SNCA

Summary

SNCA (synuclein alpha, HGNC:11138) is a protein-coding gene on chromosome 4q22.1, encoding Alpha-synuclein (P37840). Neuronal protein that plays several roles in synaptic activity such as regulation of synaptic vesicle trafficking and subsequent neurotransmitter release.

Alpha-synuclein is a member of the synuclein family, which also includes beta- and gamma-synuclein. Synucleins are abundantly expressed in the brain and alpha- and beta-synuclein inhibit phospholipase D2 selectively. SNCA may serve to integrate presynaptic signaling and membrane trafficking. Defects in SNCA have been implicated in the pathogenesis of Parkinson disease. SNCA peptides are a major component of amyloid plaques in the brains of patients with Alzheimer’s disease. Alternatively spliced transcripts encoding different isoforms have been identified for this gene.

Source: NCBI Gene 6622 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Parkinson disease (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 39
• Clinical variants (ClinVar): 176 total — 8 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 81
• Druggable target: yes — 31 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000345

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11138
Approved symbol	SNCA
Name	synuclein alpha
Location	4q22.1
Locus type	gene with protein product
Status	Approved
Aliases	NACP, PD1
Ensembl gene	ENSG00000145335
Ensembl biotype	protein_coding
OMIM	163890
Entrez	6622

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 31 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000336904, ENST00000345009, ENST00000394986, ENST00000394989, ENST00000394991, ENST00000420646, ENST00000502987, ENST00000505199, ENST00000506244, ENST00000506691, ENST00000508895, ENST00000611107, ENST00000618500, ENST00000673718, ENST00000673766, ENST00000673902, ENST00000674129, ENST00000889657, ENST00000889658, ENST00000889659, ENST00000889660, ENST00000889662, ENST00000889663, ENST00000912364, ENST00000912365, ENST00000965186, ENST00000965187, ENST00000965188, ENST00000965189, ENST00000965190, ENST00000965191, ENST00000965192

RefSeq mRNA: 9 — MANE Select: NM_000345 NM_000345, NM_001146054, NM_001146055, NM_001375285, NM_001375286, NM_001375287, NM_001375288, NM_001375290, NM_007308

CCDS: CCDS3634, CCDS43252

Canonical transcript exons

ENST00000394991 — 6 exons

Exon	Start	End
ENSE00000970012	89828143	89828184
ENSE00000970013	89822246	89822388
ENSE00000970014	89729194	89729277
ENSE00001407446	89835547	89835692
ENSE00001946342	89836962	89837161
ENSE00003902180	89724099	89726660

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.7967 / max 8300.3226, expressed in 1182 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53163	27.3545	1111
53160	6.4004	523
53161	2.9887	539
53165	2.0331	263
53162	1.0439	401
53159	0.4920	133
203283	0.4562	172
53155	0.4388	72
203282	0.2178	58
53164	0.1497	90

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	99.43	gold quality
orbitofrontal cortex	UBERON:0004167	99.38	gold quality
pons	UBERON:0000988	99.25	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.09	gold quality
endothelial cell	CL:0000115	98.76	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.76	gold quality
tendon of biceps brachii	UBERON:0008188	98.74	gold quality
postcentral gyrus	UBERON:0002581	98.72	gold quality
parietal lobe	UBERON:0001872	98.69	gold quality
middle temporal gyrus	UBERON:0002771	98.65	gold quality
monocyte	CL:0000576	98.59	gold quality
substantia nigra pars compacta	UBERON:0001965	98.58	gold quality
superior frontal gyrus	UBERON:0002661	98.58	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.58	gold quality
olfactory bulb	UBERON:0002264	98.47	gold quality
entorhinal cortex	UBERON:0002728	98.30	gold quality
mononuclear cell	CL:0000842	98.25	gold quality
right frontal lobe	UBERON:0002810	98.20	gold quality
cranial nerve II	UBERON:0000941	98.04	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.01	gold quality
prefrontal cortex	UBERON:0000451	97.98	gold quality
amygdala	UBERON:0001876	97.68	gold quality
cerebellar hemisphere	UBERON:0002245	97.65	gold quality
temporal lobe	UBERON:0001871	97.63	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.61	gold quality
Ammon’s horn	UBERON:0001954	97.55	gold quality
substantia nigra	UBERON:0002038	97.55	gold quality
cerebellar cortex	UBERON:0002129	97.52	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.51	gold quality
tibial nerve	UBERON:0001323	97.42	gold quality

Single-cell (SCXA)

Detected in 26 experiment(s), a significant marker in 22.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	5347.27
E-GEOD-75367	yes	2082.59
E-MTAB-9221	yes	1899.03
E-MTAB-9388	yes	1173.30
E-HCAD-10	yes	1027.31
E-MTAB-10042	yes	632.23
E-MTAB-9154	yes	561.48
E-MTAB-6701	yes	269.41
E-HCAD-4	yes	158.67
E-CURD-114	yes	72.47
E-CURD-112	yes	65.98
E-HCAD-5	yes	53.11
E-GEOD-135922	yes	25.53
E-HCAD-11	yes	22.71
E-CURD-122	yes	21.97

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
CADPS2	Repression

Upstream regulators (CollecTRI, top): BATF, BCL6, CEBPB, ESR1, GATA2, IRF9, ISL1, NFATC1, NONO, NR4A2, OPRD1, PARP1, PAX6, PRDM1, SRF, TBX21, VPS35, YY1, ZNF219, ZNF436, ZSCAN21

miRNA regulators (miRDB)

137 targeting SNCA, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-126-5P	100.00	72.71	3180
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-559	99.95	72.28	3609

Literature-anchored findings (GeneRIF, showing 40)

• Protofibrillar alpha-synuclein, in contrast to the monomeric and fibrillar forms, binds synthetic vesicles very tightly via a beta-sheet-rich structure, causing transient and potentially cytotoxic permeabilization. (PMID:11425308)
• alpha-synuclein expression in human neurons is up-regulated during differentiation (PMID:11472875)
• Alpha-synuclein protofibril is stabilized by a dopamine-alpha-synuclein adduct. (PMID:11701929)
• we investigated the effects of inhibitors of the mitochondrial electron-transport chain on the aggregation of alpha-synuclein, a major protein component of Lewy bodies (PMID:11724769)
• Variations in a complex repeat (NACP-Rep1) c. 10 kb upstream are associated with various levels of expression of the gene. (PMID:11751692)
• familial Parkinson’s disease-linked A30P mutant alpha-Syn is defective in binding to phospholipid vesicles in vitro as determined by vesicle ultracentrifugation, circular dichroism spectroscopy, and low-angle X-ray diffraction (PMID:11812148)
• Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins (PMID:11812782)
• Results show that Ser-129 of alpha-synuclein is selectively and extensively phosphorylated in synucleinopathy lesions, and that this phosphorylation promoted fibril formation in vitro. (PMID:11813001)
• The extent of formation of amyloid fibrils from alpha-synuclein is greatly enhanced by heparin and certain other glycosaminoglycans and charged polymers in vitro, observations that are relevant in the context of the etiology of Parkinson’s disease. (PMID:11814343)
• overexpression of human alpha-synuclein, particularly the mutant form, can cause human DA neuron death, suggesting that alpha-synuclein may have a primary role in the pathogenesis of PD. (PMID:11814405)
• alpha-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells (PMID:11821392)
• directed expression of the molecular chaperone Hsp70 prevented dopaminergic neuronal loss associated with alpha-synuclein in Drosophila model of Parkinson’s disease (PMID:11823645)
• These findings provide a link between mutations or over-expression of alpha-synuclein and apoptosis of dopaminergic neurons by lowering the threshold of these cells to oxidative damage. (PMID:11852183)
• its structural change including the post translational protein processing is a future interest in the molecular mechanism of multiple system atrophy (PMID:11889756)
• observation that amino acid residues 31-109 of constitute the core unit of the filaments (PMID:11893734)
• acceleration of fibrillization by molecular crowding (PMID:11900526)
• mutated in parkinson disease, also a major component of Lewy bodies (PMID:12025860)
• neurotoxicity is a mechanism for selective neurodegeneration in Parkinson disease. (PMID:12042811)
• Data show that both normal and mutant alpha-synuclein specifically interact with the mitochondrial complex IV enzyme, cytochrome C oxidase. (PMID:12059041)
• The fibrillation of alpha-synuclein at neutral pH was completely inhibited by methionine oxidation. (PMID:12062445)
• Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred. (PMID:12070658)
• Ala-53–>Thr mutation causes neurodegenerative disease in transgenic mice (PMID:12084935)
• the NAC sequence is essential to beta-sheet formation and the aggregation originates from the beta-sheet intermediate, which may be implicated in the pathogenesis of Parkinson’s disease (PMID:12115139)
• overexpression of wild-type or mutated human alpha-synuclein leads to dopamine neuronal cell death in rodents (PMID:12122208)
• mutant proteins form annular protofibrils(similar to pore-forming bacterial toxins), suggesting that inappropriate membrane permeabilization might be the cause of cell dysfunction and even cell death in amyloid diseases, as Alzheimers and Parkinsons (PMID:12124613)
• role in pathogenesis of Parkinson disease (PMID:12138709)
• These results suggest that mutant alpha-synuclein leads to an impairment in vesicular dopamine storage and consequent accumulation of dopamine in the cytosol. (PMID:12145295)
• new mechanism of MPP+-induced dopaminergic toxicity by an interaction between mutant alpha-synucleins and the DAT, which is independent of the function of the proteasome. (PMID:12151787)
• effects of pH and salt concentration on the in vitro assembly of human wild-type alpha-synuclein, particularly with regard to aggregation rate and aggregate morphology (PMID:12217698)
• functions as a negative regulator of Ca(++)-dependent alpha-granule release from human platelets (PMID:12239163)
• characterized the cytoplasmic alpha-synuclein aggregates using a fractionation procedure with which different aggregate species can be separated (PMID:12351642)
• Two mutations in the alpha-synuclein gene (A30P and A53T) promote the formation of alpha-synuclein protofibrils, suggesting a causal role for protofibril formation in Parkinson disease. (PMID:12367530)
• examined the biochemical characteristics of the additional, higher molecular mass species of phosphorylated alpha-synuclein-positive polypeptides that also are recovered in the Sarkosyl-insoluble fraction of synucleinopathy (PMID:12377775)
• role of alpha-synuclein in the pathobiology of Parkinson’s disease (review) (PMID:12428717)
• conformational behavior of human alpha-synuclein is modulated by familial Parkinson’s disease point mutations A30P and A53T (PMID:12428728)
• Polymorphism of the alpha synuclein promoter region (non-amyloid component of plaques (NACP)-Rep1) is associated with an increased risk of Parkinson’s disease (PD) in three separate studies. (PMID:12493604)
• The number of the N-terminal repeat domain in wild-type alpha-synuclein represents an evolutionary balance between the functional conformer of alpha-synuclein (alpha-helix and/or random coil) and its pathogenic beta-sheet conformation. (PMID:12534279)
• The critical rate-limiting step in nucleation of alpha-synuclein fibrils under physiological conditions is the oxidative formation and accumulation of a dimeric, dityrosine cross-linked prenucleus. (PMID:12534296)
• proteasomal inhibition by aggregated alpha-synuclein could be mediated by interaction with S6’. (PMID:12551928)
• role of aggregation by tissue transglutaminase in Lewy body formation in Parkinson’s disease and dementia with Lewy bodies (PMID:12576551)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Snca	ENSMUSG00000025889
rattus_norvegicus	Snca	ENSRNOG00000008656

Paralogs (2): SNCB (ENSG00000074317), SNCG (ENSG00000173267)

Protein

Protein identifiers

Alpha-synuclein — P37840 (reviewed: P37840)

Alternative names: Non-A beta component of AD amyloid, Non-A4 component of amyloid precursor

All UniProt accessions (8): A0A669KB41, A0A669KBH5, D6RA31, E7EPV7, P37840, H6UYS0, H6UYS5, H6UYS7

UniProt curated annotations — full annotation on UniProt →

Function. Neuronal protein that plays several roles in synaptic activity such as regulation of synaptic vesicle trafficking and subsequent neurotransmitter release. Participates as a monomer in synaptic vesicle exocytosis by enhancing vesicle priming, fusion and dilation of exocytotic fusion pores. Mechanistically, acts by increasing local Ca(2+) release from microdomains which is essential for the enhancement of ATP-induced exocytosis. Also acts as a molecular chaperone in its multimeric membrane-bound state, assisting in the folding of synaptic fusion components called SNAREs (Soluble NSF Attachment Protein REceptors) at presynaptic plasma membrane in conjunction with cysteine string protein-alpha/DNAJC5. This chaperone activity is important to sustain normal SNARE-complex assembly during aging. Also plays a role in the regulation of the dopamine neurotransmission by associating with the dopamine transporter (DAT1) and thereby modulating its activity.

Subunit / interactions. Soluble monomer. Homotetramer. A dynamic intracellular population of tetramers and monomers coexists normally and the tetramer plays an essential role in maintaining homeostasis. Interacts with UCHL1. Interacts with phospholipase D and histones. Interacts (via N-terminus) with synphilin-1/SNCAIP; this interaction promotes formation of SNCA inclusions in the cytoplasm. Interacts with CALM1. Interacts with STXBP1; this interaction controls SNCA self-replicating aggregation. Interacts with SNARE components VAMP2 and SNAP25; these interactions allows SNARE complex assembly and integrity. Interacts with RPH3A and RAB3A. Interacts with SERF1A; this interaction promotes the aggregation of SNCA. Interacts with SEPTIN4. Interacts with DDX10; this interaction causes DDX10 mislocalization to the nucleoplasm and cytoplasmic inclusions.

Subcellular location. Cytoplasm. Membrane. Nucleus. Synapse. Secreted. Cell projection. Axon.

Tissue specificity. Highly expressed in presynaptic terminals in the central nervous system. Expressed principally in brain.

Post-translational modifications. Phosphorylated, predominantly on serine residues. Phosphorylation by CK1 appears to occur on residues distinct from the residue phosphorylated by other kinases. Phosphorylation of Ser-129 is selective and extensive in synucleinopathy lesions. In vitro, phosphorylation at Ser-129 promoted insoluble fibril formation. Phosphorylated on Tyr-125 by a PTK2B-dependent pathway upon osmotic stress. Hallmark lesions of neurodegenerative synucleinopathies contain alpha-synuclein that is modified by nitration of tyrosine residues and possibly by dityrosine cross-linking to generated stable oligomers. Ubiquitinated. The predominant conjugate is the diubiquitinated form. Acetylation at Met-1 seems to be important for proper folding and native oligomeric structure.

Disease relevance. Genetic alterations of SNCA resulting in aberrant polymerization into fibrils, are associated with several neurodegenerative diseases (synucleinopathies). SNCA fibrillar aggregates represent the major non A-beta component of Alzheimer disease amyloid plaque, and a major component of Lewy body inclusions. They are also found within Lewy body (LB)-like intraneuronal inclusions, glial inclusions and axonal spheroids in neurodegeneration with brain iron accumulation type 1. Parkinson disease 1, autosomal dominant (PARK1) [MIM:168601] A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. The disease is caused by variants affecting the gene represented in this entry. Parkinson disease 4, autosomal dominant (PARK4) [MIM:605543] A complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (resting tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia. The disease is caused by variants affecting the gene represented in this entry. Dementia, Lewy body (DLB) [MIM:127750] A neurodegenerative disorder characterized by mental impairment leading to dementia, parkinsonism, fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Brainstem or cortical intraneuronal accumulations of aggregated proteins (Lewy bodies) are the only essential pathologic features. Patients may also have hippocampal and neocortical senile plaques, sometimes in sufficient number to fulfill the diagnostic criteria for Alzheimer disease. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ’non A-beta component of Alzheimer disease amyloid plaque’ domain (NAC domain) is involved in fibrils formation. The middle hydrophobic region forms the core of the filaments. The C-terminus may regulate aggregation and determine the diameter of the filaments.

Similarity. Belongs to the synuclein family.

Isoforms (3)

UniProt ID	Names	Canonical?
P37840-1	1, NACP140	yes
P37840-2	2-4, NACP112
P37840-3	2-5

RefSeq proteins (8): NP_000336, NP_001139526, NP_001139527, NP_001362214, NP_001362215, NP_001362216, NP_001362217, NP_009292 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001058	Synuclein	Family
IPR002460	Synuclein_alpha	Family

Pfam: PF01387

UniProt features (55 total): mutagenesis site 15, strand 12, repeat 4, modified residue 4, sequence variant 4, helix 4, region of interest 3, turn 3, binding site 2, splice variant 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

232 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8JJV	X-RAY DIFFRACTION	1.23
8JLY	X-RAY DIFFRACTION	1.29
3Q27	X-RAY DIFFRACTION	1.3
4R0U	X-RAY DIFFRACTION	1.38
6I42	X-RAY DIFFRACTION	1.38
4ZNN	ELECTRON CRYSTALLOGRAPHY	1.41
4RIL	ELECTRON CRYSTALLOGRAPHY	1.43
4R0W	X-RAY DIFFRACTION	1.5
3Q26	X-RAY DIFFRACTION	1.54
3Q28	X-RAY DIFFRACTION	1.6
5CRW	X-RAY DIFFRACTION	1.6
2X6M	X-RAY DIFFRACTION	1.62
8OG0	X-RAY DIFFRACTION	1.71
8ZVY	X-RAY DIFFRACTION	1.72
4RIK	X-RAY DIFFRACTION	1.85
3Q25	X-RAY DIFFRACTION	1.9
6CT7	X-RAY DIFFRACTION	1.9
9EUU	ELECTRON MICROSCOPY	1.93
8BQV	ELECTRON MICROSCOPY	2
9CK3	ELECTRON MICROSCOPY	2.04
8B9V	X-RAY DIFFRACTION	2.16
8A9L	ELECTRON MICROSCOPY	2.2
9CKK	ELECTRON MICROSCOPY	2.21
9FYP	ELECTRON MICROSCOPY	2.23
3Q29	X-RAY DIFFRACTION	2.3
8BQW	ELECTRON MICROSCOPY	2.3
9O9J	ELECTRON MICROSCOPY	2.3
8PJO	ELECTRON MICROSCOPY	2.31
9JC3	ELECTRON MICROSCOPY	2.39
6UFR	ELECTRON MICROSCOPY	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P37840-F1	74.29	0.28

Antibody-complex structures (SAbDab): 6 — 2X6M, 6CT7, 8B9V, 8JJV, 8JLY, 8OG0

Functional residue map

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

Ligand- & substrate-binding residues (2): 50; 2

Post-translational modifications (4): 1, 87, 125, 129

Mutagenesis-validated functional residues (15):

Position	Phenotype
2	impairs copper-binding.
35	no effect on oligomerization.
39	no effect on osmotic stress-induced phosphorylation.
50	impairs copper-binding.
57	increases oligomerization.
67–71	reduces polymerization into amyloid fibrils.
71–82	impairs polymerization into amyloid fibrils.
76–77	impairs polymerization into amyloid fibrils.
76	does not affect polymerization into amyloid fibrils.
77	does not affect polymerization into amyloid fibrils.
78	does not affect polymerization into amyloid fibrils.
85–94	reduces polymerization into amyloid fibrils.
125	abolishes osmotic stress-induced phosphorylation.
133	no effect on osmotic stress-induced phosphorylation.
136	no effect on osmotic stress-induced phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-977225	Amyloid fiber formation
R-HSA-9833482	PKR-mediated signaling
R-HSA-1169410	Antimicrobial mechanism of IFN-stimulated genes
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-913531	Interferon Signaling

MSigDB gene sets: 0 (showing top):

GO Biological Process (82): negative regulation of transcription by RNA polymerase II (GO:0000122), microglial cell activation (GO:0001774), positive regulation of receptor recycling (GO:0001921), positive regulation of neurotransmitter secretion (GO:0001956), fatty acid metabolic process (GO:0006631), neutral lipid metabolic process (GO:0006638), phospholipid metabolic process (GO:0006644), glutathione metabolic process (GO:0006749), mitochondrial membrane organization (GO:0007006), chemical synaptic transmission (GO:0007268), adult locomotory behavior (GO:0008344), response to xenobiotic stimulus (GO:0009410), response to iron(II) ion (GO:0010040), negative regulation of platelet-derived growth factor receptor signaling pathway (GO:0010642), regulation of glutamate secretion (GO:0014048), regulation of dopamine secretion (GO:0014059), synaptic vesicle exocytosis (GO:0016079), synaptic vesicle priming (GO:0016082), negative regulation of microtubule polymerization (GO:0031115), receptor internalization (GO:0031623), protein destabilization (GO:0031648), response to magnesium ion (GO:0032026), response to lipopolysaccharide (GO:0032496), response to type II interferon (GO:0034341), cellular response to oxidative stress (GO:0034599), SNARE complex assembly (GO:0035493), positive regulation of SNARE complex assembly (GO:0035543), regulation of locomotion (GO:0040012), dopamine biosynthetic process (GO:0042416), mitochondrial ATP synthesis coupled electron transport (GO:0042775), regulation of macrophage activation (GO:0043030), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), negative regulation of neuron apoptotic process (GO:0043524), cellular response to fibroblast growth factor stimulus (GO:0044344), positive regulation of endocytosis (GO:0045807), negative regulation of exocytosis (GO:0045920), positive regulation of exocytosis (GO:0045921), negative regulation of dopamine metabolic process (GO:0045963), behavioral response to cocaine (GO:0048148)

GO Molecular Function (35): SNARE binding (GO:0000149), magnesium ion binding (GO:0000287), transcription cis-regulatory region binding (GO:0000976), actin binding (GO:0003779), enzyme inhibitor activity (GO:0004857), protein kinase inhibitor activity (GO:0004860), cysteine-type endopeptidase inhibitor activity (GO:0004869), copper ion binding (GO:0005507), calcium ion binding (GO:0005509), phospholipid binding (GO:0005543), microtubule binding (GO:0008017), enzyme activator activity (GO:0008047), ferrous iron binding (GO:0008198), zinc ion binding (GO:0008270), lipid binding (GO:0008289), tubulin binding (GO:0015631), oxidoreductase activity (GO:0016491), kinesin binding (GO:0019894), enzyme binding (GO:0019899), protein domain specific binding (GO:0019904), Hsp70 protein binding (GO:0030544), histone binding (GO:0042393), identical protein binding (GO:0042802), alpha-tubulin binding (GO:0043014), phospholipase binding (GO:0043274), tau protein binding (GO:0048156), beta-tubulin binding (GO:0048487), phosphoprotein binding (GO:0051219), dynein complex binding (GO:0070840), protein sequestering activity (GO:0140311), transporter regulator activity (GO:0141108), cuprous ion binding (GO:1903136), protein binding (GO:0005515), metal ion binding (GO:0046872), molecular adaptor activity (GO:0060090)

GO Cellular Component (35): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nuclear outer membrane (GO:0005640), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), lysosome (GO:0005764), cytosol (GO:0005829), ribosome (GO:0005840), plasma membrane (GO:0005886), cell cortex (GO:0005938), actin cytoskeleton (GO:0015629), membrane (GO:0016020), inclusion body (GO:0016234), axon (GO:0030424), growth cone (GO:0030426), synaptic vesicle membrane (GO:0030672), protein-containing complex (GO:0032991), neuronal cell body (GO:0043025), terminal bouton (GO:0043195), axon terminus (GO:0043679), perinuclear region of cytoplasm (GO:0048471), Lewy body (GO:0097413), postsynapse (GO:0098794), supramolecular fiber (GO:0099512), cytoskeleton (GO:0005856), synaptic vesicle (GO:0008021), cytoplasmic vesicle membrane (GO:0030659), platelet alpha granule membrane (GO:0031092), cell projection (GO:0042995), synapse (GO:0045202), presynapse (GO:0098793)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Metabolism of proteins	1
Antimicrobial mechanism of IFN-stimulated genes	1
Interferon Signaling	1
Immune System	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
lipid metabolic process	3
protein binding	3
cytoskeletal protein binding	3
catalytic activity	3
cytoplasm	3
neurotransmitter secretion	2
mitochondrion	2
metal ion binding	2
enzyme regulator activity	2
transition metal ion binding	2
intracellular membrane-bounded organelle	2
organelle outer membrane	2
intracellular anatomical structure	2
mitochondrial membrane	2
cell periphery	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
leukocyte activation involved in inflammatory response	1
macrophage activation	1
glial cell activation	1
receptor recycling	1
regulation of receptor recycling	1
positive regulation of macromolecule metabolic process	1
positive regulation of signaling	1
regulation of neurotransmitter secretion	1
positive regulation of synaptic transmission	1
positive regulation of neurotransmitter transport	1
positive regulation of secretion by cell	1
monocarboxylic acid metabolic process	1
organophosphate metabolic process	1
modified amino acid metabolic process	1
sulfur compound metabolic process	1
mitochondrion organization	1
membrane organization	1
anterograde trans-synaptic signaling	1
locomotory behavior	1
adult behavior	1
response to chemical	1

Protein interactions and networks

STRING

4810 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SNCA	PRKN	O60260	999
SNCA	SNCAIP	Q9Y6H5	998
SNCA	TARDBP	Q13148	995
SNCA	PARK7	Q99497	986
SNCA	PRNP	P04156	984
SNCA	HTT	P42858	983
SNCA	SLC6A3	Q01959	980
SNCA	TOMM20	Q15388	980
SNCA	TH	P07101	975
SNCA	LRRK2	Q5S007	973
SNCA	VDAC1	P21796	972
SNCA	MAPT	P10636	971
SNCA	HSPA4	P34932	970
SNCA	APOE	P02649	967
SNCA	HSPA8	P11142	962

IntAct

734 interactions, top by confidence:

A	B	Type	Score
SNCA	SNCA	psi-mi:“MI:2364”(proximity)	0.990
SNCA	SNCA	psi-mi:“MI:0915”(physical association)	0.990
SNCA	SNCA	psi-mi:“MI:0407”(direct interaction)	0.990
SNCA	SNCA	psi-mi:“MI:0403”(colocalization)	0.990
SNCA	APOE	psi-mi:“MI:0915”(physical association)	0.810
SNCA	APOE	psi-mi:“MI:0403”(colocalization)	0.810
SNCA	APOE	psi-mi:“MI:0407”(direct interaction)	0.810
TPPP	SNCA	psi-mi:“MI:0407”(direct interaction)	0.720

BioGRID (2071): SNCA (Two-hybrid), SNCA (Affinity Capture-Western), HSPA8 (Reconstituted Complex), SNCA (Two-hybrid), SNCA (Affinity Capture-Western), SNCA (Affinity Capture-MS), SNCA (Affinity Capture-MS), SNCA (Affinity Capture-MS), SNCA (Affinity Capture-MS), SNCA (Affinity Capture-MS), SNCA (Reconstituted Complex), HSP104 (Synthetic Rescue), COL7A1 (Affinity Capture-MS), DHCR24 (Affinity Capture-MS), DYNC1H1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0E4AVP3, A2XG55, A3AHG5, O36029, O55042, O76070, O94724, P01094, P0CU49, P16547, P22943, P23283, P33567, P37377, P37379, P37840, P53707, P61138, P61139, P61140, P61141, P61142, P61143, P61144, P61145, P61146, P61147, Q15847, Q16143, Q2PFW6, Q39846, Q3I5G7, Q3T0G8, Q42512, Q5XF06, Q63544, Q63754, Q6TMJ3, Q8LFD5, Q91448

Diamond homologs: O55042, P33567, P37377, P37840, P61138, P61139, P61140, P61141, P61142, P61143, P61144, P61145, P61146, P61147, Q16143, Q3I5G7, Q3T0G8, Q63754, Q91448, O76070, Q91ZZ3

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
SYK	down-regulates	SNCA	phosphorylation
GRK5	“down-regulates activity”	SNCA	phosphorylation
DYRK1A	up-regulates	SNCA	phosphorylation
PLK2	“down-regulates activity”	SNCA	phosphorylation
PLK1	“down-regulates activity”	SNCA	phosphorylation
PLK3	“down-regulates activity”	SNCA	phosphorylation
PPP2CB	“down-regulates activity”	SNCA	dephosphorylation
PPP2CA	“down-regulates activity”	SNCA	dephosphorylation
LRRK2	“down-regulates activity”	SNCA	phosphorylation
ROS	“up-regulates quantity”	SNCA
SNCA	up-regulates	Lewy_body_formation
SNCA	up-regulates	“ER stress”
PRKN	“down-regulates quantity by destabilization”	SNCA	ubiquitination
SNCA	“down-regulates quantity”	VAMP2	binding
SNCA	“down-regulates quantity”	CADPS2	“transcriptional regulation”
SNCAIP	“up-regulates activity”	SNCA	binding
DAPK1	“up-regulates quantity”	SNCA	phosphorylation
NEDD4	“down-regulates quantity by destabilization”	SNCA	ubiquitination
ABL1	“up-regulates quantity”	SNCA	phosphorylation
CSNK1A1	“down-regulates activity”	SNCA	phosphorylation
CSNK1A1	up-regulates	SNCA	phosphorylation
CSNK2A1	“down-regulates activity”	SNCA	phosphorylation
CSNK2A1	up-regulates	SNCA	phosphorylation
GRK2	“down-regulates activity”	SNCA	phosphorylation
PTK2B	unknown	SNCA	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 141 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Aggrephagy	5	12.7×	3e-03
Translocation of SLC2A4 (GLUT4) to the plasma membrane	7	11.0×	6e-04
Response to elevated platelet cytosolic Ca2+	6	10.0×	2e-03
Programmed Cell Death	6	9.0×	3e-03
Platelet activation, signaling and aggregation	8	8.6×	6e-04
Apoptosis	5	8.6×	8e-03
Amyloid fiber formation	8	8.4×	6e-04
Leishmania infection	5	8.3×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
amyloid fibril formation	6	28.0×	8e-05
positive regulation of mitotic cell cycle	5	18.1×	2e-03
positive regulation of protein-containing complex assembly	5	13.1×	5e-03
negative regulation of protein ubiquitination	5	11.1×	7e-03
negative regulation of neuron apoptotic process	8	6.9×	4e-03
protein stabilization	9	4.7×	9e-03
protein ubiquitination	14	4.5×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	1
Uncertain significance	79
Likely benign	44
Benign	27

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1120010	GRCh37/hg19 4q22.1(chr4:90647764-90758128)	Pathogenic
14007	NM_000345.4(SNCA):c.157G>A (p.Ala53Thr)	Pathogenic
14010	NM_000345.4(SNCA):c.136G>A (p.Glu46Lys)	Pathogenic
1454898	NC_000004.11:g.(?90647779)(90756818_?)dup	Pathogenic
3759096	NM_000345.4(SNCA):c.158C>A (p.Ala53Glu)	Pathogenic
531846	NC_000004.11:g.(?90647315)(90756838_?)dup	Pathogenic
639372	NC_000004.11:g.(?90647315)(90756828_?)dup	Pathogenic
97000	NM_000345.4(SNCA):c.152G>A (p.Gly51Asp)	Pathogenic
14008	NM_000345.4(SNCA):c.88G>C (p.Ala30Pro)	Likely pathogenic

SpliceAI

1592 predictions. Top by Δscore:

Variant	Effect	Δscore
4:89729285:T:C	acceptor_gain	1.0000
4:89729285:T:TC	acceptor_gain	1.0000
4:89822392:G:GC	acceptor_gain	1.0000
4:89828139:TTA:T	donor_loss	1.0000
4:89828140:TAC:T	donor_loss	1.0000
4:89828141:ACCT:A	donor_loss	1.0000
4:89828142:C:A	donor_loss	1.0000
4:89835546:CCTA:C	donor_gain	1.0000
4:89835575:T:A	donor_gain	1.0000
4:89835688:CCACA:C	acceptor_gain	1.0000
4:89835689:CACA:C	acceptor_gain	1.0000
4:89835689:CACAC:C	acceptor_gain	1.0000
4:89835691:CA:C	acceptor_gain	1.0000
4:89835693:C:CC	acceptor_gain	1.0000
4:89729188:TCCTA:T	donor_loss	0.9900
4:89729189:CCTAC:C	donor_loss	0.9900
4:89729190:CTA:C	donor_loss	0.9900
4:89729191:TA:T	donor_loss	0.9900
4:89729192:A:AT	donor_loss	0.9900
4:89729193:CC:C	donor_loss	0.9900
4:89729284:T:TC	acceptor_gain	0.9900
4:89729290:G:GC	acceptor_gain	0.9900
4:89822386:CCA:C	acceptor_gain	0.9900
4:89822387:CA:C	acceptor_gain	0.9900
4:89822387:CAC:C	acceptor_gain	0.9900
4:89822389:C:CC	acceptor_gain	0.9900
4:89822392:G:C	acceptor_gain	0.9900
4:89828185:C:CC	acceptor_gain	0.9900
4:89835541:ACCT:A	donor_loss	0.9900
4:89835542:CCT:C	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000024345 (4:89793803 A>G), RS1000057944 (4:89790139 G>A), RS1000081166 (4:89781867 T>C), RS1000089202 (4:89832110 T>A), RS1000169554 (4:89806318 T>C), RS1000176413 (4:89840165 C>T), RS1000198571 (4:89837317 G>T), RS10002059 (4:89788019 T>C,G), RS10002163 (4:89788107 T>A,C), RS10002435 (4:89791360 G>A), RS10002682 (4:89747782 T>C,G), RS1000272144 (4:89837522 C>T), RS1000275835 (4:89796065 A>G), RS1000278151 (4:89752280 C>A,T), RS1000323135 (4:89755116 C>G)

Disease associations

OMIM: gene MIM:163890 | disease phenotypes: MIM:127750, MIM:168601, MIM:605543

GenCC curated gene-disease

Disease	Classification	Inheritance
Parkinson disease	Definitive	Autosomal dominant
autosomal dominant Parkinson disease 4	Definitive	Autosomal dominant
Lewy body dementia	Strong	Autosomal dominant
autosomal dominant Parkinson disease 1	Strong	Autosomal dominant
parkinsonian-pyramidal syndrome	Supportive	Autosomal recessive
hereditary late onset Parkinson disease	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Parkinson disease	Definitive	AD

Mondo (8): Lewy body dementia (MONDO:0007488), autosomal dominant Parkinson disease 1 (MONDO:0008200), young-onset Parkinson disease (MONDO:0017279), vascular dementia (MONDO:0004648), autosomal dominant Parkinson disease 4 (MONDO:0011562), Parkinson disease (MONDO:0005180), parkinsonian-pyramidal syndrome (MONDO:0009830), (MONDO:0018466)

Orphanet (3): Young-onset Parkinson disease (Orphanet:2828), Hereditary late-onset Parkinson disease (Orphanet:411602), NON RARE IN EUROPE: Dementia with Lewy body (Orphanet:1648)

HPO phenotypes

81 total (30 of 81 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000011	Neurogenic bladder
HP:0000012	Urinary urgency
HP:0000338	Hypomimic face
HP:0000514	Slow saccadic eye movements
HP:0000551	Color vision defect
HP:0000651	Diplopia
HP:0000713	Agitation
HP:0000716	Depression
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000736	Short attention span
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000744	Low frustration tolerance
HP:0000746	Delusion
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001278	Orthostatic hypotension
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001762	Talipes equinovarus
HP:0001824	Weight loss
HP:0002014	Diarrhea

GWAS associations

39 associations (top):

Study	Trait	p-value
GCST000528_4	Parkinson’s disease	2.000000e-16
GCST000530_1	Parkinson’s disease	7.000000e-17
GCST000567_6	Parkinson’s disease	7.000000e-08
GCST000772_1	Parkinson’s disease	3.000000e-11
GCST000855_3	Parkinson’s disease	9.000000e-16
GCST000874_1	Parkinson’s disease	3.000000e-08
GCST000959_7	Parkinson’s disease	2.000000e-47
GCST001126_2	Parkinson’s disease	2.000000e-19
GCST001430_2	Parkinson’s disease	8.000000e-35
GCST001445_5	Parkinson’s disease	6.000000e-65
GCST001445_6	Parkinson’s disease	5.000000e-11
GCST002353_2	Parkinson’s disease	1.000000e-09
GCST002353_3	Parkinson’s disease	3.000000e-11
GCST002544_19	Parkinson’s disease	4.000000e-73
GCST003800_1	Response to bupropion in depression	3.000000e-08
GCST003922_2	Parkinson’s disease	1.000000e-32
GCST003984_20	Parkinson’s disease	1.000000e-56
GCST004902_48	Parkinson’s disease	5.000000e-123
GCST005276_2	Dementia with Lewy bodies	9.000000e-13
GCST006585_2243	Blood protein levels	1.000000e-09
GCST006585_2824	Blood protein levels	8.000000e-30
GCST006940_1	Neurociticism	2.000000e-10
GCST006948_33	Feeling nervous	1.000000e-09
GCST007780_1	Parkinson’s disease (age of onset)	2.000000e-12
GCST007780_2	Parkinson’s disease (age of onset)	7.000000e-06
GCST008477_6	Emphysema annual change measurement in smokers (adjusted lung density)	7.000000e-06
GCST009325_30	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	1.000000e-36
GCST009325_69	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	1.000000e-48
GCST009325_70	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	5.000000e-149
GCST009325_80	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	4.000000e-154

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0009597	feeling nervous measurement
EFO:0004847	age at onset
EFO:0007626	emphysema imaging measurement
EFO:0009863	anxiety measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D010300	Parkinson Disease	C10.228.140.079.862.500; C10.228.662.600.400; C10.574.928.750
C538104	Pallidopyramidal syndrome (supp.)
C565324	Parkinson Disease 4, Autosomal Dominant Lewy Body (supp.)
C566823	Parkinson Disease, Familial, Type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL5465209 (PROTEIN-PROTEIN INTERACTION), CHEMBL5465232 (PROTEIN-PROTEIN INTERACTION), CHEMBL5483090 (PROTEIN-PROTEIN INTERACTION), CHEMBL6152 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

31 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,910,382 (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
CHEMBL135	ESTRADIOL	4	123,080
CHEMBL1405	ESTRONE	4	36,722
CHEMBL1440	TETRACYCLINE	4	324,384
CHEMBL1550	PHYTONADIONE	4	83,772
CHEMBL161	CEFTRIAXONE	4	71,135
CHEMBL1908919	FLORBETAPIR	4	690
CHEMBL193482	ESTRIOL	4	21,295
CHEMBL374478	RIFAMPIN	4	93,834
CHEMBL38	TRETINOIN	4	194,008
CHEMBL386630	TESTOSTERONE	4	129,997
CHEMBL4173394	BRILLIANT BLUE G	4	14,477
CHEMBL493	BROMOCRIPTINE	4	43,885
CHEMBL531	PERGOLIDE	4	23,128
CHEMBL59	DOPAMINE	4	217,028
CHEMBL590	MENADIONE	4	21,034
CHEMBL64894	GENTIAN VIOLET	4	111,449
CHEMBL972	SELEGILINE	4	26,801
CHEMBL986	RETINOL	4	277,603
CHEMBL140	CURCUMIN	3	93,882
CHEMBL259223	MENATETRENONE	3	2,178
CHEMBL286494	HYPERICIN	3
CHEMBL297453	EPIGALOCATECHIN GALLATE	3
CHEMBL50	QUERCETIN	3
CHEMBL1368322	PARAROSANILINE	2
CHEMBL151	LUTEOLIN	2
CHEMBL288114	GALLIC ACID	2
CHEMBL4748063	EMRUSOLMIN	2
CHEMBL5095072	MINZASOLMIN	2
CHEMBL583912	(-)-EPICATECHIN	2
CHEMBL8260	BAICALEIN	2

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Synuclein proteins

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

Ligand	Action	Affinity	Parameter
prasinezumab	Binding	10.32	pKd
MK-7337	Binding	9.05	pKi
cinpanemab	Binding	7.0	pKd

Binding affinities (BindingDB)

241 measured of 242 human assays (242 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(R)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidin-4-yl)piperazin-1-yl)-5-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)ethynyl)pyrimidine	KI	0.32 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidin-2-yl)piperazin-1-yl)-5-(2-(6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)vinyl)pyrimidine	KI	0.42 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-2-(2-((2-fluoroethoxy)methyl)-4-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)ethynyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazine	KI	0.449 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	0.5 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(2-(methoxymethyl)-4-(pyridin-2-yl)piperazin-1-yl)pyrimidine	KI	0.5 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-(1-(5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)pyrimidin-2-yl)-4-(pyrimidin-4-yl)piperazin-2-yl)methanol	KI	0.5 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(2-((2-fluoroethoxy)methyl)-4-(pyridin-4-yl)piperazin-1-yl)pyrimidine	KI	0.5 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
1-((2-((R)-4-(5-((E)-2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)pyrimidin-2-yl)-2-(methoxymethyl)piperazin-1-yl)pyrimidin-5-yl)oxy)-3-fluoropropan-2-ol	KI	0.52 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-2-(2-((2-fluoroethoxy)methyl)-4-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)ethynyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazine	KI	0.57 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyridin-3-yl)vinyl)-2-(3-(methoxymethyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	0.62 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-2-(4-(5-((2-(1-(fluoromethyl)-1H-pyrazol-4-yl)pyrimidin-5-yl)ethynyl)pyrimidin-2-yl)-2-(methoxymethyl)piperazin-1-yl)-1,3,5-triazine	KI	0.64 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-2-(4-(5-((6-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyridin-3-yl)ethynyl)pyrimidin-2-yl)-2-(methoxymethyl)piperazin-1-yl)-1,3,5-triazine	KI	0.694 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(3-(methoxymethyl)-4-(pyridin-2-yl)piperazin-1-yl)pyrimidine	KI	0.7 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-2-(4-(6-fluoropyrimidin-4-yl)-3-(methoxymethyl)piperazin-1-yl)-5-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)ethynyl)pyrimidine	KI	0.76 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(5-(2-(2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidin-4-yl)piperazin-1-yl)pyrimidin-5-yl)vinyl)pyridin-2-yl)oxazole	KI	0.78 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(2-(methoxymethyl)-4-(5-(methoxymethyl)pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	0.8 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(5-(2-(2-(3-((2-fluoroethoxy)methyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidin-5-yl)vinyl)pyridin-2-yl)oxazole	KI	0.8 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-5-(2-fluoroethoxy)-2-(2-(methoxymethyl)-4-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)ethynyl)pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	0.83 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(S)-2-(4-(5-((2-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyrimidin-5-yl)ethynyl)pyrimidin-2-yl)-3-(methoxymethyl)piperazin-1-yl)-1,3,5-triazine	KI	0.89 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-5-(5-((2-(3-((2-(2-fluoroethoxy)ethoxy)methyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidin-5-yl)ethynyl)pyridin-2-yl)oxazole	KI	0.897 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(3-(methoxymethyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	0.9 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(4-(4-fluoropyridin-2-yl)-2-(methoxymethyl)piperazin-1-yl)pyrimidine	KI	0.9 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(2-(methoxymethyl)-4-(5-methylpyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	0.9 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(4-(6-fluoropyridin-3-yl)-2-(methoxymethyl)piperazin-1-yl)pyrimidine	KI	0.9 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-2-(1 -(2-fluoroethyl)-1H-pyrazol-4-yl)-5-((2-(3-(methoxymethyl)-4-(pyrimidin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethynyl)pyrimidine	KI	0.91 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
3-(((R)-4-(5-((6-(1H-imidazol-1-yl)pyridin-3-yl)ethynyl)pyrimidin-2-yl)-1-(pyrimidin-2-yl)piperazin-2-yl)methoxy)-2-fluoropropan-1-ol	KI	0.913 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-7-(5-((2-(3-((2-fluoroethoxy)methyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidin-5-yl)ethynyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine	KI	0.915 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(5-(2-(2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-5-yl)vinyl)pyridin-2-yl)oxazole	KI	0.94 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-5-fluoro-2-(4-(5-((2-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyrimidin-5-yl)ethynyl)pyrimidin-2-yl)-2-(methoxymethyl)piperazin-1-yl)pyrimidine	KI	0.99 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(4-(6-fluoropyrimidin-4-yl)-2-(methoxymethyl)piperazin-1-yl)pyrimidine	KI	1 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-(1-(5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)pyrimidin-2-yl)-4-(6-fluoropyrimidin-4-yl)piperazin-2-yl)methanol	KI	1 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(4-(2-fluoropyridin-4-yl)-2-(methoxy methyl)piperazin-1-yl)pyrimidine	KI	1 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(2-((2-fluoroethoxy)methyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	1 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-2-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-5-((2-(4-(5-fluoropyridin-2-yl)-3-(methoxymethyl)piperazin-1-yl)pyrimidin-5-yl)ethynyl)pyrimidine	KI	1.05 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
1-(4-(6-fluoropyrimidin-4-yl)-1-(5-((6-(oxazol-5-yl)pyridin-3-yl)ethynyl)pyrimidin-2-yl)piperazin-2-yl)-N-methylmethanamine	KI	1.1 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(4-(5-fluoromethylpyrimidin-2-yl)-3-(methoxymethyl)piperazin-1-yl)pyrimidine	KI	1.1 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-5-((6-(1H-imidazol-1-yl)pyridin-3-yl)ethynyl)-2-(3-(methoxy methyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	1.1 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-5-((6-(4-(2H-1,2,3-triazol-2-yl)piperidin-1-yl)pyridin-3-yl)ethynyl)-2-(3-(methoxymethyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	1.15 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-2-(4-(5-((6-(6-fluoropyrimidin-4-yl)pyridin-3-yl)ethynyl)pyrimidin-2-yl)-2-(methoxymethyl)piperazin-1-yl)pyrimidine-5-carbonitrile	KI	1.18 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(3-((fluoromethoxy)methyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	1.2 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-(1-(-(2-(6-(1 H-imidazol-1-yl)pyridin-3-yl)vinyl)pyrimidin-2-yl)-4-(pyrazin-2-yl)piperazin-2-yl)methanol	KI	1.2 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-2-(2-((2-fluoroethoxy)methyl)-4-(5-(2-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)vinyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazine	KI	1.22 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-2-(4-(5-((2-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyrimidin-5-yl)ethynyl)pyrimidin-2-yl)-2-(methoxymethyl)piperazin-1-yl)-1,3,5-triazine	KI	1.29 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(4-(6-chloropyrimidin-4-yl)-2-(methoxymethyl)piperazin-1-yl)pyrimidine	KI	1.3 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-7-(4-(6-(2-(6-(1H-pyrazol-1-yl)pyridin-3-yl)vinyl)pyrimidin-2-yl)-3-(methoxymethyl)piperazin-1-yl)pyrrolo[1,2-a]pyrazine	KI	1.3 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-5-(2-(6-(1H-imidazol-1-yl)pyridin-3-yl)vinyl)-2-(2-(methoxymethyl)-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidine	KI	1.3 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R,E)-6-(2-(2-(2-(methoxymethyl)-4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-5-yl)vinyl)-2-methylimidazo[1,2-a]pyrimidine	KI	1.4 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-2-(3-((2-(2-(2-fluoroethoxy)ethoxy)ethoxy)methyl)-4-(pyrimidin-2-yl)piperazin-1-yl)-5-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)ethynyl)pyrimidine	KI	1.43 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(S)-5-(5-((2-(3-((2-fluoroethoxy)methyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidin-5-yl)ethynyl)pyridin-2-yl)oxazole	KI	1.48 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE
(R)-4-(4-(5-((6-(1H-imidazol-1-yl)pyridin-3-yl)ethynyl)pyrimidin-2-yl)-2-(methoxymethyl)piperazin-1-yl)-2-fluoropyrimidine	KI	1.49 nM	WO-2024186584: ALPHA-SYNUCLEIN BINDERS AND METHODS OF USE

ChEMBL bioactivities

484 potent at pChembl≥5 of 537 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.31	Kd	0.49	nM	CHEMBL5896450
9.28	Kd	0.53	nM	CHEMBL5771524
9.14	Kd	0.73	nM	CHEMBL5790440
9.10	Kd	0.79	nM	CHEMBL5843241
9.00	Kd	1	nM	CHEMBL5843281
9.00	Ki	1	nM	CHEMBL6165287
8.99	Kd	1.03	nM	CHEMBL4637732
8.93	IC50	1.18	nM	CHEMBL5286894
8.90	Kd	1.27	nM	CHEMBL5759738
8.85	Kd	1.4	nM	CHEMBL6035240
8.70	Ki	2	nM	CHEMBL6152901
8.70	Ki	2	nM	CHEMBL6144053
8.70	Ki	2	nM	CHEMBL6163459
8.68	Ki	2.1	nM	CHEMBL3593932
8.68	Ki	2.1	nM	CHEMBL6163288
8.63	Ki	2.32	nM	CHEMBL5274551
8.62	Kd	2.4	nM	CHEMBL6034599
8.55	Ki	2.8	nM	CHEMBL6152980
8.55	Ki	2.8	nM	CHEMBL6169103
8.52	Ki	3	nM	CHEMBL6152677
8.49	Kd	3.25	nM	CHEMBL6001659
8.46	Ki	3.5	nM	CHEMBL3593930
8.46	Ki	3.5	nM	CHEMBL5404722
8.42	Ki	3.8	nM	CHEMBL3593928
8.38	Ki	4.2	nM	CHEMBL3593911
8.33	Ki	4.7	nM	CHEMBL5771524
8.15	EC50	7	nM	CHEMBL2153085
8.09	Kd	8.21	nM	CHEMBL4633757
8.07	Ki	8.5	nM	CHEMBL5413730
8.05	Kd	8.9	nM	CHEMBL3593934
8.04	Ki	9.2	nM	CHEMBL5436166
8.03	Ki	9.4	nM	CHEMBL5435534
8.00	Kd	10	nM	CHEMBL5087695
7.96	Kd	10.9	nM	CHEMBL4634055
7.94	Ki	11.5	nM	CHEMBL3593904
7.89	Ki	12.9	nM	CHEMBL3593926
7.89	EC50	13	nM	CHEMBL2153086
7.85	EC50	14	nM	CHEMBL2153084
7.84	Ki	14.6	nM	CHEMBL3593922
7.84	Ki	14.6	nM	CHEMBL5420714
7.83	Ki	14.8	nM	CHEMBL5843241
7.81	Ki	15.5	nM	CHEMBL5405459
7.80	EC50	16	nM	CHEMBL2153083
7.79	Kd	16.1	nM	CHEMBL207649
7.78	Ki	16.5	nM	CHEMBL5399057
7.78	Ki	16.8	nM	CHEMBL5414142
7.78	Ki	16.5	nM	CHEMBL5422515
7.77	EC50	17	nM	CHEMBL3902249
7.77	EC50	17	nM	CHEMBL3968863
7.76	Ki	17.3	nM	CHEMBL5402429

PubChem BioAssay actives

240 with measured affinity, of 1723 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
(E)-N-[(5-fluoro-2-nitrophenyl)methyl]-3-(4-fluorophenyl)-N-(furan-2-ylmethyl)prop-2-enamide	1667190: Binding affinity to human wlid-type alpha-synuclein by SPR analysis	kd	0.0010	uM
(2Z)-2-[(E)-3-(4-methoxyphenyl)prop-2-enylidene]-5-(6-methoxy-3-pyridinyl)-1-benzofuran-3-one	1952200: Inhibition of Alpha-synuclein (unknown origin) fibrils	ic50	0.0012	uM
(3Z)-1-[[4-(2-fluoroethoxy)phenyl]methyl]-3-[(E)-3-(4-nitrophenyl)prop-2-enylidene]indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0021	uM
1-[2-[[2-[4-(dimethylamino)phenyl]-3-hydroxy-4-oxochromen-7-yl]-methylamino]ethyl]pyrrole-2,5-dione	1952199: Binding affinity to Alpha-synuclein (unknown origin) fibrils assessed as inhibition constant	ki	0.0023	uM
2-[(1-benzylindol-3-yl)methylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0035	uM
(3Z)-1-[(3,4-dimethoxyphenyl)methyl]-3-[(E)-3-(4-nitrophenyl)prop-2-enylidene]indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0035	uM
(3Z)-1-[(3-methoxyphenyl)methyl]-3-[(E)-3-(4-nitrophenyl)prop-2-enylidene]indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0038	uM
(3Z)-3-[(E)-3-[4-(dimethylamino)phenyl]prop-2-enylidene]-1-[(4-nitrophenyl)methyl]indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0042	uM
(E)-3-(4-cyanophenyl)-N-(furan-2-ylmethyl)-N-[(2-nitrophenyl)methyl]prop-2-enamide	1667190: Binding affinity to human wlid-type alpha-synuclein by SPR analysis	kd	0.0082	uM
2-[(1-benzylindol-6-yl)methylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0085	uM
(3Z)-1-[[4-(2-(18F)fluoroethoxy)phenyl]methyl]-3-[(E)-3-(4-nitrophenyl)prop-2-enylidene]indol-2-one	1235528: Binding affinity to recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1 hr by scintillation counting	kd	0.0089	uM
2-[(2E,4E)-5-(1-benzylindol-3-yl)penta-2,4-dienylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0092	uM
2-[(E)-3-(1-benzylpyrrolo[2,3-b]pyridin-3-yl)prop-2-enylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0094	uM
N-[2-[(E)-2-(4-nitrophenyl)ethenyl]phenyl]pyridine-2-carboxamide	1817921: Binding affinity to recombinant human alpha-syn aggregates assessed as dissociation constant by SPR analysis	kd	0.0100	uM
(E)-N-benzyl-N-[(5-fluoro-2-nitrophenyl)methyl]-3-(4-fluorophenyl)prop-2-enamide	1667190: Binding affinity to human wlid-type alpha-synuclein by SPR analysis	kd	0.0109	uM
(3Z)-3-[(E)-3-[4-(dimethylamino)phenyl]prop-2-enylidene]-1H-pyrrolo[2,3-b]pyridin-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0115	uM
(3Z)-1-[(4-methoxyphenyl)methyl]-3-[(E)-3-(4-nitrophenyl)prop-2-enylidene]indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0129	uM
(3Z)-3-[(E)-3-(4-nitrophenyl)prop-2-enylidene]-1H-indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0146	uM
2-[(2E,4E)-5-(1-benzylindol-5-yl)penta-2,4-dienylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0146	uM
2-[(E)-3-(1-benzylindol-6-yl)prop-2-enylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0155	uM
2-[(E)-3-(1-benzylindol-3-yl)prop-2-enylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0165	uM
methyl (E)-3-(1-benzylindol-3-yl)-2-cyanoprop-2-enoate	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0165	uM
2-[[1-(pyridin-3-ylmethyl)indol-3-yl]methylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0168	uM
2-[(2E,4E)-5-[1-(pyridin-3-ylmethyl)indol-3-yl]penta-2,4-dienylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0173	uM
2-[[1-[(4-fluorophenyl)methyl]indol-3-yl]methylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0173	uM
2-[[1-[(4-iodophenyl)methyl]indol-3-yl]methylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0174	uM
(3Z)-1-benzyl-3-[(E)-3-(4-nitrophenyl)prop-2-enylidene]indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0250	uM
2-[(2E,4E)-5-(1-benzylindol-6-yl)penta-2,4-dienylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0294	uM
(3Z)-3-[(E)-3-[4-(dimethylamino)phenyl]prop-2-enylidene]-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0298	uM
3-methyl-2-[(E)-2-(4-piperidin-1-ylphenyl)ethenyl]-1,3-benzothiazol-3-ium iodide	1952195: Binding affinity to human recombinant Alpha-synuclein assessed as dissociation constant by fluorometric method	kd	0.0300	uM
2-[(1-benzylpyrrolo[2,3-b]pyridin-3-yl)methylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0313	uM
3-methoxy-7-nitro-10H-phenothiazine	674590: Binding affinity to human alpha-synuclein expressed in Escherichia coli BL21 (DE3) cells after 1 hr by thioflavin T fluorescence assay	ki	0.0321	uM
(2E)-2-[[5-[4-(hydroxymethyl)phenyl]thiophen-2-yl]methylidene]-3H-inden-1-one	1934436: Binding affinity to human brain alpha-synuclein fibril	kd	0.0390	uM
N-[2-[(E)-2-(4-methoxyphenyl)ethenyl]phenyl]benzamide	1817921: Binding affinity to recombinant human alpha-syn aggregates assessed as dissociation constant by SPR analysis	kd	0.0400	uM
2-[(2E,4E)-5-[6-(dimethylamino)-1,3-benzothiazol-2-yl]penta-2,4-dienylidene]propanedinitrile	1952196: Binding affinity to Alpha-synuclein (unknown origin) assessed as dissociation constant	kd	0.0401	uM
(3Z)-3-[(E)-3-[4-(dimethylamino)phenyl]prop-2-enylidene]-1H-indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0407	uM
(3Z)-1-benzyl-3-[(E)-3-[4-(dimethylamino)phenyl]prop-2-enylidene]indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0409	uM
2-[(2E,4E)-5-(1-benzylindol-4-yl)penta-2,4-dienylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0424	uM
(3Z)-1-[(4-aminophenyl)methyl]-3-[(E)-3-[4-(dimethylamino)phenyl]prop-2-enylidene]indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0436	uM
(3Z)-3-[(E)-3-(4-aminophenyl)prop-2-enylidene]-1H-indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0448	uM
ethyl (3Z)-3-[(E)-3-[4-(dimethylamino)phenyl]prop-2-enylidene]-2-oxoindole-1-carboxylate	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0453	uM
(E)-N-benzyl-3-(4-fluorophenyl)-N-[(2-nitrophenyl)methyl]prop-2-enamide	1667190: Binding affinity to human wlid-type alpha-synuclein by SPR analysis	kd	0.0473	uM
3-(2-fluoroethoxy)-7-nitro-10H-phenothiazine	674590: Binding affinity to human alpha-synuclein expressed in Escherichia coli BL21 (DE3) cells after 1 hr by thioflavin T fluorescence assay	ki	0.0490	uM
2-[(2E,4E)-5-(1-benzylindol-7-yl)penta-2,4-dienylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0509	uM
(3E)-1-[(3,4-dimethoxyphenyl)methyl]-3-[(E)-3-(4-nitrophenyl)prop-2-enylidene]indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0533	uM
(3Z)-3-[(E)-3-[4-(dimethylamino)phenyl]prop-2-enylidene]-5-hydroxy-1H-indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0540	uM
(3Z)-3-[(E)-3-[4-(dimethylamino)phenyl]prop-2-enylidene]-1-[(4-methoxyphenyl)methyl]indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0546	uM
2-[(E)-3-(1-benzylindol-4-yl)prop-2-enylidene]propanedinitrile	2037032: Competitive binding affinity to recombinant alpha-synuclein (unknown origin) assessed as inhibition constant incubated for 0.5 hrs by ThT-based fluorescence microplate reader analysis	ki	0.0564	uM
3-[(E)-3-iodoprop-2-enoxy]-7-nitro-10H-phenothiazine	674590: Binding affinity to human alpha-synuclein expressed in Escherichia coli BL21 (DE3) cells after 1 hr by thioflavin T fluorescence assay	ki	0.0579	uM
(3Z)-3-[(E)-3-(4-methoxyphenyl)prop-2-enylidene]-1H-indol-2-one	1235521: Displacement of Thio-T from recombinant alpha-synuclein (unknown origin) expressed in Escherichia coli after 1.5 hrs by fluorescence assay	ki	0.0611	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Rotenone	decreases ubiquitination, affects cotreatment, increases expression, decreases reaction, increases reaction (+8 more)	27
1-Methyl-4-phenylpyridinium	decreases reaction, increases response to substance, affects reaction, affects response to substance, increases reaction (+5 more)	15
Paraquat	decreases response to substance, decreases reaction, increases response to substance, increases metabolic processing, affects cotreatment (+5 more)	14
Valproic Acid	increases expression, affects expression, affects cotreatment	9
manganese chloride	affects localization, increases activity, increases cleavage, affects binding, affects cotreatment (+7 more)	8
Dopamine	increases response to substance, affects cotreatment, increases expression, decreases abundance, decreases reaction (+4 more)	6
Decitabine	decreases methylation, affects expression, affects cotreatment, increases expression	4
Air Pollutants	affects expression, increases abundance, decreases expression, increases expression	4
Cocaine	affects expression, increases expression	4
Maneb	increases response to substance, increases abundance, increases metabolic processing, affects cotreatment, increases expression (+1 more)	4
Manganese	affects binding, decreases reaction, increases transport, affects localization, increases activity (+6 more)	4
Methamphetamine	affects localization, increases expression, decreases reaction, affects reaction, decreases expression (+3 more)	4
Particulate Matter	decreases expression, increases abundance, increases expression, affects cotreatment	4
sodium arsenite	affects binding, increases reaction, affects cotreatment, decreases expression, increases abundance (+1 more)	3
Arsenic	decreases expression, increases abundance, affects methylation, affects binding, increases reaction (+1 more)	3
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	3
Hydrogen Peroxide	increases metabolic processing, affects response to substance, increases expression, increases response to substance	3
Iron	increases reaction, increases response to substance, affects localization, affects cotreatment	3
propionaldehyde	increases expression, increases methylation	2
bisphenol A	decreases expression, increases methylation	2
geraniol	decreases reaction, increases expression, decreases abundance, increases abundance	2
trichostatin A	affects cotreatment, increases expression	2
cobaltous chloride	affects folding, decreases expression	2
butyraldehyde	increases expression, increases methylation	2
3-methyladenine	decreases expression, decreases reaction, increases expression	2
ferrous chloride	increases reaction, increases response to substance, affects folding	2
mercuric bromide	decreases expression, affects cotreatment	2
pentanal	increases methylation, increases expression	2
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression, increases phosphorylation	2
Resveratrol	affects reaction, increases degradation, affects binding	2

ChEMBL screening assays

459 unique, capped per target: 458 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5343744	Binding	PROTAC activity at CRBN/recombinant alpha-synuclein preformed fibrils seeded in HEK293T cells assessed as decrease in alpha-synuclein aggregates measured after 48 hrs by immunoblot analysis	Discovery of Small-Molecule Degraders for Alpha-Synuclein Aggregates. — J Med Chem
CHEMBL2354282	Functional	PubChem BioAssay. qHTS of alpha-syn Inhibitors. (Class of assay: confirmatory)	PubChem BioAssay data set

Cellosaurus cell lines

174 cell lines: 130 induced pluripotent stem cell, 13 transformed cell line, 13 embryonic stem cell, 8 cancer cell line, 8 finite cell line, 2 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_9S12	ESi039-A	Induced pluripotent stem cell	Male
CVCL_A1XP	EDi001-B-1	Induced pluripotent stem cell	Female
CVCL_A1XQ	EDi001-B-2	Induced pluripotent stem cell	Female
CVCL_A1XR	EDi001-B-3	Induced pluripotent stem cell	Female
CVCL_A1XS	EDi001-B-4	Induced pluripotent stem cell	Female
CVCL_A4QU	Trpl8	Induced pluripotent stem cell	Male
CVCL_A4QV	Trpl17	Induced pluripotent stem cell	Male
CVCL_A4QW	Trpl43	Induced pluripotent stem cell	Male
CVCL_A7QJ	SHSY-5Y Tet-On SNCA	Cancer cell line	Female
CVCL_A8LW	LCSBi003-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00030979	PHASE4	COMPLETED	Donepezil to Treat Dementia in Parkinson’s Disease
NCT00043849	PHASE4	COMPLETED	Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP)
NCT00095810	PHASE4	COMPLETED	Aripiprazole in Patients With Psychosis Associated With Parkinson’s Disease
NCT00125567	PHASE4	COMPLETED	Stalevo in Early Wearing-Off Patients
NCT00143026	PHASE4	COMPLETED	Study to Compare the Effect of Treatment With Carbidopa/Levodopa/Entacapone on the Quality of Life of Patients With Parkinson’s Disease. This Study is Not Recruiting in the United States
NCT00144300	PHASE4	COMPLETED	Ophthalmologic Safety Study of Pramipexole Immediate Release (IR) Versus Ropinirole in Early Parkinson’s Disease (PD) Patients
NCT00153972	PHASE4	COMPLETED	Dopamine Turnover Rate as Surrogate Parameter for Diagnosis of Early Parkinson’s Disease
NCT00174239	PHASE4	TERMINATED	Study Of Cabaser and Sinemet CR For The Treatment Of Nighttime Symptoms Associated With Parkinson’s Disease.
NCT00215904	PHASE4	COMPLETED	D-serine Adjuvant Treatment for Parkinson’s Disease
NCT00247247	PHASE4	COMPLETED	Comtess® Versus Cabaseril® as Add-on to Levodopa in the Treatment of Parkinsonian Patients Suffering From Wearing- Off.
NCT00272688	PHASE4	COMPLETED	Continuous Delivery of Levodopa in Patients With Advanced Idiopathic Parkinsons Disease - Cost-benefit
NCT00297778	PHASE4	COMPLETED	Pramipexole Versus Placebo in Parkinson’s Disease (PD) Patients With Depressive Symptoms
NCT00304161	PHASE4	COMPLETED	Effectiveness of Antidepressant Treatment for Depression in People With Parkinson’s Disease
NCT00307450	PHASE4	COMPLETED	Efficacy and Safety of Levetiracetam Versus Placebo on Levodopa-induced Dyskinesias in Advanced Parkinson’s Disease
NCT00321854	PHASE4	COMPLETED	Study of (Mirapex) Pramipexole for the Early Treatment of Parkinsons Disease (PD)
NCT00354133	PHASE4	UNKNOWN	Controlled Trial With Deep Brain Stimulation in Patients With Early Parkinson’s Disease
NCT00373087	PHASE4	COMPLETED	COMT Polymorphism and Entacapone Efficacy
NCT00391898	PHASE4	COMPLETED	Efficacy of Levodopa/Carbidopa/Entacapone vs Levodopa/Carbidopa in Parkinson’s Disease Patients With Early Wearing-off
NCT00399477	PHASE4	COMPLETED	A Non-Blinded Study Demonstrating the Effectiveness and Safety of Azilect Alone or in Combination Therapy in Parkinson’s Disease
NCT00402233	PHASE4	COMPLETED	A Randomized, Double-blind, Active (Pramipexole 0.5 mg Tid) and Placebo Controlled, Study of Pramipexole Given 0.5 mg and 0.75 mg Bid Over 12-week Treatment in Early Parkinson’s Disease (PD) Patients
NCT00437125	PHASE4	COMPLETED	Study on the Tolerability of Duloxetine in Depressed Patients With Parkinson’s Disease
NCT00443872	PHASE4	COMPLETED	Efficacy of Orally Disintegrating Selegiline in Parkinson’s Patients Experiencing Adverse Effects With Dopamine Agonists
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00462007	PHASE4	COMPLETED	Study to Evaluate Initiation of Stalevo in Early Wearing-off
NCT00462254	PHASE4	TERMINATED	Ramelteon (ROZEREM) in the Treatment of Sleep Disturbances Associated With Parkinson’s Disease
NCT00477802	PHASE4	TERMINATED	Botulinum Toxin Type A (Botox) in the Management of Levodopa-Induced Peak-Dose Dyskinesias in Parkinson’s Disease
NCT00485069	PHASE4	COMPLETED	REQUIP (Ropinirole Hydrochloride) IR Long-Term Phase 4 Study
NCT00489255	PHASE4	COMPLETED	Safety/Efficacy of Tigan® to Control Nausea/Vomiting Experienced During Apokyn® Initiation and Treatment
NCT00526630	PHASE4	COMPLETED	Methylphenidate for the Treatment of Gait Impairment in Parkinson’s Disease
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT00571285	PHASE4	TERMINATED	Clinical Effects of Vitamin D Repletion in Patients With Parkinson’s Disease
NCT00584025	PHASE4	WITHDRAWN	Keppra IV for the Treatment of Motor Fluctuations in Parkinson’s Disease
NCT00584090	PHASE4	WITHDRAWN	Solifenacin Succinate (VESIcare) for the Treatment of Urinary Incontinence in Parkinson’s Disease
NCT00590122	PHASE4	COMPLETED	Parcopa Versus Carbidopa-levodopa in a Single Dose Cross-over Comparison Study
NCT00594464	PHASE4	COMPLETED	A Trial of Neupro® (Rotigotine Transdermal Patch) in Patients With Parkinson’s Disease Undergoing Surgery
NCT00601978	PHASE4	WITHDRAWN	Carbidopa/Levodopa Versus Carbidopa/Levodopa/Entacapone on Markers of Event Related Potentials (ERPs) in Patients With Idiopathic Parkinson’s Disease (PD) and End-of-dose Wearing Off
NCT00632762	PHASE4	COMPLETED	Long-Term Effects of Amantadine in Parkinsonian (AMANDYSK)
NCT00640159	PHASE4	COMPLETED	Selegiline to Zelapar Switch Study in Parkinson Disease Patients
NCT00642356	PHASE4	TERMINATED	Carbidopa/Levodopa/Entacapone Versus Immediate Release (IR) Carbidopa/Levodopa on Non-motor Symptoms in Patients With Idiopathic Parkinson’s Disease and Demonstrating Non-motor Symptoms of Wearing Off
NCT00646204	PHASE4	COMPLETED	Namenda (Memantine) for Non-motor Symptoms in Parkinson’s Disease