Target Information
| Target General Information | Top | |||||
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| Target ID |
T66383
(Former ID: TTDC00326)
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| Target Name |
Complement factor D (CFD)
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| Synonyms |
Properdin factor D; PFD; DF; C3 convertase activator; Adipsin
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| Gene Name |
CFD
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Haemolytic anemia [ICD-11: 3A20-3A2Z] | |||||
| 2 | Retinopathy [ICD-11: 9B71] | |||||
| Function |
Factor D cleaves factor B when the latter is complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. Its function is homologous to that of C1s in the classical pathway.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.21.46
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| Sequence |
MHSWERLAVLVLLGAAACAAPPRGRILGGREAEAHARPYMASVQLNGAHLCGGVLVAEQW
VLSAAHCLEDAADGKVQVLLGAHSLSQPEPSKRLYDVLRAVPHPDSQPDTIDHDLLLLQL SEKATLGPAVRPLPWQRVDRDVAPGTLCDVAGWGIVNHAGRRPDSLQHVLLPVLDRATCN RRTHHDGAITERLMCAESNRRDSCKGDSGGPLVCGGVLEGVVTSGSRVCGNRKKPGIYTR VASYAAWIDSVLA Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 7 Clinical Trial Drugs | + | ||||
| 1 | ALXN2040 | Drug Info | Phase 3 | Paroxysmal nocturnal haemoglobinuria | [2] | |
| 2 | Lampalizumab | Drug Info | Phase 3 | Geographic retinal atrophy | [3] | |
| 3 | ACH-4471 | Drug Info | Phase 2 | Anaemia | [4] | |
| 4 | BCX-9930 | Drug Info | Phase 2 | Paroxysmal nocturnal haemoglobinuria | [5] | |
| 5 | Vemircopan | Drug Info | Phase 2 | Paroxysmal nocturnal haemoglobinuria | [6] | |
| 6 | Anti-Factor D | Drug Info | Phase 1/2 | Age-related macular degeneration | [7] | |
| 7 | ALXN2080 | Drug Info | Phase 1 | Discovery agent | [8] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 8 Inhibitor drugs | + | ||||
| 1 | ALXN2040 | Drug Info | [9] | |||
| 2 | Lampalizumab | Drug Info | [10] | |||
| 3 | ACH-4471 | Drug Info | [11] | |||
| 4 | BCX-9930 | Drug Info | [5] | |||
| 5 | Vemircopan | Drug Info | [12] | |||
| 6 | Vemircopan | Drug Info | [6] | |||
| 7 | ALXN2080 | Drug Info | [13] | |||
| 8 | example 373 [WO2012093101] | Drug Info | [14] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | HC3-1496 | Drug Info | [15] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: 3,4-dichloroisocoumarin | Ligand Info | |||||
| Structure Description | STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D | PDB:1DIC | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [16] |
| PDB Sequence |
ILGGREAEAH
25 ARPYMASVQL35 NGAHLCGGVL46 VAEQWVLSAA56 HCLEDAADGK63 VQVLLGAHSL 73 SQPEPSKRLY83 DVLRAVPHPD93 SQPDTIDHDL103 LLLQLSEKAT113 LGPAVRPLPW 124A QRVDRDVAPG133 TLCDVAGWGI143 VNHAGRRPDS154 LQHVLLPVLD164 RATCNRRTHH 172 DGAITERLMC182 AESNRRDSCK192 GDSGGPLVCG202 GVLEGVVTSG216 SRVCGNRKKP 225 GIYTRVASYA235 AWIDSVLA
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| Ligand Name: Diisopropylphosphono Group | Ligand Info | |||||
| Structure Description | FACTOR D INHIBITED BY DIISOPROPYL FLUOROPHOSPHATE | PDB:1DFP | ||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | No | [17] |
| PDB Sequence |
ILGGREAEAH
25 ARPYMASVQL35 NGAHLCGGVL46 VAEQWVLSAA56 HCLEDAADGK63 VQVLLGAHSL 73 SQPEPSKRLY83 DVLRAVPHPD93 SQPDTIDHDL103 LLLQLSEKAT113 LGPAVRPLPW 124A QRVDRDVAPG133 TLCDVAGWGI143 VNHAGRRPDS154 LQHVLLPVLD164 RATCNRRTHH 172 DGAITERLMC182 AESNRRDSCK192 GDSGGPLVCG202 GVLEGVVTSG216 SRVCGNRKKP 225 GIYTRVASYA235 AWIDSVLA
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Complement and coagulation cascades | hsa04610 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.58E-01 | Radiality | 1.23E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 1.35E+01 | Topological coefficient | 5.63E-01 | Eccentricity | 14 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Complement and coagulation cascades | |||||
| 2 | Staphylococcus aureus infection | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TGF_beta_Receptor Signaling Pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Platelet degranulation | |||||
| 2 | Alternative complement activation | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | Complement and Coagulation Cascades | |||||
| 2 | Human Complement System | |||||
| 3 | Adipogenesis | |||||
| 4 | Complement cascade | |||||
| References | Top | |||||
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| REF 1 | Association for Research in Vision and Ophthalmology (ARVO)--2010 Annual Meeting. For Sight: The Future of Eye and Vision Research--part 1. IDrugs. 2010 Jul;13(7):427-9. | |||||
| REF 2 | ClinicalTrials.gov (NCT04469465) A Phase 3 Study of Danicopan (ALXN2040) as Add-on Therapy to a C5 Inhibitor (Eculizumab or Ravulizumab) in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Have Clinically Evident Extravascular Hemolysis (EVH). U.S.National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT02745119) Long-Term Safety of Lampalizumab Intravitreal (ITV) Injections in Participants With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration (OMASPECT). U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT03053102) Study of Danicopan in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH). U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT05116774) A Randomized, Open-Label, Multicenter, Parallel-Group Study to Evaluate the Efficacy, Safety, and Tolerability of Oral BCX9930 Monotherapy for the Treatment of PNH in Subjects With Inadequate Response to C5 Inhibitor Therapy. U.S.National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT04170023) A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, Safety, and Pharmacokinetics of the Oral Factor D (FD) Inhibitor ALXN2050 (ACH-0145228) in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients as Monotherapy. U.S.National Institutes of Health. | |||||
| REF 7 | Clinical pipeline report, company report or official report of Genentech (2011). | |||||
| REF 8 | ClinicalTrials.gov (NCT05428696) A Randomized, Double-blind, Placebo-controlled First-in-Human Study of Single and Multiple Doses of ALXN2080 in Healthy Participants. U.S.National Institutes of Health. | |||||
| REF 9 | Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria. Haematologica. 2021 Dec 1;106(12):3188-3197. | |||||
| REF 10 | In Vivo Stability Profiles of Anti-factor D Molecules Support Long-Acting Delivery Approaches. Mol Pharm. 2019 Jan 7;16(1):86-95. | |||||
| REF 11 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 12 | Clinical pipeline report, company report or official report of AstraZeneca | |||||
| REF 13 | Clinical pipeline report, company report or official report of Alexion | |||||
| REF 14 | Factor D Inhibitors for the Treatment of AMD: Patent Highlight. ACS Med Chem Lett. 2012 Aug 27;3(10):781-2. | |||||
| REF 15 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2842). | |||||
| REF 16 | Structure of 3,4-dichloroisocoumarin-inhibited factor D. Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):711-7. | |||||
| REF 17 | Structure of diisopropyl fluorophosphate-inhibited factor D. Acta Crystallogr D Biol Crystallogr. 1997 Mar 1;53(Pt 2):143-50. | |||||
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