Target Information
| Target General Information | Top | |||||
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| Target ID |
T88975
(Former ID: TTDS00390)
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| Target Name |
Phosphodiesterase 3A (PDE3A)
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| Synonyms |
cGMP-inhibited 3',5'-cyclic phosphodiesterase A; Phosphodiesterase 3A; Cyclic GMP-inhibited phosphodiesterase A; Cyclic GMP inhibited phosphodiesterase A; CGI-PDE A
Click to Show/Hide
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| Gene Name |
PDE3A
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 4 Target-related Diseases | + | ||||
| 1 | Arterial occlusive disease [ICD-11: BD40] | |||||
| 2 | Asthma [ICD-11: CA23] | |||||
| 3 | Heart failure [ICD-11: BD10-BD1Z] | |||||
| 4 | Thrombocytosis [ICD-11: 3B63] | |||||
| Function |
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 |
MAVPGDAARVRDKPVHSGVSQAPTAGRDCHHRADPASPRDSGCRGCWGDLVLQPLRSSRK
LSSALCAGSLSFLLALLVRLVRGEVGCDLEQCKEAAAAEEEEAAPGAEGGVFPGPRGGAP GGGARLSPWLQPSALLFSLLCAFFWMGLYLLRAGVRLPLAVALLAACCGGEALVQIGLGV GEDHLLSLPAAGVVLSCLAAATWLVLRLRLGVLMIALTSAVRTVSLISLERFKVAWRPYL AYLAGVLGILLARYVEQILPQSAEAAPREHLGSQLIAGTKEDIPVFKRRRRSSSVVSAEM SGCSSKSHRRTSLPCIPREQLMGHSEWDHKRGPRGSQSSGTSITVDIAVMGEAHGLITDL LADPSLPPNVCTSLRAVSNLLSTQLTFQAIHKPRVNPVTSLSENYTCSDSEESSEKDKLA IPKRLRRSLPPGLLRRVSSTWTTTTSATGLPTLEPAPVRRDRSTSIKLQEAPSSSPDSWN NPVMMTLTKSRSFTSSYAISAANHVKAKKQSRPGALAKISPLSSPCSSPLQGTPASSLVS KISAVQFPESADTTAKQSLGSHRALTYTQSAPDLSPQILTPPVICSSCGRPYSQGNPADE PLERSGVATRTPSRTDDTAQVTSDYETNNNSDSSDIVQNEDETECLREPLRKASACSTYA PETMMFLDKPILAPEPLVMDNLDSIMEQLNTWNFPIFDLVENIGRKCGRILSQVSYRLFE DMGLFEAFKIPIREFMNYFHALEIGYRDIPYHNRIHATDVLHAVWYLTTQPIPGLSTVIN DHGSTSDSDSDSGFTHGHMGYVFSKTYNVTDDKYGCLSGNIPALELMALYVAAAMHDYDH PGRTNAFLVATSAPQAVLYNDRSVLENHHAAAAWNLFMSRPEYNFLINLDHVEFKHFRFL VIEAILATDLKKHFDFVAKFNGKVNDDVGIDWTNENDRLLVCQMCIKLADINGPAKCKEL HLQWTDGIVNEFYEQGDEEASLGLPISPFMDRSAPQLANLQESFISHIVGPLCNSYDSAG LMPGKWVEDSDESGDTDDPEEEEEEAPAPNEEETCENNESPKKKTFKRRKIYCQITQHLL QNHKMWKKVIEEEQRLAGIENQSLDQTPQSHSSEQIQAIKEEEEEKGKPRGEEIPTQKPD Q 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) | [+] 5 Approved Drugs | + | ||||
| 1 | Aminophylline | Drug Info | Approved | Bronchial asthma | [2] | |
| 2 | Anagrelide | Drug Info | Approved | Thrombocythemia | [3], [4] | |
| 3 | Cilostazol | Drug Info | Approved | Intermittent claudication | [5], [6] | |
| 4 | Enoximone | Drug Info | Approved | Congestive heart failure | [4] | |
| 5 | VESNARINONE | Drug Info | Approved | Cardiac failure | [7] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | BEMORADAN | Drug Info | Phase 2 | Heart failure | [8] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | LAS-31180 | Drug Info | Terminated | Heart failure | [10] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 33 Inhibitor drugs | + | ||||
| 1 | Aminophylline | Drug Info | [11], [12] | |||
| 2 | Anagrelide | Drug Info | [1] | |||
| 3 | Cilostazol | Drug Info | [13] | |||
| 4 | Enoximone | Drug Info | [14] | |||
| 5 | VESNARINONE | Drug Info | [15] | |||
| 6 | BEMORADAN | Drug Info | [7] | |||
| 7 | CI-930 | Drug Info | [16] | |||
| 8 | BMY-20844 | Drug Info | [17] | |||
| 9 | IMAZODAN | Drug Info | [18] | |||
| 10 | 1,3,9,9a-Tetrahydro-imidazo[4,5-b]quinolin-2-one | Drug Info | [19] | |||
| 11 | 1,3-Dihydro-imidazo[4,5-b]quinolin-2-one | Drug Info | [19] | |||
| 12 | 1,3-Dihydro-naphtho[2,3-d]imidazol-2-one | Drug Info | [19] | |||
| 13 | 1,5-Dihydro-imidazo[2,1-b]quinazolin-2-one | Drug Info | [20] | |||
| 14 | 2-morpholino-7-(2-phenylethynyl)-4H-chromen-4-one | Drug Info | [21] | |||
| 15 | 2-morpholino-7-phenyl-4H-chromen-4-one | Drug Info | [21] | |||
| 16 | 5-Methyl-1,3-dihydro-imidazo[4,5-b]quinolin-2-one | Drug Info | [19] | |||
| 17 | 6-(2-Imidazol-1-yl-vinyl)-1H-quinolin-2-one | Drug Info | [18] | |||
| 18 | 6-Imidazol-1-yl-3,4-dihydro-1H-quinolin-2-one | Drug Info | [18] | |||
| 19 | 6-Pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one | Drug Info | [18] | |||
| 20 | 7-Chloro-1,3-dihydro-imidazo[4,5-b]quinolin-2-one | Drug Info | [19] | |||
| 21 | 7-Ethoxy-1,3-dihydro-imidazo[4,5-b]quinolin-2-one | Drug Info | [19] | |||
| 22 | 7-Fluoro-1,3-dihydro-imidazo[4,5-b]quinolin-2-one | Drug Info | [19] | |||
| 23 | 7-Iodo-1,5-dihydro-imidazo[2,1-b]quinazolin-2-one | Drug Info | [20] | |||
| 24 | 7-Methyl-1,3-dihydro-imidazo[4,5-b]quinolin-2-one | Drug Info | [19] | |||
| 25 | 8-Chloro-1,3-dihydro-imidazo[4,5-b]quinolin-2-one | Drug Info | [19] | |||
| 26 | 8-Methyl-1,3-dihydro-imidazo[4,5-b]quinolin-2-one | Drug Info | [19] | |||
| 27 | 8-methyl-2-morpholino-7-phenoxy-4H-chromen-4-one | Drug Info | [21] | |||
| 28 | 8-methyl-2-morpholino-7-phenyl-4H-chromen-4-one | Drug Info | [21] | |||
| 29 | BENZOYLENUREA | Drug Info | [22] | |||
| 30 | isobutylmethylxanthine | Drug Info | [13] | |||
| 31 | KURAIDIN | Drug Info | [23] | |||
| 32 | SOPHOFLAVESCENOL | Drug Info | [23] | |||
| 33 | TETRAHYDROBENXIMIDAZOLE | Drug Info | [16] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | LAS-31180 | Drug Info | [10] | |||
| 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: Anagrelide | Ligand Info | |||||
| Structure Description | Cryo-EM structure of anagrelide-induced PDE3A-SLFN12 complex | PDB:7EG0 | ||||
| Method | Electron microscopy | Resolution | 3.40 Å | Mutation | Yes | [24] |
| PDB Sequence |
KPILAPEPLV
678 MDNLDSIMEQ688 LNTWNFPIFD698 LVENIGRKCG708 RILSQVSYRL718 FEDMGLFEAF 728 KIPIREFMNY738 FHALEIGYRD748 IPYHNRIHAT758 DVLHAVWYLT768 TQPIPGLSTV 778 GYVFSKTYNV809 TDDKYGCLSG819 NIPALELMAL829 YVAAAMHDYD839 HPGRTNAFLV 849 ATSAPQAVLY859 NDRSVLENHH869 AAAAWNLFMS879 RPEYNFLINL889 DHVEFKHFRF 899 LVIEAILATD909 LKKHFDFVAK919 FNGKVNDDVG929 IDWTNENDRL939 LVCQMCIKLA 949 DINGPAKCKE959 LHLQWTDGIV969 NEFYEQGDEE979 ASLGLPISPF989 MDRSAPQLAN 999 LQESFISHIV1009 GPLCNSYDSA1019 GLMPGKWVEK1070 IYCQITQHLL1080 QNHKMWKKVI 1090 EEEQRLAGIE1100 NQ
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| Ligand Name: Adenosine monophosphate | Ligand Info | |||||
| Structure Description | Crystal structure of the catalytic domain of human PDE3A bound to AMP | PDB:7L29 | ||||
| Method | X-ray diffraction | Resolution | 2.08 Å | Mutation | No | [25] |
| PDB Sequence |
KPILAPEPLV
678 MDNLDSIMEQ688 LNTWNFPIFD698 LVENIGRKCG708 RILSQVSYRL718 FEDMGLFEAF 728 KIPIREFMNY738 FHALEIGYRD748 IPYHNRIHAT758 DVLHAVWYLT768 TQPIPGLSTV 778 IGGSYVFSKT806 YNVTDDKYGC816 LSGNIPALEL826 MALYVAAAMH836 DYDHPGRTNA 846 FLVATSAPQA856 VLYNDRSVLE866 NHHAAAAWNL876 FMSRPEYNFL886 INLDHVEFKH 896 FRFLVIEAIL906 ATDLKKHFDF916 VAKFNGKVND926 DVGIDWTNEN936 DRLLVCQMCI 946 KLADINGPAK956 CKELHLQWTD966 GIVNEFYEQG976 DEEASLGLPI986 SPFMDRSAPQ 996 LANLQESFIS1006 HIVGPLCNSY1016 DSAGLMPGKW1026 VRKIYCQITQ1077 HLLQNHKMWK 1087 KVIEEE
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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 | ||
| cAMP signaling pathway | hsa04024 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Renin secretion | hsa04924 | 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 | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 4 KEGG Pathways | + | ||||
| 1 | Purine metabolism | |||||
| 2 | cGMP-PKG signaling pathway | |||||
| 3 | cAMP signaling pathway | |||||
| 4 | Morphine addiction | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | cGMP effects | |||||
| 2 | G alpha (s) signalling events | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | miR-targeted genes in muscle cell - TarBase | |||||
| 2 | miR-targeted genes in lymphocytes - TarBase | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005 Jul 7;353(1):33-45. | |||||
| REF 2 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 081142. | |||||
| REF 3 | 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. (Ligand id: 7114). | |||||
| REF 4 | Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. | |||||
| REF 5 | 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. (Ligand id: 7148). | |||||
| REF 6 | Emerging drugs in peripheral arterial disease. Expert Opin Emerg Drugs. 2006 Mar;11(1):75-90. | |||||
| REF 7 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 8 | Evaluation of the excretion, and metabolism of the cardiotonic agent bemoradan in male rats and female beagle dogs. Eur J Drug Metab Pharmacokinet. 2001 Oct-Dec;26(4):263-71. | |||||
| REF 9 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000367) | |||||
| REF 10 | Pharmacological profile of LAS 31180, a new inotropic/vasodilator quinolone derivative. Arzneimittelforschung. 2000 Nov;50(11):980-6. | |||||
| REF 11 | Topical fat reduction from the waist. Diabetes Obes Metab. 2007 May;9(3):300-3. | |||||
| REF 12 | Spasmolytic effects of colforsin daropate on serotonin-induced pulmonary hypertension and bronchoconstriction in dogs. Acta Anaesthesiol Scand. 2002 Mar;46(3):297-302. | |||||
| REF 13 | 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 14 | Inhibitors of cyclic AMP phosphodiesterase. 2. Structural variations of N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro- 2-oxoimidazo[2,1-b]quinazolin... J Med Chem. 1987 Feb;30(2):303-18. | |||||
| REF 15 | Design, synthesis and biological evaluation of 6-(benzyloxy)-4-methylquinolin-2(1H)-one derivatives as PDE3 inhibitors. Bioorg Med Chem. 2010 Jan 15;18(2):855-62. | |||||
| REF 16 | Cardiotonic agents. 9. Synthesis and biological evaluation of a series of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl)phenyl]ethenyl]-3 (2H)-pyridazi... J Med Chem. 1989 Feb;32(2):342-50. | |||||
| REF 17 | Inhibitors of blood platelet cAMP phosphodiesterase. 3. 1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives with enhanced aqueous solubility. J Med Chem. 1992 Jul 10;35(14):2688-96. | |||||
| REF 18 | 3,4-Dihydroquinolin-2(1H)-ones as combined inhibitors of thromboxane A2 synthase and cAMP phosphodiesterase. J Med Chem. 1992 Feb 21;35(4):620-8. | |||||
| REF 19 | 1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-ones--inhibitors of blood platelet cAMP phosphodiesterase and induced aggregation. J Med Chem. 1991 Sep;34(9):2906-16. | |||||
| REF 20 | Inhibitors of cyclic AMP phosphodiesterase. 3. Synthesis and biological evaluation of pyrido and imidazolyl analogues of 1,2,3,5-tetrahydro-2-oxoim... J Med Chem. 1988 Nov;31(11):2136-45. | |||||
| REF 21 | Analysis of anti-PDE3 activity of 2-morpholinochromone derivatives reveals multiple mechanisms of anti-platelet activity. Bioorg Med Chem Lett. 2006 Feb 15;16(4):969-73. | |||||
| REF 22 | CODES, a novel procedure for ligand-based virtual screening: PDE7 inhibitors as an application example. Eur J Med Chem. 2008 Jul;43(7):1349-59. | |||||
| REF 23 | A prenylated flavonol, sophoflavescenol: a potent and selective inhibitor of cGMP phosphodiesterase 5. Bioorg Med Chem Lett. 2002 Sep 2;12(17):2313-6. | |||||
| REF 24 | Structure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells. Nat Commun. 2021 Oct 27;12(1):6204. | |||||
| REF 25 | Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase. Nat Commun. 2021 Jul 16;12(1):4375. | |||||
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