fluorobenzimidazol-2-yl]-2-methyl-8-thia-3,12,19,25-tetrazapentacyclo[17.5.2.05,13.07,11.022,26]hexacosa-1(25),5,7(11),9,12,20,22(26),23-octaen-4-one	1813806: Inhibition of human PAD4 using BAEE as substrate incubated for 30 mins by spectrophotometric based assay	ic50	0.0050	uM
(5R)-14-[5-[(2R,3R)-3-amino-2-methylpiperidine-1-carbonyl]-7-chloro-1-cyclopropylbenzimidazol-2-yl]-11,11-difluoro-2-methyl-3,13,19-triazatetracyclo[11.5.2.05,7.016,20]icosa-1(19),14,16(20),17-tetraen-4-one	1813806: Inhibition of human PAD4 using BAEE as substrate incubated for 30 mins by spectrophotometric based assay	ic50	0.0060	uM
17-[5-[(1S,4R,5R)-4-amino-2-azabicyclo[3.2.1]octane-2-carbonyl]-1-cyclopropyl-7-fluorobenzimidazol-2-yl]-2,8-dimethyl-3,9,16,22-tetrazatetracyclo[14.5.2.05,10.019,23]tricosa-1(22),5(10),6,8,17,19(23),20-heptaen-4-one	1813806: Inhibition of human PAD4 using BAEE as substrate incubated for 30 mins by spectrophotometric based assay	ic50	0.0060	uM
3-[(1R)-1-[2-[7-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl]-5-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]ethyl]-1,3-oxazolidin-2-one	1875531: Inhibition of human His-Sumo-tagged PAD4 (A2 to P663 residues) expressed in Escherichia coli BL21 (DE3) cells using BAEE as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by fluorescence assay	ic50	0.0141	uM
(2S)-N-[(1R)-1-[2-[7-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl]-5-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]ethyl]-2-methylmorpholine-4-carboxamide	1875531: Inhibition of human His-Sumo-tagged PAD4 (A2 to P663 residues) expressed in Escherichia coli BL21 (DE3) cells using BAEE as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by fluorescence assay	ic50	0.0174	uM
4-[[(1R)-1-[2-[7-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl]-5-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]ethyl]amino]-4-oxobutanoic acid	1875531: Inhibition of human His-Sumo-tagged PAD4 (A2 to P663 residues) expressed in Escherichia coli BL21 (DE3) cells using BAEE as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by fluorescence assay	ic50	0.0191	uM
3-[(1R)-1-[2-[7-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl]-5-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]ethyl]-1-methyl-1-(pyridin-3-ylmethyl)urea	1875531: Inhibition of human His-Sumo-tagged PAD4 (A2 to P663 residues) expressed in Escherichia coli BL21 (DE3) cells using BAEE as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by fluorescence assay	ic50	0.0200	uM
N-[(1R)-1-[2-[7-[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl]-5-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl]-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridin-6-yl]ethyl]-N’-(benzenesulfonyl)butanediamide	1875531: Inhibition of human His-Sumo-tagged PAD4 (A2 to P663 residues) expressed in Escherichia coli BL21 (DE3) cells using BAEE as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by fluorescence assay	ic50	0.0203	uM
[(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptan-7-yl]-[2-[1-(cyclopropylmethyl)-6-(1,1-dioxo-1,2,5-thiadiazepan-2-yl)pyrrolo[2,3-b]pyridin-2-yl]-5-methoxy-3-methylimidazo[1,2-a]pyridin-7-yl]methanone	1875531: Inhibition of human His-Sumo-tagged PAD4 (A2 to P663 residues) expressed in Escherichia coli BL21 (DE3) cells using BAEE as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by fluorescence assay	ic50	0.0216	uM
[(3R)-3-aminopiperidin-1-yl]-[2-[1-(cyclopropylmethyl)indol-2-yl]-7-methoxy-1-methylbenzimidazol-5-yl]methanone	1330527: Inhibition of GST-tagged recombinant human PAD4 (1 to 663 residues) expressed in Escherichia coli using N-a-benzoyl-L-arginine ethyl ester as substrate preincubated for 30 mins followed by substrate addition after 100 mins by DTT-based fluorescence assay	ic50	0.0398	uM
[(3S,4R)-3-amino-4-hydroxypiperidin-1-yl]-[2-[1-(cyclopropylmethyl)indol-2-yl]-7-methoxy-1-methylbenzimidazol-5-yl]methanone	1625405: Displacement of GSK215 from full length PAD4 (unknown origin) after 50 mins by fluorescence polarization assay in absence of calcium	ic50	0.0500	uM
[(3R)-3-aminopiperidin-1-yl]-[7-methoxy-1-methyl-2-[1-(2,2,2-trifluoroethyl)indol-2-yl]benzimidazol-5-yl]methanone	1330527: Inhibition of GST-tagged recombinant human PAD4 (1 to 663 residues) expressed in Escherichia coli using N-a-benzoyl-L-arginine ethyl ester as substrate preincubated for 30 mins followed by substrate addition after 100 mins by DTT-based fluorescence assay	ic50	0.0501	uM
[(3S,4R)-3-amino-4-hydroxypiperidin-1-yl]-[7-methoxy-1-methyl-2-[1-(2,2,2-trifluoroethyl)indol-2-yl]benzimidazol-5-yl]methanone	1330527: Inhibition of GST-tagged recombinant human PAD4 (1 to 663 residues) expressed in Escherichia coli using N-a-benzoyl-L-arginine ethyl ester as substrate preincubated for 30 mins followed by substrate addition after 100 mins by DTT-based fluorescence assay	ic50	0.0794	uM
[(3R)-3-aminopiperidin-1-yl]-[2-(1-ethylindol-2-yl)-7-methoxy-1-methylbenzimidazol-5-yl]methanone	1330527: Inhibition of GST-tagged recombinant human PAD4 (1 to 663 residues) expressed in Escherichia coli using N-a-benzoyl-L-arginine ethyl ester as substrate preincubated for 30 mins followed by substrate addition after 100 mins by DTT-based fluorescence assay	ic50	0.1000	uM
[(3R)-3-aminopiperidin-1-yl]-[2-[1-(cyclopropylmethyl)indol-2-yl]-1-methylbenzimidazol-5-yl]methanone	1330527: Inhibition of GST-tagged recombinant human PAD4 (1 to 663 residues) expressed in Escherichia coli using N-a-benzoyl-L-arginine ethyl ester as substrate preincubated for 30 mins followed by substrate addition after 100 mins by DTT-based fluorescence assay	ic50	0.1259	uM
[(3R)-3-aminopiperidin-1-yl]-[1-methyl-2-[1-(2,2,2-trifluoroethyl)indol-2-yl]benzimidazol-5-yl]methanone	1330527: Inhibition of GST-tagged recombinant human PAD4 (1 to 663 residues) expressed in Escherichia coli using N-a-benzoyl-L-arginine ethyl ester as substrate preincubated for 30 mins followed by substrate addition after 100 mins by DTT-based fluorescence assay	ic50	0.1585	uM
[1-amino-7-methoxy-2-(1-methylpyrrolo[2,3-b]pyridin-2-yl)indol-5-yl]-[(3R)-3-aminopiperidin-1-yl]methanone	2034405: Inhibition of N-terminal GST-tagged PAD4 (unknown origin) expressed in Escherichia coli incubated for 1 hr by spectrophotometric method	ic50	0.2000	uM
6-(7-amino-5,8-dioxoquinolin-2-yl)pyridine-2-carboxylic acid	1069619: Inhibition of recombinant wild-type PAD4 (unknown origin) using N-alpha-Benzoyl-L-arginine ethyl ester as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by COLDER assay	ic50	0.2400	uM
2-[[(2S)-1-amino-5-[(1-amino-2-fluoroethylidene)amino]-1-oxopentan-2-yl]carbamoyl]benzoic acid;2,2,2-trifluoroacetic acid	627438: Irreversible inhibition of PAD4 Q346A mutant assessed as hydrolysis of benzoyl-L-arginine ethyl ester preincubated for 15 mins measured after 15 mins	ic50	0.4000	uM
7-amino-6-bromoquinoline-5,8-dione	1069619: Inhibition of recombinant wild-type PAD4 (unknown origin) using N-alpha-Benzoyl-L-arginine ethyl ester as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by COLDER assay	ic50	0.5600	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-cyclopropyl-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	0.6200	uM
7-amino-2-pyridin-2-ylquinoline-5,8-dione	1069619: Inhibition of recombinant wild-type PAD4 (unknown origin) using N-alpha-Benzoyl-L-arginine ethyl ester as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by COLDER assay	ic50	0.6400	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1H-indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	0.7000	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-(2-methylpropyl)-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	0.7100	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-methyl-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	0.7600	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	0.7900	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1H-indole-5-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	0.8000	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-(2,2-dimethoxyethyl)-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	0.9600	uM
7-aminoquinoline-5,8-dione	1069619: Inhibition of recombinant wild-type PAD4 (unknown origin) using N-alpha-Benzoyl-L-arginine ethyl ester as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by COLDER assay	ic50	1.0000	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-6-(dimethylamino)naphthalene-2-carboxamide	1813082: Inhibition of PAD4 (unknown origin)	ic50	1.0000	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-5-fluoro-1H-indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.0200	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-(4-fluorophenyl)-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.0200	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-(4-hydroxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.0800	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-pentan-3-yl-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.1000	uM
2-[[(2S)-1-amino-5-[(1-amino-2-chloroethylidene)amino]-1-oxopentan-2-yl]carbamoyl]benzoic acid;2,2,2-trifluoroacetic acid	627438: Irreversible inhibition of PAD4 Q346A mutant assessed as hydrolysis of benzoyl-L-arginine ethyl ester preincubated for 15 mins measured after 15 mins	ic50	1.1000	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-cyclohexyl-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.1100	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-(4-chlorophenyl)-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.1300	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-3H-benzimidazole-5-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.1500	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-propan-2-yl-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.1800	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-tert-butyl-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.2000	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-thiophen-2-yl-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.3200	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-(3,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.5200	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-(4-cyanophenyl)-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.6100	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.7000	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-1-pentyl-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.7500	uM
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-9H-pyrido[3,4-b]indole-3-carboxamide	2071731: Inhibition of PAD4 (unknown origin) using Nalpha-benzoyl-L-arginine ethyl ester as substrate preincubated for 60 mins followed by substrate addition and measured after 90 mins by colorimetric analysis	ic50	1.7600	uM
[4-[[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]carbamoyl]phenyl]boronic acid	2134413: Inhibition of PAD4 (unknown origin) using BAEE as substrate by colorimetric analysis	ic50	1.8900	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
YW3-56	decreases activity, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Dimethyl Sulfoxide	decreases reaction, increases expression, increases reaction	2
Estradiol	affects expression, increases reaction, increases expression	2
FR900359	increases phosphorylation	1
GSK484	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
sulforaphane	increases expression	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
clothianidin	increases expression	1
N-alpha-(2-carboxyl)benzoyl-N5-(2-fluoro-1-iminoethyl)ornithine amide	increases expression	1
N-alpha-(2-carboxyl)benzoyl-N5-(2-chloro-1-iminoethyl)ornithine amide	increases expression	1
Calcimycin	increases expression, decreases reaction	1
Fulvestrant	affects cotreatment, decreases methylation	1
Alitretinoin	increases expression, increases reaction	1
Dinitrochlorobenzene	affects binding	1
Doxorubicin	increases expression	1
Formaldehyde	decreases expression	1
Lead	decreases expression	1
Paraquat	decreases expression	1
Smoke	increases expression	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1

ChEMBL screening assays

86 unique, capped per target: 84 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1738623	Binding	PUBCHEM_BIOASSAY: Fluorescence-based biochemical dose response assay to identify inhibitors of Protein Arginine Deaminase 4 (PAD4). (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID463073, AID463083, AID485272,	PubChem BioAssay data set
CHEMBL5444483	Functional	Affinity Phenotypic Cellular interaction: (NH3 release assay (PADI4 functional assay)) EUB0000266bCl PADI4	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8LV	Abcam HCT 116 PADI4 KO	Cancer cell line	Male
CVCL_B9P1	Abcam A-549 PADI4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00056667	PHASE4	COMPLETED	Relaxation Response Training for the Treatment of Rheumatoid Arthritis
NCT00094341	PHASE4	COMPLETED	Preference of Rheumatoid Arthritis (RA) Patients of Enbrel® (Etanercept) Auto-Injector Versus Enbrel® Pre-Filled Syringes
NCT00099554	PHASE4	COMPLETED	Effectiveness and Safety of Enbrel® (Etanercept) in Rheumatoid Arthritis Subjects Who Have Failed Remicade® (Infliximab)
NCT00111410	PHASE4	COMPLETED	Evaluating the Effect of Anakinra (r-metHuIL-1ra) on Vaccine AntibodyResponse in Subjects With Rheumatoid Arthritis (RA)
NCT00115219	PHASE4	COMPLETED	Evaluating Efficacy and Safety of Etanercept 50 mg Twice Weekly (BIW) in Rheumatoid Arthritis (RA) Subjects Who Are Sub-Optimal Responders to Etanercept 50 mg Once Weekly (QW)
NCT00121043	PHASE4	COMPLETED	Evaluating Kineret® (Anakinra) in Rheumatoid Arthritis (RA) Subjects Using aSelf-Reported Questionnaire
NCT00132418	PHASE4	COMPLETED	Study of Enbrel in Rheumatoid Arthritis (RA) Subjects With Comorbid Disorders
NCT00157872	PHASE4	COMPLETED	A Study of Rofecoxib Versus Naproxen in the Treatment of Chinese Patient With Rheumatoid Arthritis (0966-231)
NCT00195494	PHASE4	COMPLETED	Study Comparing Etanercept and Methotrexate vs. Methotrexate Alone in Rheumatoid Arthritis
NCT00208364	PHASE4	TERMINATED	A Two Centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Metal-on-Metal Bearing in Primary Total Hip Replacement
NCT00208377	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the DePuy ASR™ System in Primary Hip Resurfacing Surgery
NCT00208390	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the Summit™ Hip in Primary Total Hip Replacement
NCT00208429	PHASE4	WITHDRAWN	A Multi-centre Study to Assess the Long-term Performance of the Pinnacle™ Cup With a Polyethylene-on-metal Bearing in Primary Total Hip Replacement
NCT00208455	PHASE4	TERMINATED	A Multi-centre Study to Assess the Long-term Performance of the DePuy PROXIMA™ Hip in Primary Total Hip Replacement
NCT00209859	PHASE4	COMPLETED	Methotrexate and Cyclosporine in Treatment of Early Rheumatoid Arthritis
NCT00216177	PHASE4	UNKNOWN	Comparison of Adalimumab and Infliximab Treatment of Rheumatoid Arthritis
NCT00233558	PHASE4	TERMINATED	Open-Label Steroid Reduction Study of Adalimumab With Methotrexate in Patients With Active Rheumatoid Arthritis
NCT00234234	PHASE4	COMPLETED	Predictors of the Response to Adalimumab in Rheumatoid Arthritis
NCT00234897	PHASE4	COMPLETED	Efficacy of HUMIRA in Subjects With Active Rheumatoid Arthritis
NCT00244556	PHASE4	COMPLETED	Study Comparing Enbrel (Etanercept) Plus Methotrexate Versus Enbrel Alone in Active Rheumatoid Arthritis Despite Current Methotrexate Therapy
NCT00252668	PHASE4	COMPLETED	Study Evaluating the Combination of Etanercept and Methotrexate in Rheumatoid Arthritis Subjects
NCT00259610	PHASE4	COMPLETED	Treatment of Early Aggressive Rheumatoid Arthritis (TEAR)
NCT00291915	PHASE4	UNKNOWN	Multicenter Randomized Prospective Trial Comparing Methotrexate Alone or in Combination With Adalimumab in Early Arthritis
NCT00319917	PHASE4	COMPLETED	A Double Blind Placebo Controlled Study to Assess the Efficacy on Joint Damage in RA Patients
NCT00334620	PHASE4	COMPLETED	Effectiveness of Radon Spa Therapy in Multimodal Rehabilitative Treatment of Rheumatoid Arthritis
NCT00346294	PHASE4	COMPLETED	An Open-Label Study to Assess the Rate of Failure of an Enbrel® (Etanercept) SureClick™ Auto-injector in Subjects With Rheumatoid Arthritis
NCT00356473	PHASE4	COMPLETED	Effects of Atorvastatin on Disease Activity and HDL Cholesterol Function in Patients With Rheumatoid Arthritis
NCT00369187	PHASE4	COMPLETED	Study of a Large Protein Molecule Administered With Escalating Doses of Recombinant Human Hyaluronidase
NCT00385528	PHASE4	COMPLETED	Effects of a Multi-Faceted Psychiatric Intervention Targeted at the Complex Medically Ill: a Randomized Controlled Trial
NCT00396747	PHASE4	COMPLETED	A Comparison of Methotrexate Alone or Combined to Infliximab or to Pulse Methylprednisolone in Early Rheumatoid Arthritis: A Magnetic Resonance Imaging Study
NCT00420927	PHASE4	COMPLETED	Study of the Optimal Protocol for Methotrexate and Adalimumab Combination Therapy in Early Rheumatoid Arthritis
NCT00422227	PHASE4	COMPLETED	Study Comparing Etanercept With Usual DMARD Therapy in Subjects With Rheumatoid Arthritis in the Asia Pacific Region
NCT00424502	PHASE4	COMPLETED	A Study of MabThera (Rituximab) in Patients With Rheumatoid Arthritis Who Have Had an Inadequate Response to a TNF-Blocker.
NCT00434200	PHASE4	UNKNOWN	Rheumatoid Arthritis Patients in Training
NCT00439062	PHASE4	COMPLETED	Treatment of Rheumatoid Arthritis With Roxithromycin
NCT00447759	PHASE4	COMPLETED	The Standard Care Versus Celecoxib Outcome Trial
NCT00462072	PHASE4	COMPLETED	Centocor Microarray Study of Patients
NCT00462345	PHASE4	COMPLETED	A Study of MabThera (Rituximab) in Combination With Methotrexate in Patients With Rheumatoid Arthritis Who Have Had an Inadequate Response to Anti-TNF Therapies.
NCT00480272	PHASE4	COMPLETED	Prospective Study on Intensive Early Rheumatoid Arthritis Treatment
NCT00502853	PHASE4	COMPLETED	A Pilot Study of MabThera (Rituximab) Evaluated by MRI in Patients With Rheumatoid Arthritis.