Target Information
| Target General Information | Top | |||||
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| Target ID |
T55703
(Former ID: TTDI02366)
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| Target Name |
Plasma retinol-binding protein (RBP4)
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| Synonyms |
Retinol-binding protein 4; RBP4; RBP; Plasma retinol-binding protein(1-176); PRBP
Click to Show/Hide
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| Gene Name |
RBP4
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Inherited retinal dystrophy [ICD-11: 9B70] | |||||
| Function |
Delivers retinol from the liver stores to the peripheral tissues. In plasma, the RBP-retinol complex interacts with transthyretin, this prevents its loss by filtration through the kidney glomeruli.
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| BioChemical Class |
Calycin family
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| UniProt ID | ||||||
| Sequence |
MKWVWALLLLAALGSGRAERDCRVSSFRVKENFDKARFSGTWYAMAKKDPEGLFLQDNIV
AEFSVDETGQMSATAKGRVRLLNNWDVCADMVGTFTDTEDPAKFKMKYWGVASFLQKGND DHWIVDTDYDTYAVQYSCRLLNLDGTCADSYSFVFSRDPNGLPPEAQKIVRQRQEELCLA RQYRLIVHNGYCDGRSERNLL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T94WHJ | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Tinlarebant | Drug Info | Phase 3 | Stargardt disease | [2] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | Tinlarebant | Drug Info | [3] | |||
| Inhibitor | [+] 11 Inhibitor drugs | + | ||||
| 1 | A1-10436 | Drug Info | [4] | |||
| 2 | A1-10438 | Drug Info | [4] | |||
| 3 | US8586571, 12 | Drug Info | [5] | |||
| 4 | US8586571, 36 | Drug Info | [5] | |||
| 5 | US8586571, 6 | Drug Info | [5] | |||
| 6 | US8853215, 3 | Drug Info | [4] | |||
| 7 | US9434727, 120 | Drug Info | [6] | |||
| 8 | US9434727, 153 | Drug Info | [6] | |||
| 9 | US9434727, 40 | Drug Info | [7] | |||
| 10 | US9434727, 63 | Drug Info | [6] | |||
| 11 | US9434727, 93 | Drug Info | [8] | |||
| 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: Vitamin A | Ligand Info | |||||
| Structure Description | Structure of human holo plasma RBP4 | PDB:5NU7 | ||||
| Method | X-ray diffraction | Resolution | 1.50 Å | Mutation | No | [9] |
| PDB Sequence |
ERDCRVSSFR
10 VKENFDKARF20 SGTWYAMAKK30 DPEGLFLQDN40 IVAEFSVDET50 GQMSATAKGR 60 VRLLNNWDVC70 ADMVGTFTDT80 EDPAKFKMKY90 WGVASFLQKG100 NDDHWIVDTD 110 YDTYAVQYSC120 RLLNLDGTCA130 DSYSFVFSRD140 PNGLPPEAQK150 IVRQRQEELC 160 LARQYRLIVH170 NGYCD
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LEU35
3.581
PHE36
3.594
LEU37
3.977
ALA43
4.024
PHE45
4.068
ALA55
3.927
THR56
4.429
ALA57
4.095
VAL61
3.720
LEU63
4.470
ALA71
4.657
MET73
3.654
VAL74
4.335
GLY75
4.536
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Tretinoin | Ligand Info | |||||
| Structure Description | RETINOL BINDING PROTEIN COMPLEXED WITH TRANSTHYRETIN | PDB:1RLB | ||||
| Method | X-ray diffraction | Resolution | 3.10 Å | Mutation | No | [10] |
| PDB Sequence |
ERDCRVSSFR
10 VKENFDKARF20 AGTWYAMAKK30 DPEGLFLQDN40 IVAEFSVDEN50 GHMSATAKGR 60 VRLLNNWDVC70 ADMVGTFTDT80 EDPAKFKMKY90 WGVASFLQKG100 NDDHWIIDTD 110 YETFAVQYSC120 RLLNLDGTCA130 DSYSFVFARD140 PSGFSPQVQK150 IVRQRQEELC 160 LARQYRLIPH170 NGYC
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LEU35
2.963
PHE36
3.477
LEU37
2.832
ILE41
4.278
ALA43
4.025
PHE45
4.420
ALA55
3.693
THR56
4.536
ALA57
3.359
VAL61
3.633
LEU63
4.129
ALA71
4.764
MET73
3.529
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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).
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
Biological Network Descriptors
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Apolipoprotein D (APOD) | 28.221 (46/163) | 8.11E-10 |
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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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| Degree | 4 | Degree centrality | 4.30E-04 | Betweenness centrality | 4.45E-04 |
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| Closeness centrality | 1.54E-01 | Radiality | 1.22E+01 | Clustering coefficient | 3.33E-01 |
| Neighborhood connectivity | 4.75E+00 | Topological coefficient | 3.46E-01 | Eccentricity | 12 |
| 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 | ||
| References | Top | |||||
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| REF 1 | Design, Synthesis, and Preclinical Efficacy of Novel Nonretinoid Antagonists of Retinol-Binding Protein 4 in the Mouse Model of Hepatic Steatosis. J Med Chem. 2019 Jun 13;62(11):5470-5500. | |||||
| REF 2 | ClinicalTrials.gov (NCT05244304) Phase 3, Multicenter, Randomized, Double-Masked, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Tinlarebant in the Treatment of Stargardt Disease in Adolescent Subjects. U.S.National Institutes of Health. | |||||
| REF 3 | Retinol binding protein 4 antagonists and protein synthesis inhibitors: Potential for therapeutic development. Eur J Med Chem. 2021 Dec 15;226:113856. | |||||
| REF 4 | Derivatives of N-acyl-N-phenylpiperazine useful (inter alia) for the prophylaxis or treatment of diabetes. US8853215. | |||||
| REF 5 | Heterocyclic compound. US8586571. | |||||
| REF 6 | Substituted 4-phenylpiperidines, their preparation and use. US9434727. | |||||
| REF 7 | Substituted 4-phenylpiperidines, their preparation and use. US9777010. | |||||
| REF 8 | Substituted 4-phenylpiperidines, their preparation and use. US10072016. | |||||
| REF 9 | Human plasma retinol-binding protein (RBP4) is also a fatty acid-binding protein. Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Apr;1863(4):458-466. | |||||
| REF 10 | Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science. 1995 May 19;268(5213):1039-41. | |||||
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