CFD

Summary

CFD (complement factor D, HGNC:2771) is a protein-coding gene on chromosome 19p13.3, encoding Complement factor D (P00746). Serine protease that initiates the alternative pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system.

This gene encodes a member of the S1, or chymotrypsin, family of serine peptidases. This protease catalyzes the cleavage of factor B, the rate-limiting step of the alternative pathway of complement activation. This protein also functions as an adipokine, a cell signaling protein secreted by adipocytes, which regulates insulin secretion in mice. Mutations in this gene underlie complement factor D deficiency, which is associated with recurrent bacterial meningitis infections in human patients. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate the mature protease.

Source: NCBI Gene 1675 — RefSeq curated summary.

At a glance

• Gene–disease (curated): recurrent Neisseria infections due to factor D deficiency (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 341 total — 9 pathogenic, 10 likely-pathogenic (top 10% of genes corpus-wide)
• GTEx eGene: eQTL in 32 tissues, sQTL in 3 (q < 0.05)
• Phenotypes (HPO): 3
• Drug target: yes — 2 curated mechanism-of-action drugs; 1 molecules with ChEMBL bioactivity
• Approved drugs (ChEMBL mechanism of action): 1 — Danicopan
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.95 (unconstrained)
• MANE Select transcript: NM_001928

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2771
Approved symbol	CFD
Name	complement factor D
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	ADN
Ensembl gene	ENSG00000197766
Ensembl biotype	protein_coding
OMIM	134350
Entrez	1675

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

MANE Select: ENST00000327726

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

ENST00000327726, ENST00000592860, ENST00000695942, ENST00000695943, ENST00000695944, ENST00000695945, ENST00000695946, ENST00000866187, ENST00000965842, ENST00001123575, ENST00001123576

RefSeq mRNA: 2 — MANE Select: NM_001928 NM_001317335, NM_001928

CCDS: CCDS12046, CCDS82261

Canonical transcript exons

ENST00000327726 — 5 exons

Exon	Start	End
ENSE00001231555	860861	861005
ENSE00001374327	861699	861956
ENSE00003965553	863092	863641
ENSE00003965554	860617	860773
ENSE00003965558	859664	859744

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 99.71.

FANTOM5 (CAGE): breadth broad, TPM avg 134.2784 / max 8799.6452, expressed in 870 samples.

Highest expression (Bgee): subcutaneous adipose tissue, adipose tissue, mucosa of stomach, omental fat pad, coronary artery.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CFD is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 32 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 35 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	7.2e-160	+1.08	19:859368:G:T
Spleen	eqtl	4.4e-37	+0.87	19:859368:G:T
Cells EBV-transformed lymphocytes	eqtl	2.3e-20	-0.65	19:860852:G:C
Muscle Skeletal	eqtl	2.4e-18	-0.27	19:859368:G:T
Esophagus Muscularis	eqtl	3.0e-10	-0.24	19:859368:G:T
Adipose Visceral Omentum	eqtl	1.0e-09	-0.26	19:859368:G:T
Thyroid	eqtl	2.1e-09	-0.32	19:850574:G:A
Heart Left Ventricle	eqtl	5.2e-09	-0.20	19:859368:G:T
Lung	eqtl	6.2e-09	+0.24	19:859368:G:T
Esophagus Gastroesophageal Junction	eqtl	4.6e-08	-0.24	19:859368:G:T
Brain Cerebellar Hemisphere	eqtl	1.0e-07	+0.81	19:864181:G:A
Brain Frontal Cortex BA9	eqtl	1.1e-07	-0.54	19:887226:G:T
Cells Cultured fibroblasts	eqtl	1.8e-07	-0.13	19:859831:T:G
Artery Tibial	eqtl	4.7e-07	+0.16	19:850793:T:A
Brain Cortex	eqtl	5.5e-07	-0.54	19:869198:C:T
Brain Caudate basal ganglia	eqtl	1.1e-06	-0.42	19:869198:C:T
Adipose Subcutaneous	eqtl	2.0e-06	-0.16	19:859368:G:T
Brain Nucleus accumbens basal ganglia	eqtl	3.4e-06	-0.43	19:871222:G:A
Brain Putamen basal ganglia	eqtl	7.5e-06	-0.46	19:869198:C:T
Brain Cerebellum	eqtl	8.8e-06	+0.86	19:871604:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
172800	133.8404	868
172799	0.4380	168

Top tissues by expression

showing 100 of 133 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
subcutaneous adipose tissue	UBERON:0002190	99.71	gold quality
adipose tissue	UBERON:0001013	99.64	gold quality
mucosa of stomach	UBERON:0001199	99.63	gold quality
omental fat pad	UBERON:0010414	99.60	gold quality
right coronary artery	UBERON:0001625	99.52	gold quality
right atrium auricular region	UBERON:0006631	99.44	gold quality
apex of heart	UBERON:0002098	99.24	gold quality
vagina	UBERON:0000996	99.23	gold quality
tibial nerve	UBERON:0001323	99.23	gold quality
right lung	UBERON:0002167	99.23	gold quality
left coronary artery	UBERON:0001626	99.19	gold quality
fundus of stomach	UBERON:0001160	99.17	gold quality
endocervix	UBERON:0000458	99.12	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.04	gold quality
skin of abdomen	UBERON:0001416	98.99	gold quality
ectocervix	UBERON:0012249	98.94	gold quality
skin of leg	UBERON:0001511	98.91	gold quality
left uterine tube	UBERON:0001303	98.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.77	gold quality
lower esophagus	UBERON:0013473	98.75	gold quality
zone of skin	UBERON:0000014	98.64	gold quality
right lobe of thyroid gland	UBERON:0001119	98.59	gold quality
thoracic mammary gland	UBERON:0005200	98.55	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.15	gold quality
heart left ventricle	UBERON:0002084	98.02	gold quality
left lobe of thyroid gland	UBERON:0001120	97.92	gold quality
popliteal artery	UBERON:0002250	97.92	gold quality
tibial artery	UBERON:0007610	97.92	gold quality
transverse colon	UBERON:0001157	97.87	gold quality
upper lobe of left lung	UBERON:0008952	97.81	gold quality
granulocyte	CL:0000094	97.77	gold quality
minor salivary gland	UBERON:0001830	97.65	gold quality
leukocyte	CL:0000738	97.64	gold quality
monocyte	CL:0000576	97.61	gold quality
mucosa of transverse colon	UBERON:0004991	97.41	gold quality
esophagus	UBERON:0001043	97.19	gold quality
saliva-secreting gland	UBERON:0001044	97.17	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.10	gold quality
lower esophagus mucosa	UBERON:0035834	96.97	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.93	gold quality
small intestine	UBERON:0002108	96.77	gold quality
colon	UBERON:0001155	96.64	gold quality
thyroid gland	UBERON:0002046	96.63	gold quality
body of stomach	UBERON:0001161	96.43	gold quality
heart	UBERON:0000948	96.40	gold quality
gastrocnemius	UBERON:0001388	96.38	gold quality
uterine cervix	UBERON:0000002	96.34	gold quality
calcaneal tendon	UBERON:0003701	96.34	gold quality
esophagus mucosa	UBERON:0002469	96.23	gold quality
blood	UBERON:0000178	95.95	gold quality
prostate gland	UBERON:0002367	95.92	gold quality
muscle of leg	UBERON:0001383	95.90	gold quality
ascending aorta	UBERON:0001496	95.70	gold quality
thoracic aorta	UBERON:0001515	95.55	gold quality
intestine	UBERON:0000160	95.52	gold quality
skeletal muscle tissue	UBERON:0001134	93.63	gold quality
stomach	UBERON:0000945	93.59	gold quality
urinary bladder	UBERON:0001255	93.10	gold quality
lung	UBERON:0002048	93.10	gold quality
colonic epithelium	UBERON:0000397	92.85	gold quality
placenta	UBERON:0001987	92.79	gold quality
descending thoracic aorta	UBERON:0002345	92.04	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.86	gold quality
duodenum	UBERON:0002114	91.79	gold quality
right ovary	UBERON:0002118	89.55	gold quality
multicellular organism	UBERON:0000468	89.48	gold quality
muscle tissue	UBERON:0002385	89.30	gold quality
left ovary	UBERON:0002119	89.14	gold quality
left testis	UBERON:0004533	89.06	gold quality
myometrium	UBERON:0001296	88.95	gold quality
right adrenal gland cortex	UBERON:0035827	88.72	gold quality
testis	UBERON:0000473	88.54	gold quality
sural nerve	UBERON:0015488	87.74	gold quality
body of pancreas	UBERON:0001150	87.66	gold quality
right testis	UBERON:0004534	87.44	gold quality
ovary	UBERON:0000992	86.73	gold quality
left adrenal gland	UBERON:0001234	86.69	gold quality
left adrenal gland cortex	UBERON:0035825	86.64	gold quality
spleen	UBERON:0002106	86.27	gold quality
body of uterus	UBERON:0009853	86.08	gold quality
metanephros cortex	UBERON:0010533	85.71	gold quality
right adrenal gland	UBERON:0001233	84.79	gold quality
fallopian tube	UBERON:0003889	84.76	gold quality
right uterine tube	UBERON:0001302	84.49	gold quality
adrenal gland	UBERON:0002369	83.10	gold quality
bone marrow cell	CL:0002092	83.09	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.80	gold quality
bone marrow	UBERON:0002371	82.36	gold quality
rectum	UBERON:0001052	81.10	gold quality
vermiform appendix	UBERON:0001154	79.76	gold quality
cortex of kidney	UBERON:0001225	79.39	gold quality
adult mammalian kidney	UBERON:0000082	78.36	gold quality
gall bladder	UBERON:0002110	78.04	gold quality
tonsil	UBERON:0002372	76.88	gold quality
pancreas	UBERON:0001264	76.87	gold quality
right lobe of liver	UBERON:0001114	75.85	gold quality
liver	UBERON:0002107	75.63	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	75.37	gold quality
pituitary gland	UBERON:0000007	74.96	gold quality
kidney	UBERON:0002113	74.41	gold quality

Single-cell (SCXA)

Detected in 39 experiment(s), a significant marker in 37.

Experiment	Marker?	Max mean expression
E-HCAD-36	yes	15088.57
E-MTAB-8322	yes	13487.77
E-MTAB-8410	yes	12995.91
E-MTAB-8495	yes	10336.81
E-CURD-126	yes	8539.47
E-CURD-79	yes	8083.20
E-MTAB-9543	yes	6775.69
E-GEOD-124263	yes	4803.22
E-HCAD-11	yes	4276.19
E-MTAB-6701	yes	3667.85
E-HCAD-4	yes	3565.47
E-GEOD-134144	yes	2317.58
E-MTAB-8142	yes	2293.72
E-HCAD-24	yes	1708.64
E-MTAB-8884	yes	1239.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 74 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Vagina	tissue	700.8
Adipose tissue	tissue	462.0
Skeletal muscle	tissue	99.8
Breast	tissue	89.1
Skin 1	tissue	60.9
Small intestine	tissue	57.9
Colon	tissue	55.1
Cervix	tissue	48.9
Salivary gland	tissue	47.3
Urinary bladder	tissue	43.6
Lung	tissue	42.4
Spinal cord	tissue	39.9
Duodenum	tissue	36.8
Prostate	tissue	33.6
Tongue	tissue	32.6
Heart muscle	tissue	24.8
Placenta	tissue	24.3
Stomach 1	tissue	23.5
Bone marrow	tissue	20.6
Substantia nigra	tissue	19.4
Medulla oblongata	tissue	16.6
Pons	tissue	15.6
Superior colliculi	tissue	15.5
Corpus callosum	tissue	15.4
Midbrain	tissue	14.7
Adrenal gland	tissue	14.6
Testis	tissue	13.6
Appendix	tissue	13.5
Rectum	tissue	13.4
Hypothalamus	tissue	13.2
Esophagus	tissue	12.5
Thalamus	tissue	12.5
Periaqueductal gray	tissue	12.5
Choroid plexus	tissue	12.2
Pancreas	tissue	12.0
Gallbladder	tissue	11.4
Septum	tissue	11.2
Putamen	tissue	9.8
Ventral forebrain	tissue	9.6
Locus coeruleus	tissue	9.5
Hippocampus	tissue	9.4
Seminal vesicle	tissue	8.8
Nucleus accumbens	tissue	8.8
Spleen	tissue	8.4
Pituitary gland	tissue	8.3
Hippocampal formation	tissue	8.3
Basal ganglia	tissue	8.2
Cerebellum	tissue	7.9
Amygdala	tissue	7.8
Cerebral cortex	tissue	7.4
Motor cortex	tissue	7.4
Entorhinal cortex	tissue	7.4
Insular cortex	tissue	7.4
Postcentral gyrus	tissue	7.2
Olfactory bulb	tissue	7.1
Temporal cortex	tissue	7.1
Retrosplenial and cingulate cortex	tissue	6.6
Retrosplenial cortex	tissue	6.6
Prefrontal cortex	tissue	6.5
Somatosensory cortex	tissue	6.2

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Blood vessel (630.3), Dorsal spinal cord (39.9), Ventral spinal cord (23.4), Lateral funiculus (white matter) (17.2), White matter (15.4).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HES1, IFI16, PPARG, TFAP2A, TSC22D3

miRNA regulators (miRDB)

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

8 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-7158-5P	99.25	67.95	796
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-3674	97.01	68.86	1171
HSA-MIR-3907	96.76	65.04	662
HSA-MIR-3193	92.99	64.93	116
HSA-MIR-4707-3P	86.55	62.02	99

Functional genomics

gnomAD constraint: pLI 2.43e-12, LOEUF 1.95, missense Z -4.96 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000327726 — one region, missense o/e 1.40. ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 38)

• As adiponectin and adipsin levels in CSF did not correlate with their levels in plasma, it seems that there could be a secondary intrathecal synthesis of these adipocytokines in multiple sclerosis (PMID:19538214)
• increased serum levels in patients with seasonal allergic rhinitis (PMID:19699327)
• CFD may not play a major role in the genetic susceptibility to age-related macular degeneration. (PMID:21139680)
• crystal structure of C3bB at 4 A and complex with factor D at 3.5 A; data show how factor B binding to C3b forms open “activation” state of C3bB; Factor D binds open conformation of factor B through a site distant from the catalytic center (PMID:21205667)
• CFD regulates activation of the alternative complement pathway, which is implicated in age related macular degeneration pathogenesis. (PMID:22003108)
• Anti factor D Fab fragment inhibits FD proteolytic function by interfering with macromolecular substrate access rather than by inhibiting FD catalysis. (PMID:22362762)
• Increased activation of the alternative complement pathway in vitreous was controlled by disease stage and genetic variation in the complement pathway, supporting a role for complement activation in macular degeneration disease pathogenesis. (PMID:22930722)
• We demonstrate novel secretion of adipsin and ASP by placental Hofbauer cells. (PMID:23956345)
• Complement factor D (FD) is activated by its substrate through interactions outside the active site which lock the unbound native state into an ordered inactive conformation via the self-inhibitory loop in FD. (PMID:24598742)
• Data indicate that a urinary protein, adipsin, was significantly increased in patients with preeclampsia. (PMID:24958499)
• Study demonstrates that T2DM patients with beta cell failure are deficient in adipsin. (PMID:24995977)
• Overall adipsin levels among male asbestos industry workers were significantly higher than among control subjects. (PMID:25840635)
• our findings set up a novel mechanism for FABP4, adipsin and adiponectin through gut microbiota mediating expression in gut Paneth cells. (PMID:26687459)
• MASP-3 is the exclusive pro-factor D activator in resting blood: the lectin and the alternative complement pathways are fundamentally linked. (PMID:27535802)
• The strong association of PLIN1, CFD and ADIPOQ genes with adipogenesis prompted authors to study the influence the bone health status as evaluated by quantitative ultrasound (QUS) bone densitometer in a North Indian cohort. Overall, ADIPOQ (rs1501299 and rs3774261) and combined cluster of PLIN1 rs2304796 and rs2304795) and CFD (rs1683563) demonstrated correlation. (PMID:28189761)
• TZDs (pioglitazone, rosiglitazone, and ciglitazone) slow tumor cell growth in vitro and in vivo with decreases in cell proliferation and increases in PPARg and adipsin (PMID:28219679)
• disturbance of reciprocal relationships between adipsin and leptin in obesity is associated with the development of insulin resistance (PMID:28864895)
• The results suggested that elevated IL-17A and IL-9 expressions and decreased levels of adipsin and CCL11 were positively associated with adult asthma. (PMID:29138487)
• increased circulating levels of adipsin and decreased circulating levels of visfatin and adiponectin were independently associated with the increased risk of nonalcoholic fatty liver disease (PMID:30541001)
• Senescent dermal fibroblasts negatively influence fibroblast extracellular matrix-related gene expression (such as MMP1) partly via secretion of complement factor D. (PMID:31026383)
• High plasma adipsin levels are associated with mild cognitive impairment. (PMID:31651303)
• these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes. (PMID:31700183)
• Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. (PMID:32877502)
• The function of adipsin and C9 protein in the complement system in HIV-associated preeclampsia. (PMID:33881585)
• Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells. (PMID:34155972)
• Complement Factor D (adipsin) Levels Are Elevated in Acquired Partial Lipodystrophy (Barraquer-Simons syndrome). (PMID:34205507)
• Long-term physical activity modulates adipsin and ANGPTL4 serum levels, a potential link to exercise-induced metabolic changes. (PMID:34309331)
• Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway. (PMID:34566967)
• Adipsin Serum Concentrations and Adipose Tissue Expression in People with Obesity and Type 2 Diabetes. (PMID:35216336)
• Plasma and aqueous levels of alarin and adipsin in patients with and without diabetic retinopathy. (PMID:35436912)
• Complement factor D as a predictor of Achilles tendon healing and long-term patient outcomes. (PMID:35596679)
• Elevated Adipsin and Reduced C5a Levels in the Maternal Serum and Follicular Fluid During Implantation Are Associated With Successful Pregnancy in Obese Women. (PMID:35909516)
• Serum and salivary adipsin levels and its association with insulin resistance in acne vulgaris patients. (PMID:36459421)
• The Role of Adipsin, Complement Factor D, in the Pathogenesis of Graves’ Orbitopathy. (PMID:37555734)
• Complement factor D regulates collagen type I expression and fibroblast migration to enhance human tendon repair and healing outcomes. (PMID:37744351)
• Adipsin in the pathogenesis of cardiovascular diseases. (PMID:38114042)
• Combinatorial Inhibition of Complement Factor D and BCL2 for Early-Onset Colorectal Cancer. (PMID:38479005)
• Adipose tissue-derived adipsin marks human aging in non-type 2 diabetes population. (PMID:39209774)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cfd	ENSDARG00000039579
mus_musculus	Cfd	ENSMUSG00000061780
rattus_norvegicus	Cfd	ENSRNOG00000033564

Paralogs (16): F7 (ENSG00000057593), F11 (ENSG00000088926), F9 (ENSG00000101981), HGFAC (ENSG00000109758), F10 (ENSG00000126218), KLK10 (ENSG00000129451), F12 (ENSG00000131187), C1RL (ENSG00000139178), C1R (ENSG00000159403), KLKB1 (ENSG00000164344), C1S (ENSG00000182326), PRSS55 (ENSG00000184647), CFI (ENSG00000205403), PRSS51 (ENSG00000253649), HP (ENSG00000257017), HPR (ENSG00000261701)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:87931) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
impaired complement alternative pathway	2
abnormal adrenal gland morphology	1
abnormal kidney morphology	1
increased susceptibility to bacterial infection	1
abnormal caudal vertebrae morphology	1
small adrenal glands	1
small kidney	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Papio hamadryas	P52195	98.8%	Diamond
Macaca fascicularis	P56435	98.8%	Diamond
Ovis aries	O46683	90.2%	Diamond
Meriones unguiculatus	P50341	87.0%	Diamond
Sus scrofa	P51779	86.9%	Diamond
Bos taurus	Q3T0A3	86.9%	Diamond
Canis lupus familiaris	P21842	83.2%	Diamond
Xenopus laevis	Q63ZK0	82.6%	Diamond
Xenopus tropicalis	Q6P326	82.6%	Diamond
Equus caballus	P37357	81.5%	Diamond
Cavia porcellus	A7WPL7	77.7%	Diamond
Oryctolagus cuniculus	P85202	70.0%	Diamond
Drosophila melanogaster	A8JUP7	65.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
RNU6-9	snRNA	101954271
ELANE	protein-coding	1991
R3HDM4	protein-coding	91300
MED16	protein-coding	10025
KISS1R	protein-coding	84634
PRTN3	protein-coding	5657
AZU1	protein-coding	566
MIR3187	ncRNA	100422854
PLPPR3	protein-coding	79948

Protein

Protein identifiers

Complement factor D — P00746 (reviewed: P00746)

Alternative names: Adipsin, C3 convertase activator, Properdin factor D

All UniProt accessions (5): A0A8Q3WKV6, A0A8Q3WKW0, A0A8Q3WLE6, P00746, K7ERG9

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease that initiates the alternative pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system. In contrast to other complement pathways (classical, lectin and GZMK) that are directly activated by pathogens or antigen-antibody complexes, the alternative complement pathway is initiated by the spontaneous hydrolysis of complement C3. The alternative complement pathway acts as an amplification loop that enhances complement activation by mediating the formation of C3 and C5 convertases. Activated CFD cleaves factor B (CFB) when the latter is complexed with complement C3b, activating the C3 convertase of the alternative pathway.

Subcellular location. Secreted.

Post-translational modifications. CFD is activated by the removal of 5 residues at the N-terminus, named activation peptide, by the MASP-3 isoform of MASP1.

Disease relevance. Complement factor D deficiency (CFDD) [MIM:613912] An immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Circulates in plasma in a mature but self-inhibited form. Activated by factor B (CFB), which displaces the self-inhibition loop. Associates with CFB complexed with complement C3b. Specifically inhibited by anti-factor D Fab fragment (AFD) antibody.

Domain organisation. The self-inhibition loop inhibits the serine protease activity in absence of factor B (CFB) substrate.

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (2): NP_001304264, NP_001919* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR043504

Pfam: PF00089

Enzyme classification (BRENDA)

• EC 3.4.21.46 — complement factor D (BRENDA: 9 organisms, 37 substrates, 121 inhibitors, 8 Km, 8 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BENZYLOXYCARBONYL-LYS-THIOBENZYL ESTER	2.95–11.44	8

UniProt features (72 total): strand 19, sequence conflict 18, helix 9, mutagenesis site 6, disulfide bond 4, turn 4, sequence variant 3, active site 3, signal peptide 1, propeptide 1, chain 1, domain 1, region of interest 1, site 1

Structure

Experimental structures (PDB)

showing 30 of 40 structures by resolution:

PDB	Title	Method	Resolution (Å)
5NAT	Complement factor D in complex with the inhibitor (S)-Pyrrolidine-1,2-dicarboxylic acid …	X-RAY DIFFRACTION	1.17
2XW9	Crystal Structure of Complement Factor D mutant S183A	X-RAY DIFFRACTION	1.2
5NAW	Complement factor D in complex with the inhibitor …	X-RAY DIFFRACTION	1.25
5MT0	COMPLEMENT FACTOR D IN COMPLEX WITH A REVERSIBLE INDOLE CARBOXYLIC ACID BASED INHIBITOR	X-RAY DIFFRACTION	1.29
5NB7	Complement factor D	X-RAY DIFFRACTION	1.33
6FUH	Complement factor D in complex with the inhibitor …	X-RAY DIFFRACTION	1.37
6FUI	Complement factor D in complex with the inhibitor …	X-RAY DIFFRACTION	1.38
5FBE	COMPLEMENT FACTOR D IN COMPLEX WITH COMPOUND2	X-RAY DIFFRACTION	1.43
5FBI	COMPLEMENT FACTOR D IN COMPLEX WITH COMPOUND 3b	X-RAY DIFFRACTION	1.47
1BIO	HUMAN COMPLEMENT FACTOR D IN COMPLEX WITH ISATOIC ANHYDRIDE INHIBITOR	X-RAY DIFFRACTION	1.5
6FUT	Complement factor D in complex with the inhibitor …	X-RAY DIFFRACTION	1.5
5NAR	Complement factor D in complex with the inhibitor (S)-pyrrolidine-1,2-dicarboxylic acid …	X-RAY DIFFRACTION	1.55
5MT4	COMPLEMENT FACTOR D IN COMPLEX WITH A REVERSIBLE BENZOIC ACID BASED INHIBITOR	X-RAY DIFFRACTION	1.65
6FTY	COMPLEMENT FACTOR D COMPLEXED WITH COMPOUND 5	X-RAY DIFFRACTION	1.67
6FTZ	COMPLEMENT FACTOR D COMPLEXED WITH COMPOUND 6	X-RAY DIFFRACTION	1.67
5NB6	Complement factor D in complex with the inhibitor …	X-RAY DIFFRACTION	1.75
1DIC	STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D	X-RAY DIFFRACTION	1.8
4CBN	Crystal structure of Complement Factor D mutant R202A after conventional refinement	X-RAY DIFFRACTION	1.8
4CBO	Crystal structure of Complement Factor D mutant R202A after ensemble refinement	X-RAY DIFFRACTION	1.8
6QMT	Complement factor D in complex with the inhibitor …	X-RAY DIFFRACTION	1.8
5FCK	COMPLEMENT FACTOR D IN COMPLEX WITH COMPOUND 5	X-RAY DIFFRACTION	1.86
5NBA	Complement factor D in complex with the inhibitor …	X-RAY DIFFRACTION	1.87
8DG6	Scaffold Hopping via Ring Opening Enables Identification of Acyclic Compounds as New …	X-RAY DIFFRACTION	1.99
1DST	MUTANT OF FACTOR D WITH ENHANCED CATALYTIC ACTIVITY	X-RAY DIFFRACTION	2
1DSU	HUMAN FACTOR D, COMPLEMENT ACTIVATING ENZYME	X-RAY DIFFRACTION	2
6QMR	Complement factor D in complex with the inhibitor …	X-RAY DIFFRACTION	2
1FDP	PROENZYME OF HUMAN COMPLEMENT FACTOR D, RECOMBINANT PROFACTOR D	X-RAY DIFFRACTION	2.1
8D95	Scaffold Hopping via Ring Opening Enables Identification of Acyclic Compounds as New …	X-RAY DIFFRACTION	2.17
6FUG	Complement factor D in complex with the inhibitor …	X-RAY DIFFRACTION	2.21
8DEA	Scaffold Hopping via Ring Opening Enables Identification of Acyclic Compounds as New …	X-RAY DIFFRACTION	2.21

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00746-F1	91.19	0.80

Antibody-complex structures (SAbDab)

3 antibodies co-crystallized with this protein: 4D9R, 6VMJ, 6VMK

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Serine-type peptidases, Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes, Primary immunodeficiency

Protein evidence: Evidence at protein level

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)

Position	Role
66	charge relay system
114	charge relay system
208	charge relay system
25–26	cleavage; by masp-3 isoform of masp1

Disulfide bonds (4)

Type	Positions
Disulfide bond	148–214, 179–195, 204–229, 51–67

Mutagenesis-validated functional residues (6)

Position	Phenotype
158	abolished ability to cleave cfb.
182	abolished ability to cleave cfb.
208	abolished serine endopeptidase activity.
227	increased serine endopeptidase activity in absence of cfb, while decreased ability to cleave cfb.
227	abolished ability to cleave cfb.
228	abolished ability to cleave cfb.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 10; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

10 pathways:

ID	Pathway	Evidence
R-HSA-173736	Alternative complement activation	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-114608	Platelet degranulation	curated
R-HSA-166658	Complement cascade	—
R-HSA-109582	Hemostasis	—
R-HSA-168256	Immune System	—
R-HSA-166663	Initial triggering of complement	—
R-HSA-168249	Innate Immune System	—
R-HSA-76002	Platelet activation, signaling and aggregation	—
R-HSA-76005	Response to elevated platelet cytosolic Ca2+	—

MSigDB gene sets: 268 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, MCLACHLAN_DENTAL_CARIES_UP, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, MODULE_45, HUMMERICH_BENIGN_SKIN_TUMOR_DN, HUMMERICH_MALIGNANT_SKIN_TUMOR_DN, GOBP_VASCULAR_ASSOCIATED_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, MODULE_16, YORDY_RECIPROCAL_REGULATION_BY_ETS1_AND_SP100_DN, MARTINEZ_RB1_TARGETS_UP, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_COMPLEMENT_ACTIVATION

GO Biological Process (7): proteolysis (GO:0006508), complement activation (GO:0006956), complement activation, alternative pathway (GO:0006957), zymogen activation (GO:0031638), protein maturation (GO:0051604), immune system process (GO:0002376), innate immune response (GO:0045087)

GO Molecular Function (4): serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (5): extracellular region (GO:0005576), platelet alpha granule lumen (GO:0031093), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

7 top-level categories:

Category	Pathways
Innate Immune System	2
Response to elevated platelet cytosolic Ca2+	1
Initial triggering of complement	1
Complement cascade	1
Immune System	1
Hemostasis	1
Platelet activation, signaling and aggregation	1

GO top-level categories

27 GO namespaces:

Category	Terms
protein metabolic process	2
immune effector process	1
activation of immune response	1
humoral immune response	1
protein activation cascade	1
complement activation	1
innate immune response	1
protein processing	1
gene expression	1
biological_process	1
immune response	1
defense response to symbiont	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cellular anatomical structure	1
platelet alpha granule	1
secretory granule lumen	1
secretory granule	1
cytoplasmic vesicle lumen	1
extracellular vesicle	1
intracellular organelle lumen	1
ficolin-1-rich granule	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 17 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
complement activation, alternative pathway	BP	direct assay
zymogen activation	BP	direct assay
extracellular exosome	CC	high-throughput assay
serine-type endopeptidase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,363 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CFD	RETN	Q9HD89	862
CFD	ADIPOQ	Q15848	851
CFD	CFP	P27918	762
CFD	C3	P01024	742
CFD	RETNLB	Q9BQ08	719
CFD	LEP	P41159	718
CFD	NAMPT	P43490	606
CFD	FABP4	P15090	593
CFD	PPARG	P37231	593
CFD	PCSK4	Q6UW60	584
CFD	CFB	P00751	581
CFD	PCSK6	P29122	571
CFD	INS	P01308	570
CFD	CD36	P16671	567
CFD	SCARB2	Q14108	552

IntAct

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

1 partners by confidence:

Partner	Interaction type	MIscore	Records
CFHR4	physical association	0.400	1

BioGRID (5 interactions; top human partners by supporting records): ALB (Affinity Capture-MS), DDX24 (Affinity Capture-MS), GZMM (Negative Genetic), HNRNPH1 (Affinity Capture-RNA), SERPINF2 (Reconstituted Complex)

SIGNOR signaling

showing 1 of 2 signaling interactions:

A	Effect	B	Mechanism
CFD	“up-regulates activity”	CFB	cleavage

Disease & clinical

Genetic variants

Variant evidence for CFD: 341 ClinVar records (19 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	10
Uncertain significance	173
Likely benign	132
Benign	4

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 19 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
16745	NM_001972.4(ELANE):c.377C>T (p.Ser126Leu)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
939547	NM_001972.4(ELANE):c.607G>C (p.Gly203Arg)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1454250	NM_001928.4(CFD):c.285C>A (p.Tyr95Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
636704	NM_001928.4(CFD):c.56-1G>C	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
2417863	NM_001928.4(CFD):c.212+2T>G	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
16564	NM_001928.4(CFD):c.125C>A (p.Ser42Ter)	Pathogenic	criteria provided, single submitter	4
1412951	NM_001928.4(CFD):c.153C>A (p.Cys51Ter)	Pathogenic	criteria provided, single submitter	1
2011547	NM_001928.4(CFD):c.40G>T (p.Gly14Ter)	Pathogenic	criteria provided, single submitter	1
2900060	NM_001928.4(CFD):c.132del (p.Gln44fs)	Pathogenic	criteria provided, single submitter	1
3616379	NM_001928.4(CFD):c.444C>A (p.Cys148Ter)	Pathogenic	criteria provided, single submitter	1
4447255	NM_001928.4(CFD):c.212+1G>A	Likely pathogenic	criteria provided, single submitter	2
1961905	NM_001928.4(CFD):c.213-2A>C	Likely pathogenic	criteria provided, single submitter	1
2077091	NM_001928.4(CFD):c.358-259_461delinsCATTGA	Likely pathogenic	criteria provided, single submitter	1
3779511	NM_001928.4(CFD):c.213-1G>C	Likely pathogenic	criteria provided, single submitter	1
3779512	NM_001928.4(CFD):c.278_279dup (p.Leu94fs)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

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

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 379):

Position(s)	Effect	Δscore	Sites
19:861957–861958	donor_loss	1.0000	4
19:861006–861007	donor_loss	0.9900	5
19:861697–861698	acceptor_loss	0.9900	6
19:861958	donor_loss	0.9900
19:860774–860775	donor_loss	0.9800	4
19:861007	donor_loss	0.9800
19:863087	acceptor_gain	0.9800
19:863090–863091	acceptor_loss	0.9800	4
19:860774–860775	donor_loss	0.9700	2
19:860778	donor_loss	0.9700

AlphaMissense

545 missense substitutions predicted likely pathogenic (of 1,609 scored), across 160 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D207	8	0.980	0.993
D114	8	0.967	0.990
D202	8	0.948	0.979
H66	8	0.881	0.948
H49	8	0.813	0.930
W153	7	0.987	0.999
C148	7	0.986	0.996
C179	7	0.985	0.995
C195	7	0.978	0.995
C204	7	0.978	0.992
C229	7	0.977	0.991
C67	7	0.969	0.986
C51	7	0.967	0.989
W247	7	0.963	0.996
C214	7	0.961	0.982
W60	7	0.920	0.986
G209	6	0.969	0.991
G154	6	0.956	0.992
S63	6	0.927	0.994
G152	6	0.927	0.982

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:134350 | disease phenotypes: MIM:613912, MIM:162800, MIM:202700

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
recurrent Neisseria infections due to factor D deficiency	Strong	Autosomal recessive	2

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (2 panels, 2 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

2 panels:

Panel	Rating
COVID-19 research	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green

Mondo (3): recurrent Neisseria infections due to factor D deficiency (MONDO:0013487), cyclic neutropenia (MONDO:0008090), neutropenia, severe congenital, 1, autosomal dominant (MONDO:0042490)

Orphanet (2): Recurrent Neisseria infections due to factor D deficiency (Orphanet:169467), Cyclic neutropenia (Orphanet:2686)

HPO phenotypes

3 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0002718	Recurrent bacterial infections
HP:0008338	Partial functional complement factor D deficiency

GWAS associations

2 associations:

Study	Trait	p-value
GCST90002386_159	High light scatter reticulocyte percentage of red cells	6e-28
GCST90002405_145	Reticulocyte count	8e-25

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0007986	reticulocyte count

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
C565027	Complement Factor D Deficiency *(supp.)*
C536227	Cyclic neutropenia *(supp.)*
C565969	Neutropenia, Severe Congenital, Autosomal Dominant 1 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2176771 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CFD protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

2 curated-mechanism drugs:

Drug	Modality	Max phase
DANICOPAN	Small molecule	4
LAMPALIZUMAB	Antibody	3

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 308 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL4250860	DANICOPAN	4	308

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Complement factor D

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
lampalizumab	Binding	10.7	pKi
danicopan	Inhibition	9.0	pKd
example 373 [WO2012093101]	Inhibition	9.0	pIC50
compound 2 [PMID: 28621538]	Inhibition	8.22	pIC50

Binding affinities (BindingDB)

1750 measured of 5290 human assays (5423 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL5399926	IC50	0.4 nM
4-[(1R)-3-[4-(4-amino-8-fluoro-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-1-[(3-methyloxetan-3-yl)methylamino]-3-oxopropyl]benzonitrile	IC50	1 nM	US-9452990: Complement pathway modulators and uses thereof
(1R,3S,5R)-2-N-[1-carbamoyl-5-(cyanomethoxy)indol-3-yl]-3-N-[(3-chloro-2-fluorophenyl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	IC50	1 nM	US-9085555: Complement pathway modulators and uses thereof
CHEMBL2220483	IC50	1.6 nM
2-[1-carbamoyl-3-[[(2S,4R)-2-[(3-chloro-2-fluorophenyl)methylcarbamoyl]-4-fluoro-4-methylpyrrolidine-1-carbonyl]amino]indol-5-yl]oxyacetic acid	IC50	2 nM	US-9085555: Complement pathway modulators and uses thereof
CHEMBL3109655	IC50	2 nM
(3S)-2-N-(1-carbamoylindol-3-yl)-3-N-[(3-chloro-2-fluorophenyl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	IC50	3 nM	US-9085555: Complement pathway modulators and uses thereof
(2S,4R)-1-N-(1-carbamoyl-5-methoxyindol-3-yl)-2-N-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidine-1,2-dicarboxamide	IC50	3 nM	US-9085555: Complement pathway modulators and uses thereof
methyl 2-[1-carbamoyl-3-[[(2S,4R)-2-[(3-chloro-2-fluorophenyl)methylcarbamoyl]-4-fluoro-4-methylpyrrolidine-1-carbonyl]amino]indol-5-yl]oxyacetate	IC50	3 nM	US-9085555: Complement pathway modulators and uses thereof
(1R,3S,5R)-2-N-(1-carbamoyl-5-hydroxyindol-3-yl)-3-N-[(3-chloro-2-fluorophenyl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	IC50	3 nM	US-9085555: Complement pathway modulators and uses thereof
2-[1-carbamoyl-3-[[(1R,3S,5R)-3-[(3-chloro-2-fluorophenyl)methylcarbamoyl]-2-azabicyclo[3.1.0]hexane-2-carbonyl]amino]indol-5-yl]oxyacetic acid	IC50	3 nM	US-9085555: Complement pathway modulators and uses thereof
1-[2-[(1R,3S,5R)-3-[(3-chloro-2-fluorophenyl)methylcarbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]indazole-3-carboxamide	IC50	3 nM	US-9085555: Complement pathway modulators and uses thereof
1-[2-[(2S,3S,4S)-2-[(3-chloro-2-fluorophenyl)methylcarbamoyl]-4-fluoro-3-methoxypyrrolidin-1-yl]-2-oxoethyl]-5-ethylpyrazolo[5,4-c]pyridine-3-carboxamide	IC50	3 nM	US-9085555: Complement pathway modulators and uses thereof
1-[2-[(1R,3S,5R)-3-[(6-bromo-2-pyridinyl)carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]-5-ethylpyrazolo[5,4-c]pyridine-3-carboxamide	IC50	3 nM	US-9085555: Complement pathway modulators and uses thereof
(1R,3S,5R)-2-[2-(3-acetylindazol-1-yl)acetyl]-N-(6-bromopyrazin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide	IC50	3 nM	US-9085555: Complement pathway modulators and uses thereof
4-[(1R)-3-[4-(4-amino-8-fluoro-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-3-oxo-1-(propan-2-ylamino)propyl]benzonitrile	IC50	3 nM	US-9452990: Complement pathway modulators and uses thereof
(2R)-4-[4-(4-amino-8-fluoro-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-N-ethyl-2-(4-fluorophenyl)-4-oxobutanamide	IC50	3 nM	US-9452990: Complement pathway modulators and uses thereof
(1R,3S,5R)-2-[2-[3-acetyl-5-[(1-methyl-1,2,4-triazol-3-yl)methoxy]indazol-1-yl]acetyl]-N-[(1R)-1-[(1R)-2,2-dichlorocyclopropyl]ethyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide	IC50	3 nM	US-9468661: Pyrrolidine derivatives and their use as complement pathway modulators
(1R,3S,5R)-2-[2-[3-acetyl-5-[(5-methyl-1H-pyrazol-3-yl)methoxy]indazol-1-yl]acetyl]-N-[(1R)-1-[(1R)-2,2-dichlorocyclopropyl]ethyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide	IC50	3 nM	US-9468661: Pyrrolidine derivatives and their use as complement pathway modulators
(1R,3S,5R)-2-[2-[3-acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl]-N-[[(1S)-2,2-dichloro-3-methylcyclopropyl]methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide	IC50	3 nM	US-9468661: Pyrrolidine derivatives and their use as complement pathway modulators
tert-butyl 2-[1-carbamoyl-3-[[(1R,3S,5R)-3-[(3-chloro-2-fluorophenyl)methylcarbamoyl]-2-azabicyclo[3.1.0]hexane-2-carbonyl]amino]indol-6-yl]acetate	IC50	3 nM	US-9085555: Complement pathway modulators and uses thereof
CHEMBL3109654	IC50	3 nM
(1R,3S,5R)-2-N-(1-acetylindol-3-yl)-3-N-[(1S)-1-(3-chloro-2-fluorophenyl)-2-hydroxyethyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	IC50	4 nM	US-9085555: Complement pathway modulators and uses thereof
(3S)-2-N-(1-carbamoyl-5-methoxyindol-3-yl)-3-N-[(3-chloro-2-fluorophenyl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	IC50	4 nM	US-9085555: Complement pathway modulators and uses thereof
ethyl 2-[1-carbamoyl-3-[[(1R,3S,5R)-3-[(3-chloro-2-fluorophenyl)methylcarbamoyl]-2-azabicyclo[3.1.0]hexane-2-carbonyl]amino]indol-5-yl]acetate	IC50	4 nM	US-9085555: Complement pathway modulators and uses thereof
(2S,4R)-1-N-[1-carbamoyl-5-(2-hydroxyethoxy)indol-3-yl]-2-N-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-4-methylpyrrolidine-1,2-dicarboxamide	IC50	4 nM	US-9085555: Complement pathway modulators and uses thereof
1-[2-[(1R,3S,5R)-3-[(6-bromo-2-pyridinyl)carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]-5-methylpyrazolo[5,4-c]pyridine-3-carboxamide	IC50	4 nM	US-9085555: Complement pathway modulators and uses thereof
1-[2-[(1R,3S,5R)-3-[(6-bromo-2-pyridinyl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]indazole-3-carboxamide	IC50	4 nM	US-9085555: Complement pathway modulators and uses thereof
(1R,3S,5R)-2-[2-[3-acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl]-N-(6-bromo-2-pyridinyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide	IC50	4 nM	US-9085555: Complement pathway modulators and uses thereof
1-[2-[(1R,3S,5R)-3-[(6-bromo-2-pyridinyl)carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]-6-chloroindazole-3-carboxamide	IC50	4 nM	US-9085555: Complement pathway modulators and uses thereof
(2S,4R)-2-N-(6-bromo-2-pyridinyl)-1-N-(1-carbamoylindol-3-yl)-4-fluoropyrrolidine-1,2-dicarboxamide	IC50	4 nM	US-9085555: Complement pathway modulators and uses thereof
4-[(1R)-3-[4-(4-amino-8-fluoro-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-1-(methylamino)-3-oxopropyl]benzonitrile	IC50	4 nM	US-9452990: Complement pathway modulators and uses thereof
(3R)-1-[4-(4-amino-8-fluoro-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-3-(cyclopropylmethylamino)-3-thiophen-3-ylpropan-1-one	IC50	4 nM	US-9452990: Complement pathway modulators and uses thereof
6-chloro-1-[2-[(1R,3S,5R)-3-[[(1R)-1-[(1R)-2,2-dichlorocyclopropyl]ethyl]carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]indazole-3-carboxamide	IC50	4 nM	US-9468661: Pyrrolidine derivatives and their use as complement pathway modulators
(1R,3S,5R)-2-[2-[3-acetyl-6-methyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl]-N-[(1R)-1-[(1R)-2,2-dichlorocyclopropyl]ethyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide	IC50	4 nM	US-9468661: Pyrrolidine derivatives and their use as complement pathway modulators
(1R,3S,5R)-2-[2-[3-acetyl-5-[(1-methylpyrazol-3-yl)methoxy]indazol-1-yl]acetyl]-N-[(1R)-1-[(1R)-2,2-dichlorocyclopropyl]ethyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide	IC50	4 nM	US-9468661: Pyrrolidine derivatives and their use as complement pathway modulators
CHEMBL4636415	IC50	4 nM
(3S)-2-N-[1-carbamoyl-5-(2-methoxyethoxy)indol-3-yl]-3-N-[(3-chloro-2-fluorophenyl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	IC50	5 nM	US-9085555: Complement pathway modulators and uses thereof
(3S)-2-N-(1-carbamoyl-5-fluoroindol-3-yl)-3-N-[(3-chloro-2-fluorophenyl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	IC50	5 nM	US-9085555: Complement pathway modulators and uses thereof
(3S)-2-N-(1-carbamoylindol-3-yl)-3-N-[(3-chloro-2-fluorophenyl)methyl]-3,4-dihydropyrazole-2,3-dicarboxamide	IC50	5 nM	US-9085555: Complement pathway modulators and uses thereof
(1R,3S,5R)-2-N-[1-carbamoyl-5-(2-hydroxyethoxy)indol-3-yl]-3-N-[(3-chloro-2-fluorophenyl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	IC50	5 nM	US-9085555: Complement pathway modulators and uses thereof
(2S,3S,4S)-1-[2-[3-acetyl-5-(pyrimidin-2-ylmethoxy)indazol-1-yl]acetyl]-4-fluoro-N-[2-fluoro-3-(trifluoromethoxy)phenyl]-3-methoxypyrrolidine-2-carboxamide	IC50	5 nM	US-9085555: Complement pathway modulators and uses thereof
1-[2-[(1R,3S,5R)-3-[[3-(2-chlorophenyl)-2-fluorophenyl]carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]pyrazolo[5,4-c]pyridine-3-carboxamide	IC50	5 nM	US-9085555: Complement pathway modulators and uses thereof
1-[2-[(1R,3S,5R)-3-[(6-bromo-2-pyridinyl)carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]-5,7-dimethylpyrazolo[5,4-c]pyridine-3-carboxamide	IC50	5 nM	US-9085555: Complement pathway modulators and uses thereof
1-[2-[(1R,3S,5R)-3-[(6-bromo-2-pyridinyl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]-5-methylpyrazolo[5,4-c]pyridine-3-carboxamide	IC50	5 nM	US-9085555: Complement pathway modulators and uses thereof
1-[2-[(2S,3S,4S)-2-[(6-bromo-2-pyridinyl)carbamoyl]-4-fluoro-3-methoxypyrrolidin-1-yl]-2-oxoethyl]indazole-3-carboxamide	IC50	5 nM	US-9085555: Complement pathway modulators and uses thereof
(1R,3S,5R)-3-N-(6-bromo-2-pyridinyl)-2-N-(1-carbamoylindol-3-yl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	IC50	5 nM	US-9085555: Complement pathway modulators and uses thereof
(1R,3S,5R)-2-[2-[3-acetyl-5-(1,3-thiazol-2-ylmethoxy)indazol-1-yl]acetyl]-N-[[(1R)-2,2-dichlorocyclopropyl]methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide	IC50	5 nM	US-9468661: Pyrrolidine derivatives and their use as complement pathway modulators
methyl 2-[1-carbamoyl-3-[[(3S)-3-[(3-chloro-2-fluorophenyl)methylcarbamoyl]-2-azabicyclo[3.1.0]hexane-2-carbonyl]amino]indol-5-yl]oxyacetate	IC50	6 nM	US-9085555: Complement pathway modulators and uses thereof
(2S)-3-N-(1-carbamoylindol-3-yl)-2-N-[(3-chloro-2-fluorophenyl)methyl]-1,3-thiazolidine-2,3-dicarboxamide	IC50	6 nM	US-9085555: Complement pathway modulators and uses thereof

ChEMBL bioactivities

1944 potent at pChembl≥5 of 2040 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL2180765
9.00	IC50	1	nM	CHEMBL4114217
9.00	IC50	1	nM	CHEMBL4106993
8.70	IC50	2	nM	CHEMBL2180764
8.70	IC50	2	nM	CHEMBL3109655
8.52	IC50	3	nM	CHEMBL2180766
8.52	IC50	3	nM	CHEMBL3109654
8.52	IC50	3	nM	CHEMBL3668673
8.52	IC50	3	nM	CHEMBL3673724
8.52	IC50	3	nM	CHEMBL3673750
8.52	IC50	3	nM	CHEMBL3673802
8.52	IC50	3	nM	CHEMBL3673804
8.52	IC50	3	nM	CHEMBL3678905
8.52	IC50	3	nM	CHEMBL3678910
8.52	IC50	3	nM	CHEMBL3678945
8.52	IC50	3	nM	CHEMBL3683717
8.52	IC50	3	nM	CHEMBL4107243
8.52	IC50	3	nM	CHEMBL4113469
8.52	IC50	3	nM	CHEMBL4115620
8.52	IC50	3	nM	CHEMBL4106731
8.52	IC50	3	nM	CHEMBL4111856
8.52	IC50	3	nM	CHEMBL4535197
8.40	IC50	4	nM	CHEMBL3668636
8.40	IC50	4	nM	CHEMBL3673732
8.40	IC50	4	nM	CHEMBL3673738
8.40	IC50	4	nM	CHEMBL3673812
8.40	IC50	4	nM	CHEMBL3678944
8.40	IC50	4	nM	CHEMBL3683720
8.40	IC50	4	nM	CHEMBL3683724
8.40	IC50	4	nM	CHEMBL3683725
8.40	IC50	4	nM	CHEMBL3683739
8.40	IC50	4	nM	CHEMBL4108959
8.40	IC50	4	nM	CHEMBL4111681
8.40	IC50	4	nM	CHEMBL4112203
8.40	IC50	4	nM	CHEMBL4114056
8.40	IC50	4	nM	CHEMBL4111206
8.40	IC50	4	nM	DANICOPAN
8.40	IC50	4	nM	CHEMBL4246585
8.30	IC50	5	nM	CHEMBL3668669
8.30	IC50	5	nM	CHEMBL3673726
8.30	IC50	5	nM	CHEMBL3673793
8.30	IC50	5	nM	CHEMBL3673808
8.30	IC50	5	nM	CHEMBL3678852
8.30	IC50	5	nM	CHEMBL3678898
8.30	IC50	5	nM	CHEMBL3683717
8.30	IC50	5	nM	CHEMBL3683719
8.30	IC50	5	nM	CHEMBL3965664
8.30	IC50	5	nM	CHEMBL3683730
8.30	IC50	5	nM	CHEMBL3683737
8.30	IC50	5	nM	CHEMBL4114574

PubChem BioAssay actives

171 with measured affinity, of 276 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
Danicopan	1393250: Binding affinity to human factor D by SPR analysis	kd	0.0010	uM
(1R,3S,5R)-2-N-[1-carbamoyl-5-(cyanomethoxy)indol-3-yl]-3-N-[(3-chloro-2-fluorophenyl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	704668: Inhibition of recombinant human complement factor D after 1 hr	ic50	0.0010	uM
2-[1-carbamoyl-3-[[(2S,4R)-2-[(3-chloro-2-fluorophenyl)methylcarbamoyl]-4-fluoro-4-methylpyrrolidine-1-carbonyl]amino]indol-5-yl]oxyacetic acid	704668: Inhibition of recombinant human complement factor D after 1 hr	ic50	0.0020	uM
1-[2-[(1R,3S,5R)-3-[(6-bromo-2-pyridinyl)carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]-5-(fluoromethyl)pyrazolo[5,4-c]pyridine-3-carboxamide	1065276: Inhibition of recombinant human factor D expressed in Escherichia coli using Z-Lys-thiobenzyl and 2,4-dinitrobenzenesulfonyl-fluoresceine as substrate preincubated for 1 hr followed by substrate addition by spectrofluorimetric analysis	ic50	0.0020	uM
2-[2-[[3-[3-[(1S)-1-amino-2-hydroxyethyl]phenyl]-5-bromophenyl]methoxy]phenyl]acetic acid	1595848: Inhibition of 2-((1E,3E,5E)-5-(1-(6-((((3S,5S)-1-((1-carbamoyl-1H-indol-3-yl)carbamoyl)-5-((3-chloro-2-fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3-yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indol-1-ium binding to biotin-labeled recombinant human FD expressed in Escherichia coli measured after 2 hrs by TR-FRET assay	ic50	0.0030	uM
tert-butyl 2-[1-carbamoyl-3-[[(1R,3S,5R)-3-[(3-chloro-2-fluorophenyl)methylcarbamoyl]-2-azabicyclo[3.1.0]hexane-2-carbonyl]amino]indol-6-yl]acetate	704668: Inhibition of recombinant human complement factor D after 1 hr	ic50	0.0030	uM
1-[2-[(1R,3S,5R)-3-[(6-iodo-2-pyridinyl)carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]indazole-3-carboxamide	1065276: Inhibition of recombinant human factor D expressed in Escherichia coli using Z-Lys-thiobenzyl and 2,4-dinitrobenzenesulfonyl-fluoresceine as substrate preincubated for 1 hr followed by substrate addition by spectrofluorimetric analysis	ic50	0.0030	uM
2-[2-[[3-[3-[(1S)-1-amino-2-hydroxyethyl]phenyl]-5-(hydroxymethyl)phenyl]methoxy]phenyl]acetic acid	1393249: Inhibition of human factor D expressed in Escherichia coli using CVF-FB as substrate assessed as decrease in formation of factor B cleavage product Ba after 1 hr by ELISA	ic50	0.0040	uM
1-[2-[(1R,3S,5R)-3-[(6-bromo-2-pyridinyl)carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]indazole-3-carboxamide	1445601: Inhibition of recombinant human complement factor D catalytic domain using Z-Lys-thiobenzylester as substrate preincubated for 1 hr followed by substrate addition by 2,4-dinitrobenzenesulfonyl-2,7-desmethyl-fluorecein probe based spectrofluorimetric assay	ic50	0.0050	uM
(1R,3S,5R)-3-N-(6-bromo-2-pyridinyl)-2-N-(1-carbamoylindol-3-yl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	1445601: Inhibition of recombinant human complement factor D catalytic domain using Z-Lys-thiobenzylester as substrate preincubated for 1 hr followed by substrate addition by 2,4-dinitrobenzenesulfonyl-2,7-desmethyl-fluorecein probe based spectrofluorimetric assay	ic50	0.0060	uM
1-[2-[(1R,3S,5R)-3-[[(1S)-1-(3-chloro-2-fluorophenyl)ethyl]carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]pyrazolo[5,4-b]pyridine-3-carboxamide	1674158: Inhibition of CFD in 10% human serum assessed as reduction in alternate complement pathway-mediated hemolysis incubated for 1 hr	ic50	0.0060	uM
1-[2-[(1R,3S,5R)-3-[[(1R)-1-(3-chloro-2-fluorophenyl)ethyl]carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]pyrazolo[5,4-c]pyridine-3-carboxamide	1802178: SPR Binding Affinity Assay (Single Cycle) from Article 10.1038/nchembio.2208: “Small-molecule factor D inhibitors targeting the alternative complement pathway.”	kd	0.0060	uM
5,7-dimethyl-1-[2-oxo-2-[(1R,3S,5R)-3-[[6-(trifluoromethyl)-2-pyridinyl]carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]ethyl]pyrazolo[5,4-c]pyridine-3-carboxamide	1065276: Inhibition of recombinant human factor D expressed in Escherichia coli using Z-Lys-thiobenzyl and 2,4-dinitrobenzenesulfonyl-fluoresceine as substrate preincubated for 1 hr followed by substrate addition by spectrofluorimetric analysis	ic50	0.0060	uM
2-[2-[[3-[3-[(1S)-1-amino-2-hydroxyethyl]phenyl]-5-(2-hydroxypropan-2-yl)phenyl]methoxy]phenyl]acetic acid	1595848: Inhibition of 2-((1E,3E,5E)-5-(1-(6-((((3S,5S)-1-((1-carbamoyl-1H-indol-3-yl)carbamoyl)-5-((3-chloro-2-fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3-yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indol-1-ium binding to biotin-labeled recombinant human FD expressed in Escherichia coli measured after 2 hrs by TR-FRET assay	ic50	0.0080	uM
2-[2-[[3-[3-(aminomethyl)phenyl]phenyl]methoxy]phenyl]acetic acid	1595848: Inhibition of 2-((1E,3E,5E)-5-(1-(6-((((3S,5S)-1-((1-carbamoyl-1H-indol-3-yl)carbamoyl)-5-((3-chloro-2-fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3-yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indol-1-ium binding to biotin-labeled recombinant human FD expressed in Escherichia coli measured after 2 hrs by TR-FRET assay	ic50	0.0080	uM
2-[2-[[3-[3-[(1S)-1-amino-2-hydroxyethyl]phenyl]-5-(methoxymethyl)phenyl]methoxy]phenyl]acetic acid	1595848: Inhibition of 2-((1E,3E,5E)-5-(1-(6-((((3S,5S)-1-((1-carbamoyl-1H-indol-3-yl)carbamoyl)-5-((3-chloro-2-fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3-yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indol-1-ium binding to biotin-labeled recombinant human FD expressed in Escherichia coli measured after 2 hrs by TR-FRET assay	ic50	0.0100	uM
1-[2-[(1R,3S,5R)-3-[(3-bromo-2-fluorophenyl)carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]indazole-3-carboxamide	1445601: Inhibition of recombinant human complement factor D catalytic domain using Z-Lys-thiobenzylester as substrate preincubated for 1 hr followed by substrate addition by 2,4-dinitrobenzenesulfonyl-2,7-desmethyl-fluorecein probe based spectrofluorimetric assay	ic50	0.0100	uM
2-[2-[[3-[3-[(1S)-1-amino-2-hydroxyethyl]phenyl]phenyl]methoxy]phenyl]acetic acid	1595848: Inhibition of 2-((1E,3E,5E)-5-(1-(6-((((3S,5S)-1-((1-carbamoyl-1H-indol-3-yl)carbamoyl)-5-((3-chloro-2-fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3-yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indol-1-ium binding to biotin-labeled recombinant human FD expressed in Escherichia coli measured after 2 hrs by TR-FRET assay	ic50	0.0120	uM
(1R,3S,5R)-2-N-(1-carbamoylindol-3-yl)-3-N-[2-fluoro-3-(trifluoromethoxy)phenyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	1445601: Inhibition of recombinant human complement factor D catalytic domain using Z-Lys-thiobenzylester as substrate preincubated for 1 hr followed by substrate addition by 2,4-dinitrobenzenesulfonyl-2,7-desmethyl-fluorecein probe based spectrofluorimetric assay	ic50	0.0120	uM
(1R,3S,5R)-2-N-(1-carbamoylindol-3-yl)-3-N-[6-(trifluoromethyl)-2-pyridinyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	1445601: Inhibition of recombinant human complement factor D catalytic domain using Z-Lys-thiobenzylester as substrate preincubated for 1 hr followed by substrate addition by 2,4-dinitrobenzenesulfonyl-2,7-desmethyl-fluorecein probe based spectrofluorimetric assay	ic50	0.0140	uM
2-[2-[[3-[3-[(1S)-1-amino-2-hydroxyethyl]phenyl]-5-(propan-2-ylamino)phenyl]methoxy]phenyl]acetic acid	1595848: Inhibition of 2-((1E,3E,5E)-5-(1-(6-((((3S,5S)-1-((1-carbamoyl-1H-indol-3-yl)carbamoyl)-5-((3-chloro-2-fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3-yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indol-1-ium binding to biotin-labeled recombinant human FD expressed in Escherichia coli measured after 2 hrs by TR-FRET assay	ic50	0.0150	uM
(1R,3S,5R)-2-[2-(3-acetylindazol-1-yl)acetyl]-N-(6-bromo-2-pyridinyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide	1445601: Inhibition of recombinant human complement factor D catalytic domain using Z-Lys-thiobenzylester as substrate preincubated for 1 hr followed by substrate addition by 2,4-dinitrobenzenesulfonyl-2,7-desmethyl-fluorecein probe based spectrofluorimetric assay	ic50	0.0150	uM
1-[2-[(1R,3S,5R)-3-[(6-bromo-2-pyridinyl)carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]pyrazolo[5,4-b]pyridine-3-carboxamide	1325988: Binding affinity to recombinant human C-terminal 6His-tagged/biotinylated complement factor D (26 to 253 residues) expressed in Sf9 insect cells by biolayer interferometry method	kd	0.0170	uM
1-[2-[[2-[(3-chloro-2-fluorophenyl)methylamino]-2-oxoethyl]-cyclopropylamino]-2-oxoethyl]-5-[[methyl-(1-methylpiperidin-4-yl)carbamoyl]amino]indazole-3-carboxamide	1918209: Inhibition of human complement factor D using Z-L-Lys-SBzl hydrochloride as substrate preincubated for 15 mins followed by substrate addition and measured by colorimetric method based esterolytic assay	ki	0.0185	uM
(2S)-N-(6-bromo-2-pyridinyl)-3-[2-(3-carbamoylpyrazolo[5,4-b]pyridin-1-yl)acetyl]-1,3-thiazolidine-2-carboxamide	1325988: Binding affinity to recombinant human C-terminal 6His-tagged/biotinylated complement factor D (26 to 253 residues) expressed in Sf9 insect cells by biolayer interferometry method	kd	0.0188	uM
(1R,3S,5R)-N-(6-bromo-2-pyridinyl)-2-(2-indazol-1-ylacetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide	1325992: Inhibition of human serum factor D-mediated complement activation in rabbit erythrocytes assessed as reduction in rabbit erythrocyte hemolysis preincubated with human serum for 15 mins followed by addition of rabbit erythrocytes and Mg-EGTA measured after 30 mins	ic50	0.0190	uM
2-[2-[[6-[3-(aminomethyl)phenyl]pyridine-2-carbonyl]amino]phenyl]acetic acid	1595853: Inhibition of FD-mediated alternative complementation pathway in 50% human whole blood assessed as reduction in zymosan-induced membrane-attack complex formation preincubated for 15 mins followed by zymosan stimulation and measured after 40 mins by ELISA	ic50	0.0200	uM
2-[2-[[3-[3-(2-amino-2-oxoethyl)-2-fluorophenyl]-5-(1-methylpyrazol-4-yl)phenyl]methoxy]phenyl]acetic acid	1393253: Displacement of Cy5 from recombinant human biotin labeled factor D expressed in Escherichia coli after 2 hrs by TR-FRET assay	ic50	0.0230	uM
(1R,3S,5R)-2-N-(1-carbamoylindol-3-yl)-3-N-[2-fluoro-3-(trifluoromethyl)phenyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	1445601: Inhibition of recombinant human complement factor D catalytic domain using Z-Lys-thiobenzylester as substrate preincubated for 1 hr followed by substrate addition by 2,4-dinitrobenzenesulfonyl-2,7-desmethyl-fluorecein probe based spectrofluorimetric assay	ic50	0.0230	uM
2-[2-[[3-[3-[(1R)-1-aminoethyl]phenyl]phenyl]methoxy]phenyl]acetic acid	1595848: Inhibition of 2-((1E,3E,5E)-5-(1-(6-((((3S,5S)-1-((1-carbamoyl-1H-indol-3-yl)carbamoyl)-5-((3-chloro-2-fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3-yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indol-1-ium binding to biotin-labeled recombinant human FD expressed in Escherichia coli measured after 2 hrs by TR-FRET assay	ic50	0.0250	uM
3-carbamoyl-1-[2-[[2-[(3-chloro-2-fluorophenyl)methylamino]-2-oxoethyl]-cyclopropylamino]-2-oxoethyl]indazole-6-carboxylic acid	1918209: Inhibition of human complement factor D using Z-L-Lys-SBzl hydrochloride as substrate preincubated for 15 mins followed by substrate addition and measured by colorimetric method based esterolytic assay	ic50	0.0270	uM
1-[2-[[2-[(3-chloro-2-fluorophenyl)methylamino]-2-oxoethyl]-cyclopropylamino]-2-oxoethyl]-5-[(4-cyclopropylpiperazine-1-carbonyl)amino]indazole-3-carboxamide	1918209: Inhibition of human complement factor D using Z-L-Lys-SBzl hydrochloride as substrate preincubated for 15 mins followed by substrate addition and measured by colorimetric method based esterolytic assay	ic50	0.0280	uM
2-[2-[[3-[3-[(1R)-1-amino-3-hydroxypropyl]phenyl]phenyl]methoxy]phenyl]acetic acid	1595848: Inhibition of 2-((1E,3E,5E)-5-(1-(6-((((3S,5S)-1-((1-carbamoyl-1H-indol-3-yl)carbamoyl)-5-((3-chloro-2-fluorobenzyl)carbamoyl)-3-fluoropyrrolidin-3-yl)methyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfoindolin-2-ylidene)penta-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indol-1-ium binding to biotin-labeled recombinant human FD expressed in Escherichia coli measured after 2 hrs by TR-FRET assay	ic50	0.0300	uM
1-[2-[[2-[(3-chloro-2-fluorophenyl)methylamino]-2-oxoethyl]-cyclopropylamino]-2-oxoethyl]-5-[[4-[(4-fluorophenyl)methyl]piperazine-1-carbonyl]amino]indazole-3-carboxamide	1918209: Inhibition of human complement factor D using Z-L-Lys-SBzl hydrochloride as substrate preincubated for 15 mins followed by substrate addition and measured by colorimetric method based esterolytic assay	ic50	0.0300	uM
1-[2-[(1R,3S,5R)-3-[[(1S)-1-(3-chloro-2-fluorophenyl)ethyl]carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]pyrazolo[5,4-c]pyridine-3-carboxamide	1393245: Inhibition of human factor D using CVF-FB as substrate assessed as decrease in formation of factor B cleavage product Ba by ELISA	ic50	0.0300	uM
1-[2-[[2-[(3-chloro-2-fluorophenyl)methylamino]-2-oxoethyl]-cyclopropylamino]-2-oxoethyl]-5-(cyclohexylcarbamoylamino)indazole-3-carboxamide	1918209: Inhibition of human complement factor D using Z-L-Lys-SBzl hydrochloride as substrate preincubated for 15 mins followed by substrate addition and measured by colorimetric method based esterolytic assay	ic50	0.0340	uM
1-[2-[[2-[(3-chloro-2-fluorophenyl)methylamino]-2-oxoethyl]-cyclopropylamino]-2-oxoethyl]-5-[(3,3-difluoropiperidine-1-carbonyl)amino]indazole-3-carboxamide	1918209: Inhibition of human complement factor D using Z-L-Lys-SBzl hydrochloride as substrate preincubated for 15 mins followed by substrate addition and measured by colorimetric method based esterolytic assay	ic50	0.0340	uM
2-[2-[[3-[(3S)-3-amino-2,3-dihydro-1-benzofuran-5-yl]-5-(2-cyanopropan-2-yl)phenyl]methoxy]phenyl]acetic acid	1660713: Inhibition of human complement FD by TR-FRET assay	ic50	0.0400	uM
2-[2-[[3-[(3S)-3-amino-2,3-dihydro-1-benzofuran-5-yl]-5-propan-2-ylphenyl]methoxy]phenyl]acetic acid	1660713: Inhibition of human complement FD by TR-FRET assay	ic50	0.0400	uM
(1R,3S,5R)-3-N-(3-bromophenyl)-2-N-(1-carbamoylindol-3-yl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	1445601: Inhibition of recombinant human complement factor D catalytic domain using Z-Lys-thiobenzylester as substrate preincubated for 1 hr followed by substrate addition by 2,4-dinitrobenzenesulfonyl-2,7-desmethyl-fluorecein probe based spectrofluorimetric assay	ic50	0.0450	uM
2-[2-[[5-[(3S)-3-amino-2,3-dihydro-1-benzofuran-5-yl]-3,3-dimethyl-2H-1-benzofuran-7-yl]methoxy]phenyl]acetic acid	1660713: Inhibition of human complement FD by TR-FRET assay	ic50	0.0500	uM
(2S,4R)-1-N-(1-carbamoylindol-3-yl)-4-fluoro-2-N-[3-(trifluoromethoxy)phenyl]pyrrolidine-1,2-dicarboxamide	1445601: Inhibition of recombinant human complement factor D catalytic domain using Z-Lys-thiobenzylester as substrate preincubated for 1 hr followed by substrate addition by 2,4-dinitrobenzenesulfonyl-2,7-desmethyl-fluorecein probe based spectrofluorimetric assay	ic50	0.0500	uM
(1R,3S,5R)-2-N-(1-carbamoylindol-3-yl)-3-N-[3-(trifluoromethoxy)phenyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide	1445601: Inhibition of recombinant human complement factor D catalytic domain using Z-Lys-thiobenzylester as substrate preincubated for 1 hr followed by substrate addition by 2,4-dinitrobenzenesulfonyl-2,7-desmethyl-fluorecein probe based spectrofluorimetric assay	ic50	0.0500	uM
1-[2-[[2-[(3-chloro-2-fluorophenyl)methylamino]-2-oxoethyl]-cyclopropylamino]-2-oxoethyl]-6-hydroxyindazole-3-carboxamide	1918209: Inhibition of human complement factor D using Z-L-Lys-SBzl hydrochloride as substrate preincubated for 15 mins followed by substrate addition and measured by colorimetric method based esterolytic assay	ic50	0.0540	uM
2-[(2R)-2-[3-[(3S)-3-amino-2,3-dihydro-1-benzofuran-5-yl]-5-propan-2-ylphenyl]-3,4-dihydro-2H-1,4-benzoxazin-8-yl]acetic acid	1660713: Inhibition of human complement FD by TR-FRET assay	ic50	0.0600	uM
1-[2-[(1R,3S,5R)-3-[(6-bromo-2-pyridinyl)carbamoyl]-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl]indole-3-carboxamide	1445601: Inhibition of recombinant human complement factor D catalytic domain using Z-Lys-thiobenzylester as substrate preincubated for 1 hr followed by substrate addition by 2,4-dinitrobenzenesulfonyl-2,7-desmethyl-fluorecein probe based spectrofluorimetric assay	ic50	0.0660	uM
1-[2-[(2S)-2-[(6-bromo-2-pyridinyl)carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]indazole-3-carboxamide	1918209: Inhibition of human complement factor D using Z-L-Lys-SBzl hydrochloride as substrate preincubated for 15 mins followed by substrate addition and measured by colorimetric method based esterolytic assay	ic50	0.0670	uM
(2S)-N-(6-bromo-2-pyridinyl)-3-(2-indazol-1-ylacetyl)-1,3-thiazolidine-2-carboxamide	1325992: Inhibition of human serum factor D-mediated complement activation in rabbit erythrocytes assessed as reduction in rabbit erythrocyte hemolysis preincubated with human serum for 15 mins followed by addition of rabbit erythrocytes and Mg-EGTA measured after 30 mins	ic50	0.0770	uM
1-[2-[[2-[(3-chloro-2-fluorophenyl)methylamino]-2-oxoethyl]-cyclopropylamino]-2-oxoethyl]-6-(hydroxymethyl)indazole-3-carboxamide	1918209: Inhibition of human complement factor D using Z-L-Lys-SBzl hydrochloride as substrate preincubated for 15 mins followed by substrate addition and measured by colorimetric method based esterolytic assay	ic50	0.0770	uM
tert-butyl N-[3-carbamoyl-1-[2-[[2-[(3-chloro-2-fluorophenyl)methylamino]-2-oxoethyl]-cyclopropylamino]-2-oxoethyl]indazol-5-yl]carbamate	1918209: Inhibition of human complement factor D using Z-L-Lys-SBzl hydrochloride as substrate preincubated for 15 mins followed by substrate addition and measured by colorimetric method based esterolytic assay	ic50	0.0840	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects reaction, increases expression, affects cotreatment, affects expression, increases methylation	10
Dexamethasone	increases expression, affects cotreatment	4
Particulate Matter	decreases expression, increases abundance	3
bisphenol A	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Air Pollutants	decreases expression, increases abundance	2
Cisplatin	increases expression, affects expression, affects cotreatment	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	increases expression	1
TAK-243	increases sumoylation	1
graphene oxide	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
tobacco tar	decreases expression, decreases reaction	1
diallyl disulfide	decreases expression, decreases reaction	1
ferrous chloride	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects secretion	1
Temozolomide	increases expression	1
Decitabine	affects expression	1
Arsenic Trioxide	decreases expression	1
Troglitazone	increases expression	1

ChEMBL screening assays

82 unique, capped per target: 81 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2188699	Binding	Inhibition of recombinant human complement factor D after 1 hr	Factor D Inhibitors for the Treatment of AMD: Patent Highlight. — *ACS Med Chem Lett*
CHEMBL4621383	ADMET	Inhibition of human complement FD by TR-FRET assay	Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach. — *J Med Chem*

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1VS	Abcam A-549 CFD KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

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