Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT8Q1AP)

• DOT Name: cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A)
• Synonyms: EC 3.1.4.35; cGMP-binding cGMP-specific phosphodiesterase; CGB-PDE
• Gene Name: PDE5A
• UniProt ID: PDE5A_HUMAN
• PDB ID: 1RKP ; 1T9R ; 1T9S ; 1TBF ; 1UDT ; 1UDU ; 1UHO ; 1XOZ ; 1XP0 ; 2CHM ; 2H40 ; 2H42 ; 2H44 ; 2XSS ; 3B2R ; 3BJC ; 3HC8 ; 3HDZ ; 3JWQ ; 3JWR ; 3LFV ; 3MF0 ; 3SHY ; 3SHZ ; 3SIE ; 3TGE ; 3TGG ; 4G2W ; 4G2Y ; 4I9Z ; 4IA0 ; 4MD6 ; 4OEW ; 4OEX ; 5JO3 ; 5ZZ2 ; 6ACB ; 6IWI ; 6L6E ; 6VBI ; 7FAQ ; 7FAR ; 8W4S ; 8W4T
• EC Number: 3.1.4.35
• Pfam ID: PF01590 ; PF00233
• Sequence:
  MERAGPSFGQQRQQQQPQQQKQQQRDQDSVEAWLDDHWDFTFSYFVRKATREMVNAWFAE
  RVHTIPVCKEGIRGHTESCSCPLQQSPRADNSAPGTPTRKISASEFDRPLRPIVVKDSEG
  TVSFLSDSEKKEQMPLTPPRFDHDEGDQCSRLLELVKDISSHLDVTALCHKIFLHIHGLI
  SADRYSLFLVCEDSSNDKFLISRLFDVAEGSTLEEVSNNCIRLEWNKGIVGHVAALGEPL
  NIKDAYEDPRFNAEVDQITGYKTQSILCMPIKNHREEVVGVAQAINKKSGNGGTFTEKDE
  KDFAAYLAFCGIVLHNAQLYETSLLENKRNQVLLDLASLIFEEQQSLEVILKKIAATIIS
  FMQVQKCTIFIVDEDCSDSFSSVFHMECEELEKSSDTLTREHDANKINYMYAQYVKNTME
  PLNIPDVSKDKRFPWTTENTGNVNQQCIRSLLCTPIKNGKKNKVIGVCQLVNKMEENTGK
  VKPFNRNDEQFLEAFVIFCGLGIQNTQMYEAVERAMAKQMVTLEVLSYHASAAEEETREL
  QSLAAAVVPSAQTLKITDFSFSDFELSDLETALCTIRMFTDLNLVQNFQMKHEVLCRWIL
  SVKKNYRKNVAYHNWRHAFNTAQCMFAALKAGKIQNKLTDLEILALLIAALSHDLDHRGV
  NNSYIQRSEHPLAQLYCHSIMEHHHFDQCLMILNSPGNQILSGLSIEEYKTTLKIIKQAI
  LATDLALYIKRRGEFFELIRKNQFNLEDPHQKELFLAMLMTACDLSAITKPWPIQQRIAE
  LVATEFFDQGDRERKELNIEPTDLMNREKKNKIPSMQVGFIDAICLQLYEALTHVSEDCF
  PLLDGCRKNRQKWQALAEQQEKMLINGESGQAKRN
• Function: Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP. Specifically regulates nitric-oxide-generated cGMP.
• Tissue Specificity: Expressed in aortic smooth muscle cells, heart, placenta, skeletal muscle and pancreas and, to a much lesser extent, in brain, liver and lung.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  cGMP-PKG sig.ling pathway (hsa04022)
• Reactome Pathway:
  Smooth Muscle Contraction (R-HSA-445355)
  RHOBTB1 GTPase cycle (R-HSA-9013422)
  cGMP effects (R-HSA-418457)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A) affects the response to substance of Temozolomide.	[21]
DTI-015	DMXZRW0	Approved	cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A) affects the response to substance of DTI-015.	[21]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cyclic guanosine monophosphate	DMOU93V	Investigative	cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A) decreases the abundance of Cyclic guanosine monophosphate.	[11]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[1]

21 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[9]
Dipyridamole	DMXY30O	Approved	Dipyridamole decreases the activity of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[10]
Rhucin	DM3ADGP	Approved	Rhucin decreases the activity of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[11]
Tadalafil	DMJZHT1	Approved	Tadalafil decreases the activity of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[12]
Vardenafil	DMTBGW8	Approved	Vardenafil decreases the activity of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the activity of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[14]
EXISULIND	DMBY56U	Phase 3	EXISULIND decreases the activity of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[15]
ICARIIN	DMOJQGT	Phase 3	ICARIIN decreases the activity of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[16]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[20]
3,7-Bis(2-hydroxyethyl)icaritin	DMQADXL	Investigative	3,7-Bis(2-hydroxyethyl)icaritin decreases the activity of cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A).	[16]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Comparative effects of raloxifene, tamoxifen and estradiol on human osteoblasts in vitro: estrogen receptor dependent or independent pathways of raloxifene. J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):281-9.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1. Clin Cancer Res. 2000 Oct;6(10):4136-41.
• [11] Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology. 1999 Jul;91(1):307-10. doi: 10.1097/00000542-199907000-00041.
• [12] Pharmacotherapy of erectile dysfunction: focus on cardiovascular safety. Expert Opin Drug Saf. 2005 May;4(3):531-40. doi: 10.1517/14740338.4.3.531.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] In vitro inhibition of human cGMP-specific phosphodiesterase-5 by polyphenols from red grapes. J Agric Food Chem. 2005 Mar 23;53(6):1960-5.
• [15] Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. Cancer Res. 2000 Jul 1;60(13):3338-42.
• [16] Potent inhibition of human phosphodiesterase-5 by icariin derivatives. J Nat Prod. 2008 Sep;71(9):1513-7.
• [17] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [18] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [19] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [20] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [21] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.