Target Information
| Target General Information | Top | |||||
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| Target ID |
T24836
(Former ID: TTDS00470)
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| Target Name |
Vitamin K-dependent protein C (PROC)
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| Synonyms |
Vitamin K-dependent protein C light chain; Vitamin K-dependent protein C heavy chain; PROC; Blood coagulation factor XIV; Autoprothrombin IIA; Anticoagulant protein C; Activation peptide
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| Gene Name |
PROC
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Chronic lower extremities peripheral venous insufficiency [ICD-11: BD74] | |||||
| 2 | Hemangioma [ICD-11: 2E81-2F2Y] | |||||
| Function |
Protein C is avitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.21.69
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| Sequence |
MWQLTSLLLFVATWGISGTPAPLDSVFSSSERAHQVLRIRKRANSFLEELRHSSLERECI
EEICDFEEAKEIFQNVDDTLAFWSKHVDGDQCLVLPLEHPCASLCCGHGTCIDGIGSFSC DCRSGWEGRFCQREVSFLNCSLDNGGCTHYCLEEVGWRRCSCAPGYKLGDDLLQCHPAVK FPCGRPWKRMEKKRSHLKRDTEDQEDQVDPRLIDGKMTRRGDSPWQVVLLDSKKKLACGA VLIHPSWVLTAAHCMDESKKLLVRLGEYDLRRWEKWELDLDIKEVFVHPNYSKSTTDNDI ALLHLAQPATLSQTIVPICLPDSGLAERELNQAGQETLVTGWGYHSSREKEAKRNRTFVL NFIKIPVVPHNECSEVMSNMVSENMLCAGILGDRQDACEGDSGGPMVASFHGTWFLVGLV SWGEGCGLLHNYGVYTKVSRYLDWIHGHIRDKEAPQKSWAP Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Sodium Tetradecyl Sulfate | Drug Info | Approved | Hemangioma | [2], [3] | |
| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | Ancrod | Drug Info | Phase 3 | Blood forming organ disorder | [4] | |
| 2 | 3K3A-APC | Drug Info | Phase 2 | Cerebrovascular ischaemia | [5] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | GED-aPC | Drug Info | Discontinued in Phase 1 | Cardiovascular disease | [6] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 4 Inhibitor drugs | + | ||||
| 1 | Sodium Tetradecyl Sulfate | Drug Info | [1] | |||
| 2 | PMID24418773C37 | Drug Info | [10] | |||
| 3 | RPR-118071 | Drug Info | [11] | |||
| 4 | RPR-120844 | Drug Info | [11] | |||
| Modulator | [+] 3 Modulator drugs | + | ||||
| 1 | Ancrod | Drug Info | [7] | |||
| 2 | 3K3A-APC | Drug Info | [8] | |||
| 3 | GED-aPC | Drug Info | [9] | |||
| 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: Gamma-Carboxy-Glutamic Acid | Ligand Info | |||||
| Structure Description | Crystal structure of the Endothelial protein C receptor with phospholipid in the groove in complex with Gla domain of protein C. | PDB:1LQV | ||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | Yes | [12] |
| PDB Sequence |
ANSFLLRHSS
12 LRCIICDFAK28 IFQN
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ALA1
2.720
ASN2
2.999
SER3
2.978
PHE4
3.112
LEU5
1.338
LEU8
1.348
ARG9
2.855
HIS10
4.861
SER11
3.259
SER12
2.813
LEU13
1.332
ARG15
1.329
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: phosphatidylethanolamine | Ligand Info | |||||
| Structure Description | Crystal structure of the Endothelial protein C receptor with phospholipid in the groove in complex with Gla domain of protein C. | PDB:1LQV | ||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | Yes | [12] |
| PDB Sequence |
ANSFLLRHSS
12 LRCIICDFAK28 IFQN
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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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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 | 11 | Degree centrality | 1.18E-03 | Betweenness centrality | 5.30E-05 |
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| Closeness centrality | 1.84E-01 | Radiality | 1.31E+01 | Clustering coefficient | 3.82E-01 |
| Neighborhood connectivity | 1.13E+01 | Topological coefficient | 2.01E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| 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 | [+] 1 KEGG Pathways | + | ||||
| 1 | Complement and coagulation cascades | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Blood coagulation | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | Beta2 integrin cell surface interactions | |||||
| Reactome | [+] 6 Reactome Pathways | + | ||||
| 1 | Intrinsic Pathway of Fibrin Clot Formation | |||||
| 2 | Common Pathway of Fibrin Clot Formation | |||||
| 3 | Gamma-carboxylation of protein precursors | |||||
| 4 | Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus | |||||
| 5 | Removal of aminoterminal propeptides from gamma-carboxylated proteins | |||||
| 6 | Cell surface interactions at the vascular wall | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | Complement and Coagulation Cascades | |||||
| 2 | PTM: gamma carboxylation, hypusine formation and arylsulfatase activation | |||||
| 3 | Formation of Fibrin Clot (Clotting Cascade) | |||||
| 4 | Cell surface interactions at the vascular wall | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. | |||||
| REF 2 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 040541. | |||||
| REF 3 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 4 | ClinicalTrials.gov (NCT00141011) Ancrod (Viprinex for the Treatment of Acute, Ischemic Stroke. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT02222714) Safety Evaluation of 3K3A-APC in Ischemic Stroke. U.S. National Institutes of Health. | |||||
| REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026237) | |||||
| REF 7 | Ancrod (Arvin) as an alternative to heparin anticoagulation for cardiopulmonary bypass. Anesthesiology. 1989 Dec;71(6):870-7. | |||||
| REF 8 | Preclinical safety and pharmacokinetic profile of 3K3A-APC, a novel, modified activated protein C for ischemic stroke. Curr Pharm Des. 2012;18(27):4215-22. | |||||
| REF 9 | 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: 2396). | |||||
| REF 10 | Design, synthesis, and SAR of a series of activated protein C (APC) inhibitors with selectivity against thrombin for the treatment of haemophilia. Bioorg Med Chem Lett. 2014 Feb 1;24(3):821-7. | |||||
| REF 11 | Design and structure-activity relationships of potent and selective inhibitors of blood coagulation factor Xa. J Med Chem. 1999 Sep 9;42(18):3557-71. | |||||
| REF 12 | The crystal structure of the endothelial protein C receptor and a bound phospholipid. J Biol Chem. 2002 Jul 12;277(28):24851-4. | |||||
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