Target Information
| Target General Information | Top | |||||
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| Target ID |
T77400
(Former ID: TTDR00256)
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| Target Name |
Phosphodiesterase 2A (PDE2A)
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| Synonyms |
cGMP-dependent 3',5'-cyclic phosphodiesterase; PDE-II; Cyclic-GMP phosphodiesterase; Cyclic GMP-stimulated phosphodiesterase; Cyclic GMP stimulated phosphodiesterase; CGSPDE; CGS-PDE
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| Gene Name |
PDE2A
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 4 Target-related Diseases | + | ||||
| 1 | Inborn purine/pyrimidine/nucleotide metabolism error [ICD-11: 5C55] | |||||
| 2 | Indeterminate colitis [ICD-11: DD72] | |||||
| 3 | Irritable bowel syndrome [ICD-11: DD91] | |||||
| 4 | Mood disorder [ICD-11: 6A60-6E23] | |||||
| Function |
Plays an important role in growth and invasion of malignant melanoma cells (e. g. pseudomyxoma peritonei (PMP) cell line). Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.
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| BioChemical Class |
Phosphoric diester hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.1.4.17
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| Sequence |
MGQACGHSILCRSQQYPAARPAEPRGQQVFLKPDEPPPPPQPCADSLQDALLSLGSVIDI
SGLQRAVKEALSAVLPRVETVYTYLLDGESQLVCEDPPHELPQEGKVREAIISQKRLGCN GLGFSDLPGKPLARLVAPLAPDTQVLVMPLADKEAGAVAAVILVHCGQLSDNEEWSLQAV EKHTLVALRRVQVLQQRGPREAPRAVQNPPEGTAEDQKGGAAYTDRDRKILQLCGELYDL DASSLQLKVLQYLQQETRASRCCLLLVSEDNLQLSCKVIGDKVLGEEVSFPLTGCLGQVV EDKKSIQLKDLTSEDVQQLQSMLGCELQAMLCVPVISRATDQVVALACAFNKLEGDLFTD EDEHVIQHCFHYTSTVLTSTLAFQKEQKLKCECQALLQVAKNLFTHLDDVSVLLQEIITE ARNLSNAEICSVFLLDQNELVAKVFDGGVVDDESYEIRIPADQGIAGHVATTGQILNIPD AYAHPLFYRGVDDSTGFRTRNILCFPIKNENQEVIGVAELVNKINGPWFSKFDEDLATAF SIYCGISIAHSLLYKKVNEAQYRSHLANEMMMYHMKVSDDEYTKLLHDGIQPVAAIDSNF ASFTYTPRSLPEDDTSMAILSMLQDMNFINNYKIDCPTLARFCLMVKKGYRDPPYHNWMH AFSVSHFCYLLYKNLELTNYLEDIEIFALFISCMCHDLDHRGTNNSFQVASKSVLAALYS SEGSVMERHHFAQAIAILNTHGCNIFDHFSRKDYQRMLDLMRDIILATDLAHHLRIFKDL QKMAEVGYDRNNKQHHRLLLCLLMTSCDLSDQTKGWKTTRKIAELIYKEFFSQGDLEKAM GNRPMEMMDREKAYIPELQISFMEHIAMPIYKLLQDLFPKAAELYERVASNREHWTKVSH KFTIRGLPSNNSLDFLDEEYEVPDLDGTRAPINGCCSLDAE Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T99TRQ | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | CP-461 | Drug Info | Phase 2 | Inflammatory bowel disease | [2] | |
| 2 | Tofisopam | Drug Info | Phase 2 | Irritable bowel syndrome | [3] | |
| 3 | ND7001 | Drug Info | Phase 1 | Mood disorder | [4] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 65 Inhibitor drugs | + | ||||
| 1 | CP-461 | Drug Info | [1] | |||
| 2 | Tofisopam | Drug Info | [5] | |||
| 3 | 1,2,4-triazole [1,5-a]pyrimidin-7-yl derivative 1 | Drug Info | [6] | |||
| 4 | 1,2,4-triazole [1,5-a]pyrimidin-7-yl derivative 2 | Drug Info | [6] | |||
| 5 | 1,2,4-triazole [1,5-a]pyrimidin-7-yl derivative 3 | Drug Info | [6] | |||
| 6 | 1,2,4-triazole [4,3-a]quinoxaline derivative 1 | Drug Info | [6] | |||
| 7 | 1,2,4-triazole [4,3-a]quinoxaline derivative 2 | Drug Info | [6] | |||
| 8 | 1,2,4-triazole [4,3-a]quinoxaline derivative 3 | Drug Info | [6] | |||
| 9 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivative 1 | Drug Info | [6] | |||
| 10 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivative 2 | Drug Info | [6] | |||
| 11 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivative 3 | Drug Info | [6] | |||
| 12 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivative 4 | Drug Info | [6] | |||
| 13 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivative 5 | Drug Info | [6] | |||
| 14 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivative 6 | Drug Info | [6] | |||
| 15 | Benzodiazepine derivative 2 | Drug Info | [6] | |||
| 16 | Imidazo triazine derivative 1 | Drug Info | [6] | |||
| 17 | Imidazo triazine derivative 2 | Drug Info | [6] | |||
| 18 | Imidazo triazine derivative 3 | Drug Info | [6] | |||
| 19 | Imidazo triazine derivative 4 | Drug Info | [6] | |||
| 20 | Imidazo triazine derivative 5 | Drug Info | [6] | |||
| 21 | Imidazotriazinone derivative 1 | Drug Info | [6] | |||
| 22 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 1 | Drug Info | [6] | |||
| 23 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 2 | Drug Info | [6] | |||
| 24 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 3 | Drug Info | [6] | |||
| 25 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 4 | Drug Info | [6] | |||
| 26 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 5 | Drug Info | [6] | |||
| 27 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 6 | Drug Info | [6] | |||
| 28 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 7 | Drug Info | [6] | |||
| 29 | Imidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine derivative 8 | Drug Info | [6] | |||
| 30 | Imidazo[5,1-c][1,2,4]benzotriazine derivative 1 | Drug Info | [6] | |||
| 31 | Imidazo[5,1-c][1,2,4]benzotriazine derivative 2 | Drug Info | [6] | |||
| 32 | Imidazo[5,1-c][1,2,4]benzotriazine derivative 3 | Drug Info | [6] | |||
| 33 | Imidazo[5,1-c][1,2,4]benzotriazine derivative 4 | Drug Info | [6] | |||
| 34 | Oxindole derivative 1 | Drug Info | [6] | |||
| 35 | PMID27321640-Compound-58 | Drug Info | [6] | |||
| 36 | PMID27321640-Compound-59 | Drug Info | [6] | |||
| 37 | PMID27321640-Compound-74 | Drug Info | [6] | |||
| 38 | PMID27321640-Compound-75 | Drug Info | [6] | |||
| 39 | PMID27321640-Compound-76 | Drug Info | [6] | |||
| 40 | Purin-6-one derivative 1 | Drug Info | [6] | |||
| 41 | Pyrazolo[3,4-d]pyrimidine derivative 1 | Drug Info | [6] | |||
| 42 | Pyrazolo[3,4-d]pyrimidine derivative 2 | Drug Info | [6] | |||
| 43 | Pyrazolo[3,4-d]pyrimidine derivative 3 | Drug Info | [6] | |||
| 44 | Pyrazolo[3,4-d]pyrimidine derivative 4 | Drug Info | [6] | |||
| 45 | Pyrido[1,2,4]triazolo[4,3-a]pyrazine derivative 1 | Drug Info | [6] | |||
| 46 | Pyrido[1,2,4]triazolo[4,3-a]pyrazine derivative 2 | Drug Info | [6] | |||
| 47 | Pyrido[1,2,4]triazolo[4,3-a]pyrazine derivative 3 | Drug Info | [6] | |||
| 48 | Pyrido[2,3-d]pyrimidine-2,4-diamine derivative 1 | Drug Info | [6] | |||
| 49 | Pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazine derivative 1 | Drug Info | [6] | |||
| 50 | Pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazine derivative 2 | Drug Info | [6] | |||
| 51 | Triazolo-phthalazine derivative 1 | Drug Info | [6] | |||
| 52 | Triazolo-pyridine derivative 2 | Drug Info | [6] | |||
| 53 | Triazolo-pyridine derivative 3 | Drug Info | [6] | |||
| 54 | Triazolo-pyridine derivative 4 | Drug Info | [6] | |||
| 55 | Triazolo-pyridine derivative 5 | Drug Info | [6] | |||
| 56 | Triazolo-pyridine derivative 6 | Drug Info | [6] | |||
| 57 | IMAZODAN | Drug Info | [7] | |||
| 58 | (2R,3S)-3-(6-Amino-purin-9-yl)-nonan-2-ol | Drug Info | [8] | |||
| 59 | 2-Morpholin-4-yl-8-phenylethynyl-chromen-4-one | Drug Info | [9] | |||
| 60 | BAY-60-7550 | Drug Info | [8] | |||
| 61 | Benzyl-(2-pyridin-3-yl-quinazolin-4-yl)-amine | Drug Info | [10] | |||
| 62 | Benzyl-(2-pyridin-4-yl-quinazolin-4-yl)-amine | Drug Info | [10] | |||
| 63 | Cyclic Guanosine Monophosphate | Drug Info | [11] | |||
| 64 | EHNA | Drug Info | [12] | |||
| 65 | isobutylmethylxanthine | Drug Info | [13], [14] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | ND7001 | Drug Info | [4] | |||
| 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: (2S,3R)-3-(6-amino-9H-purin-9-yl)nonan-2-ol | Ligand Info | |||||
| Structure Description | Selective Inhibitors of PDE2, PDE9, and PDE10: Modulators of Activity of the Central Nervous System | PDB:4C1I | ||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | No | [15] |
| PDB Sequence |
EYTKLLHDGI
590 QPVAAIDSNF600 ASFTYTPRSL610 PEDDTSMAIL620 SMLQDMNFIN630 NYKIDCPTLA 640 RFCLMVKKGY650 RDPPYHNWMH660 AFSVSHFCYL670 LYKNLELTNY680 LEDIEIFALF 690 ISCMCHDLDH700 RGTNNSFQVA710 SKSVLAALYS720 SEGSVMERHH730 FAQAIAILNT 740 HGCNIFDHFS750 RKDYQRMLDL760 MRDIILATDL770 AHHLRIFKDL780 QKMAEVGYDR 790 NNKQHHRLLL800 CLLMTSCDLS810 DQTKGWKTTR820 KIAELIYKEF830 FSQGDLEKAM 840 GNRPMEMMDR850 EKAYIPELQI860 SFMEHIAMPI870 YKLLQDLFPK880 AAELYERVAS 890 NREHWTKVSH900 KFTIR
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| Ligand Name: Isobutylmethylxanthine | Ligand Info | |||||
| Structure Description | hPDE2A catalytic domain complexed with IBMX | PDB:3ITU | ||||
| Method | X-ray diffraction | Resolution | 1.58 Å | Mutation | No | [16] |
| PDB Sequence |
DDEYTKLLHD
588 GIQPVAAIDS598 NFASFTYTPR608 SLPEDDTSMA618 ILSMLQDMNF628 INNYKIDCPT 638 LARFCLMVKK648 GYRDPPYHNW658 MHAFSVSHFC668 YLLYKNLELT678 NYLEDIEIFA 688 LFISCMCHDL698 DHRGTNNSFQ708 VASKSVLAAL718 YSSEGSVMER728 HHFAQAIAIL 738 NTHGCNIFDH748 FSRKDYQRML758 DLMRDIILAT768 DLAHHLRIFK778 DLQKMAEVGY 788 DRNNKQHHRL798 LLCLLMTSCD808 LSDQTKGWKT818 TRKIAELIYK828 EFFSQGDLEK 838 AMGNRPMEMM848 DREKAYIPEL858 QISFMEHIAM868 PIYKLLQDLF878 PKAAELYERV 888 ASNREHWTKV898 SHKFTIRGLP908 SNNSLDFL
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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 | ||
| cGMP-PKG signaling pathway | hsa04022 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Olfactory transduction | hsa04740 | Affiliated Target |
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| Class: Organismal Systems => Sensory system | Pathway Hierarchy | ||
| Aldosterone synthesis and secretion | hsa04925 | 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 | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Purine metabolism | |||||
| 2 | cGMP-PKG signaling pathway | |||||
| 3 | Morphine addiction | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TSH Signaling Pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | cGMP effects | |||||
| 2 | G alpha (s) signalling events | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Sulindac and its derivatives: a novel class of anticancer agents. Curr Opin Investig Drugs. 2001 May;2(5):677-83. | |||||
| REF 2 | ClinicalTrials.gov (NCT00060710) CP-461 in the Treatment of Patients With Advanced Melanoma. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT00486876) A Study of 3 Doses of Dextofisopam in Females With Irritable Bowel Syndrome. U.S. National Institutes of Health. | |||||
| REF 4 | Phosphodiesterase 2 inhibitors promote axonal outgrowth in organotypic slice co-cultures. Neurosignals. 2013;21(3-4):197-212. | |||||
| REF 5 | The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis. J Neural Transm (Vienna). 2010 Nov;117(11):1319-25. | |||||
| REF 6 | Towards selective phosphodiesterase 2A (PDE2A) inhibitors: a patent review (2010 - present).Expert Opin Ther Pat. 2016 Aug;26(8):933-46. | |||||
| REF 7 | Cardiotonic agents. 1. 4,5-Dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3 (2H)-pyridazinones: novel positive inotropic agents for the treatment of conges... J Med Chem. 1984 Sep;27(9):1099-101. | |||||
| REF 8 | The next generation of phosphodiesterase inhibitors: structural clues to ligand and substrate selectivity of phosphodiesterases. J Med Chem. 2005 May 19;48(10):3449-62. | |||||
| REF 9 | PDE2 inhibition by the PI3 kinase inhibitor LY294002 and analogues. Bioorg Med Chem Lett. 2004 Jun 7;14(11):2847-51. | |||||
| REF 10 | Discovery of potent cyclic GMP phosphodiesterase inhibitors. 2-Pyridyl- and 2-imidazolylquinazolines possessing cyclic GMP phosphodiesterase and th... J Med Chem. 1995 Sep 1;38(18):3547-57. | |||||
| REF 11 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 12 | Rapid regulation of PDE-2 and PDE-4 cyclic AMP phosphodiesterase activity following ligation of the T cell antigen receptor on thymocytes: analysis using the selective inhibitors erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) and rolipram. Cell Signal. 1996 Feb;8(2):97-110. | |||||
| REF 13 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 14 | A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity. J Med Chem. 1985 May;28(5):537-45. | |||||
| REF 15 | Chapter 4: Selective Inhibitors of Pde2, Pde9, and Pde10: Modulators of Activity of the Central Nervous System | |||||
| REF 16 | Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18225-30. | |||||
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