Target Information
| Target General Information | Top | |||||
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| Target ID |
T05904
(Former ID: TTDR01310)
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| Target Name |
Phosphodiesterase 8 (PDE8)
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| Synonyms |
High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A
Click to Show/Hide
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| Gene Name |
PDE8A
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| Target Type |
Patented-recorded target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Itching [ICD-11: 1F28-1G07] | |||||
| 2 | Postoperative inflammation [ICD-11: 1A00-CA43] | |||||
| Function |
May be involved in maintaining basal levels of the cyclic nucleotide and/or in the cAMP regulation of germ cell development. Binding to RAF1 reduces RAF1 'Ser-259' inhibitory-phosphorylation and stimulates RAF1-dependent EGF-activated ERK-signaling. Protects against cell death induced by hydrogen peroxide and staurosporine. Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
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| BioChemical Class |
Phosphoric diester hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.1.4.53
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| Sequence |
MGCAPSIHISERLVAEDAPSPAAPPLSSGGPRLPQGQKTAALPRTRGAGLLESELRDGSG
KKVAVADVQFGPMRFHQDQLQVLLVFTKEDNQCNGFCRACEKAGFKCTVTKEAQAVLACF LDKHHDIIIIDHRNPRQLDAEALCRSIRSSKLSENTVIVGVVRRVDREELSVMPFISAGF TRRYVENPNIMACYNELLQLEFGEVRSQLKLRACNSVFTALENSEDAIEITSEDRFIQYA NPAFETTMGYQSGELIGKELGEVPINEKKADLLDTINSCIRIGKEWQGIYYAKKKNGDNI QQNVKIIPVIGQGGKIRHYVSIIRVCNGNNKAEKISECVQSDTHTDNQTGKHKDRRKGSL DVKAVASRATEVSSQRRHSSMARIHSMTIEAPITKVINIINAAQESSPMPVTEALDRVLE ILRTTELYSPQFGAKDDDPHANDLVGGLMSDGLRRLSGNEYVLSTKNTQMVSSNIITPIS LDDVPPRIARAMENEEYWDFDIFELEAATHNRPLIYLGLKMFARFGICEFLHCSESTLRS WLQIIEANYHSSNPYHNSTHSADVLHATAYFLSKERIKETLDPIDEVAALIAATIHDVDH PGRTNSFLCNAGSELAILYNDTAVLESHHAALAFQLTTGDDKCNIFKNMERNDYRTLRQG IIDMVLATEMTKHFEHVNKFVNSINKPLATLEENGETDKNQEVINTMLRTPENRTLIKRM LIKCADVSNPCRPLQYCIEWAARISEEYFSQTDEEKQQGLPVVMPVFDRNTCSIPKSQIS FIDYFITDMFDAWDAFVDLPDLMQHLDNNFKYWKGLDEMKLRNLRPPPE Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| 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: Clofarabine | Ligand Info | |||||
| Structure Description | Crystal structure of PDE8A catalytic domain in complex with clofarabine | PDB:7CWA | ||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [6] |
| PDB Sequence |
DDVPPRIARA
491 MENEEYWDFD501 IFELEAATHN511 RPLIYLGLKM521 FARFGICEFL531 HCSESTLRSW 541 LQIIEANYHS551 SNPYHNSTHS561 ADVLHATAYF571 LSKERIKETL581 DPIDEVAALI 591 AATIHDVDHP601 GRTNSFLCNA611 GSELAILYND621 TAVLESHHAA631 LAFQLTTGDD 641 KCNIFKNMER651 NDYRTLRQGI661 IDMVLATEMT671 KHFEHVNKFV681 NSINKPLATL 691 EENGETDKNQ701 EVINTMLRTP711 ENRTLIKRML721 IKCADVSNPC731 RPLQYCIEWA 741 ARISEEYFSQ751 TDEEKQQGLP761 VVMPVFDRNT771 CSIPKSQISF781 IDYFITDMFD 791 AWDAFVDLPD801 LMQHLDNNFK811 YWKGLDEM
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| Ligand Name: Isobutylmethylxanthine | Ligand Info | |||||
| Structure Description | Crystal structure of PDE8A catalytic domain in complex with IBMX | PDB:3ECN | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [7] |
| PDB Sequence |
DDVPPRIARA
491 MENEEYWDFD501 IFELEAATHN511 RPLIYLGLKM521 FARFGICEFL531 HCSESTLRSW 541 LQIIEANYHS551 SNPYHNSTHS561 ADVLHATAYF571 LSKERIKETL581 DPIDEVAALI 591 AATIHDVDHP601 GRTNSFLCNA611 GSELAILYND621 TAVLESHHAA631 LAFQLTTGDD 641 KCNIFKNMER651 NDYRTLRQGI661 IDMVLATEMT671 KHFEHVNKFV681 NSINKPLATL 691 EENGETDKNQ701 EVINTMLRTP711 ENRTLIKRML721 IKCADVSNPC731 RPLQYCIEWA 741 ARISEEYFSQ751 TDEEKQQGLP761 VVMPVFDRNT771 CSIPKSQISF781 IDYFITDMFD 791 AWDAFVDLPD801 LMQHLDNNFK811 YWKGLDEM
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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).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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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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| Purine metabolism | hsa00230 | Affiliated Target |
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| Class: Metabolism => Nucleotide metabolism | Pathway Hierarchy | ||
| Cortisol synthesis and secretion | hsa04927 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| 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 | ||||||
| References | Top | |||||
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| REF 1 | PDE8 regulates rapid Teff cell adhesion and proliferation independent of ICER. PLoS One. 2010 Aug 9;5(8):e12011. | |||||
| REF 2 | Inhibitors of phosphodiesterase 11 (PDE11). US9173884. | |||||
| REF 3 | Therapeutic applications in the cardiovascular field of quinazolinedione derivatives. US8846654. | |||||
| REF 4 | Optically active PDE10 inhibitor. US9493447. | |||||
| REF 5 | Differential Expression and Function of PDE8 and PDE4 in Effector T cells: Implications for PDE8 as a Drug Target in Inflammation.Front Pharmacol. 2016 Aug 23;7:259. | |||||
| REF 6 | Rational Design of 2-Chloroadenine Derivatives as Highly Selective Phosphodiesterase 8A Inhibitors. J Med Chem. 2020 Dec 24;63(24):15852-15863. | |||||
| REF 7 | Kinetic and structural studies of phosphodiesterase-8A and implication on the inhibitor selectivity. Biochemistry. 2008 Dec 2;47(48):12760-8. | |||||
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