Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT75U9M4)

• DOT Name: Prostaglandin G/H synthase 2 (PTGS2)
• Synonyms: EC 1.14.99.1; Cyclooxygenase-2; COX-2; PHS II; Prostaglandin H2 synthase 2; PGH synthase 2; PGHS-2; Prostaglandin-endoperoxide synthase 2
• Gene Name: PTGS2
• UniProt ID: PGH2_HUMAN
• PDB ID: 5F19; 5F1A; 5IKQ; 5IKR; 5IKT; 5IKV; 5KIR
• EC Number: 1.14.99.1
• Pfam ID: PF03098
• Sequence:
  MLARALLLCAVLALSHTANPCCSHPCQNRGVCMSVGFDQYKCDCTRTGFYGENCSTPEFL
  TRIKLFLKPTPNTVHYILTHFKGFWNVVNNIPFLRNAIMSYVLTSRSHLIDSPPTYNADY
  GYKSWEAFSNLSYYTRALPPVPDDCPTPLGVKGKKQLPDSNEIVEKLLLRRKFIPDPQGS
  NMMFAFFAQHFTHQFFKTDHKRGPAFTNGLGHGVDLNHIYGETLARQRKLRLFKDGKMKY
  QIIDGEMYPPTVKDTQAEMIYPPQVPEHLRFAVGQEVFGLVPGLMMYATIWLREHNRVCD
  VLKQEHPEWGDEQLFQTSRLILIGETIKIVIEDYVQHLSGYHFKLKFDPELLFNKQFQYQ
  NRIAAEFNTLYHWHPLLPDTFQIHDQKYNYQQFIYNNSILLEHGITQFVESFTRQIAGRV
  AGGRNVPPAVQKVSQASIDQSRQMKYQSFNEYRKRFMLKPYESFEELTGEKEMSAELEAL
  YGDIDAVELYPALLVEKPRPDAIFGETMVEVGAPFSLKGLMGNVICSPAYWKPSTFGGEV
  GFQIINTASIQSLICNNVKGCPFTSFSVPDPELIKTVTINASSSRSGLDDINPTVLLKER
  STEL
• Function: Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate, AA, C20:4(n-6)), with a particular role in the inflammatory response. The cyclooxygenase activity oxygenates AA to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide prostaglandin H2 (PGH2), the precursor of all 2-series prostaglandins and thromboxanes. This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons. Similarly catalyzes successive cyclooxygenation and peroxidation of dihomo-gamma-linoleate (DGLA, C20:3(n-6)) and eicosapentaenoate (EPA, C20:5(n-3)) to corresponding PGH1 and PGH3, the precursors of 1- and 3-series prostaglandins. In an alternative pathway of prostanoid biosynthesis, converts 2-arachidonoyl lysophopholipids to prostanoid lysophopholipids, which are then hydrolyzed by intracellular phospholipases to release free prostanoids. Metabolizes 2-arachidonoyl glycerol yielding the glyceryl ester of PGH2, a process that can contribute to pain response. Generates lipid mediators from n-3 and n-6 polyunsaturated fatty acids (PUFAs) via a lipoxygenase-type mechanism. Oxygenates PUFAs to hydroperoxy compounds and then reduces them to corresponding alcohols. Plays a role in the generation of resolution phase interaction products (resolvins) during both sterile and infectious inflammation. Metabolizes docosahexaenoate (DHA, C22:6(n-3)) to 17R-HDHA, a precursor of the D-series resolvins (RvDs). As a component of the biosynthetic pathway of E-series resolvins (RvEs), converts eicosapentaenoate (EPA, C20:5(n-3)) primarily to 18S-HEPE that is further metabolized by ALOX5 and LTA4H to generate 18S-RvE1 and 18S-RvE2. In vascular endothelial cells, converts docosapentaenoate (DPA, C22:5(n-3)) to 13R-HDPA, a precursor for 13-series resolvins (RvTs) shown to activate macrophage phagocytosis during bacterial infection. In activated leukocytes, contributes to oxygenation of hydroxyeicosatetraenoates (HETE) to diHETES (5,15-diHETE and 5,11-diHETE). Can also use linoleate (LA, (9Z,12Z)-octadecadienoate, C18:2(n-6)) as substrate and produce hydroxyoctadecadienoates (HODEs) in a regio- and stereospecific manner, being (9R)-HODE ((9R)-hydroxy-(10E,12Z)-octadecadienoate) and (13S)-HODE ((13S)-hydroxy-(9Z,11E)-octadecadienoate) its major products. During neuroinflammation, plays a role in neuronal secretion of specialized preresolving mediators (SPMs) 15R-lipoxin A4 that regulates phagocytic microglia.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
  NF-kappa B sig.ling pathway (hsa04064)
  Efferocytosis (hsa04148)
  VEGF sig.ling pathway (hsa04370)
  C-type lectin receptor sig.ling pathway (hsa04625)
  IL-17 sig.ling pathway (hsa04657)
  TNF sig.ling pathway (hsa04668)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Serotonergic sy.pse (hsa04726)
  Ovarian steroidogenesis (hsa04913)
  Oxytocin sig.ling pathway (hsa04921)
  Regulation of lipolysis in adipocytes (hsa04923)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Leishmaniasis (hsa05140)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - D. adducts (hsa05204)
  MicroR.s in cancer (hsa05206)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  Synthesis of 15-eicosatetraenoic acid derivatives (R-HSA-2142770)
  Synthesis of Prostaglandins (PG) and Thromboxanes (TX) (R-HSA-2162123)
  Interleukin-10 signaling (R-HSA-6783783)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Biosynthesis of DHA-derived SPMs (R-HSA-9018677)
  Biosynthesis of EPA-derived SPMs (R-HSA-9018679)
  Biosynthesis of DPAn-3 SPMs (R-HSA-9025094)
  Biosynthesis of electrophilic -3 PUFA oxo-derivatives (R-HSA-9027604)
  Nicotinamide salvaging (R-HSA-197264)
• BioCyc Pathway: MetaCyc:HS01115-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cyclophosphamide	DM4O2Z7	Approved	Prostaglandin G/H synthase 2 (PTGS2) affects the response to substance of Cyclophosphamide.	[65]
Ibuprofen	DM8VCBE	Approved	Prostaglandin G/H synthase 2 (PTGS2) increases the response to substance of Ibuprofen.	[46]
Methylenedioxyamphetamine	DMP204G	Investigative	Prostaglandin G/H synthase 2 (PTGS2) increases the response to substance of Methylenedioxyamphetamine.	[67]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
2-arachidonoylglycerol	DMM0KOJ	Investigative	Prostaglandin G/H synthase 2 (PTGS2) increases the metabolism of 2-arachidonoylglycerol.	[66]

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 Prostaglandin G/H synthase 2 (PTGS2).	[1]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin affects the localization of Prostaglandin G/H synthase 2 (PTGS2).	[2]
Aspirin	DM672AH	Approved	Aspirin decreases the degradation of Prostaglandin G/H synthase 2 (PTGS2).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Prostaglandin G/H synthase 2 (PTGS2).	[15]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[17]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[18]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[5]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[19]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[20]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[21]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[22]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[3]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[23]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[24]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[25]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[26]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[14]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[27]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[29]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[30]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[14]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[31]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[14]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[32]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[33]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[34]
Mitomycin	DMH0ZJE	Approved	Mitomycin increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[35]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[36]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[37]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[38]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[39]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[3]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[41]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[42]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[14]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[43]
Imatinib	DM7RJXL	Approved	Imatinib decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[44]
Sertraline	DM0FB1J	Approved	Sertraline decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[45]
Rofecoxib	DM3P5DA	Approved	Rofecoxib increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[46]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[14]
Dinoprostone	DMTYOPD	Approved	Dinoprostone increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[47]
Chenodiol	DMQ8JIK	Approved	Chenodiol increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[48]
Docetaxel	DMDI269	Approved	Docetaxel increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[49]
Isoproterenol	DMK7MEY	Approved	Isoproterenol decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Lovastatin	DM9OZWQ	Approved	Lovastatin increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[50]
Capecitabine	DMTS85L	Approved	Capecitabine decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[51]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[48]
Glucosamine	DM4ZLFD	Approved	Glucosamine increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[52]
Isoniazid	DM5JVS3	Approved	Isoniazid increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Eicosapentaenoic acid/docosa-hexaenoic acid	DMMUCG4	Approved	Eicosapentaenoic acid/docosa-hexaenoic acid increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[53]
Mebendazole	DMO14SG	Approved	Mebendazole increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Mitotane	DMU1GX0	Approved	Mitotane increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[54]
Gamolenic acid	DMQN30Z	Approved	Gamolenic acid increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[55]
Propranolol	DM79NTF	Approved	Propranolol decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[56]
Flutamide	DMK0O7U	Approved	Flutamide increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Busulfan	DMXYJ9C	Approved	Busulfan increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[57]
Amodiaquine	DME4RA8	Approved	Amodiaquine decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Flurbiprofen	DMGN4BY	Approved	Flurbiprofen increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[58]
Nicotinamide	DMUPE07	Approved	Nicotinamide increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[59]
Naproxen	DMZ5RGV	Approved	Naproxen decreases the activity of Prostaglandin G/H synthase 2 (PTGS2).	[60]
Etodolac	DM6WJO9	Approved	Etodolac increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[58]
Salbutamol	DMN9CWF	Approved	Salbutamol decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Vemurafenib	DM62UG5	Approved	Vemurafenib decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[61]
Tolcapone	DM8MNVO	Approved	Tolcapone increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Dobutamine	DMD1B8Z	Approved	Dobutamine decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Zafirlukast	DMHNQOG	Approved	Zafirlukast increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Fexofenadine	DM17ONX	Approved	Fexofenadine decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Entacapone	DMLBVKQ	Approved	Entacapone increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Paroxetine	DM5PVQE	Approved	Paroxetine decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[45]
Trazodone	DMK1GBJ	Approved	Trazodone increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Bromfenac	DMKB79O	Approved	Bromfenac increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Metoprolol	DMOJ0V6	Approved	Metoprolol decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[56]
Fludrocortisone	DMUDIR8	Approved	Fludrocortisone decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Amikacin	DM5PDRB	Approved	Amikacin decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Lumiracoxib	DM1S4AG	Approved	Lumiracoxib decreases the activity of Prostaglandin G/H synthase 2 (PTGS2).	[60]
Trihexyphenidyl	DMB19L8	Approved	Trihexyphenidyl increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Procyclidine	DMHFJDT	Approved	Procyclidine increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Penbutolol	DM4ES8F	Approved	Penbutolol increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Niflumic acid	DMJ3I1Q	Approved	Niflumic acid increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[62]
Aciclovir	DMYLOVR	Approved	Aciclovir increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Bupivacaine	DM4PRFC	Approved	Bupivacaine increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[63]
Flufenamic Acid	DMC8VNH	Approved	Flufenamic Acid increases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[64]
Levofloxacin	DMS60RB	Approved	Levofloxacin decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]
Diphenhydramine	DMKQTBA	Approved	Diphenhydramine decreases the expression of Prostaglandin G/H synthase 2 (PTGS2).	[40]

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