Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCI2YDI)

• DOT Name: Glucocorticoid receptor (NR3C1)
• Synonyms: GR; Nuclear receptor subfamily 3 group C member 1
• Gene Name: NR3C1
• Related Disease: Glucocorticoid resistance
• UniProt ID: GCR_HUMAN
• PDB ID: 1M2Z ; 1NHZ ; 1P93 ; 3BQD ; 3CLD ; 3E7C ; 3H52 ; 3K22 ; 3K23 ; 4CSJ ; 4HN5 ; 4HN6 ; 4LSJ ; 4MDD ; 4P6W ; 4P6X ; 4UDC ; 4UDD ; 5CBX ; 5CBY ; 5CBZ ; 5CC1 ; 5E69 ; 5E6A ; 5E6B ; 5E6C ; 5E6D ; 5EMC ; 5EMP ; 5EMQ ; 5G3J ; 5G5W ; 5NFP ; 5NFT ; 5UC1 ; 5UC3 ; 5VA0 ; 5VA7 ; 6BQU ; 6CFN ; 6DXK ; 6EL6 ; 6EL7 ; 6EL9 ; 6X6D ; 6X6E ; 6YMO ; 6YO8 ; 6YOS ; 7KRJ ; 7KW7 ; 7PRV ; 7PRW ; 7PRX ; 8A9G ; 8FFV ; 8FFW
• Pfam ID: PF02155 ; PF00104 ; PF00105
• Sequence:
  MDSKESLTPGREENPSSVLAQERGDVMDFYKTLRGGATVKVSASSPSLAVASQSDSKQRR
  LLVDFPKGSVSNAQQPDLSKAVSLSMGLYMGETETKVMGNDLGFPQQGQISLSSGETDLK
  LLEESIANLNRSTSVPENPKSSASTAVSAAPTEKEFPKTHSDVSSEQQHLKGQTGTNGGN
  VKLYTTDQSTFDILQDLEFSSGSPGKETNESPWRSDLLIDENCLLSPLAGEDDSFLLEGN
  SNEDCKPLILPDTKPKIKDNGDLVLSSPSNVTLPQVKTEKEDFIELCTPGVIKQEKLGTV
  YCQASFPGANIIGNKMSAISVHGVSTSGGQMYHYDMNTASLSQQQDQKPIFNVIPPIPVG
  SENWNRCQGSGDDNLTSLGTLNFPGRTVFSNGYSSPSMRPDVSSPPSSSSTATTGPPPKL
  CLVCSDEASGCHYGVLTCGSCKVFFKRAVEGQHNYLCAGRNDCIIDKIRRKNCPACRYRK
  CLQAGMNLEARKTKKKIKGIQQATTGVSQETSENPGNKTIVPATLPQLTPTLVSLLEVIE
  PEVLYAGYDSSVPDSTWRIMTTLNMLGGRQVIAAVKWAKAIPGFRNLHLDDQMTLLQYSW
  MFLMAFALGWRSYRQSSANLLCFAPDLIINEQRMTLPCMYDQCKHMLYVSSELHRLQVSY
  EEYLCMKTLLLLSSVPKDGLKSQELFDEIRMTYIKELGKAIVKREGNSSQNWQRFYQLTK
  LLDSMHEVVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNIKKLLFHQK
• Function: Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Involved in chromatin remodeling. Plays a role in rapid mRNA degradation by binding to the 5' UTR of target mRNAs and interacting with PNRC2 in a ligand-dependent manner which recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth; [Isoform Alpha]: Has transcriptional activation and repression activity. Mediates glucocorticoid-induced apoptosis. Promotes accurate chromosome segregation during mitosis. May act as a tumor suppressor. May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic gene expression; [Isoform Beta]: Acts as a dominant negative inhibitor of isoform Alpha. Has intrinsic transcriptional activity independent of isoform Alpha when both isoforms are coexpressed. Loses this transcription modulator function on its own. Has no hormone-binding activity. May play a role in controlling glucose metabolism by maintaining insulin sensitivity. Reduces hepatic gluconeogenesis through down-regulation of PEPCK in an isoform Alpha-dependent manner. Directly regulates STAT1 expression in isoform Alpha-independent manner ; [Isoform Alpha-2]: Has lower transcriptional activation activity than isoform Alpha. Exerts a dominant negative effect on isoform Alpha trans-repression mechanism.; [Isoform GR-P]: Increases activity of isoform Alpha; [Isoform Alpha-B]: More effective than isoform Alpha in transcriptional activation, but not repression activity; [Isoform 10]: Has transcriptional activation activity; [Isoform Alpha-C1]: Has transcriptional activation activity; [Isoform Alpha-C2]: Has transcriptional activation activity; [Isoform Alpha-C3]: Has highest transcriptional activation activity of all isoforms created by alternative initiation. Has transcriptional repression activity. Mediates glucocorticoid-induced apoptosis ; [Isoform Alpha-D1]: Has transcriptional activation activity; [Isoform Alpha-D2]: Has transcriptional activation activity; [Isoform Alpha-D3]: Has lowest transcriptional activation activity of all isoforms created by alternative initiation. Has transcriptional repression activity.
• Tissue Specificity: Widely expressed including bone, stomach, lung, liver, colon, breast, ovary, pancreas and kidney . In the heart, detected in left and right atria, left and right ventricles, aorta, apex, intraventricular septum, and atrioventricular node as well as whole adult and fetal heart .; [Isoform Beta]: Widely expressed including brain, bone marrow, thymus, spleen, liver, kidney, pancreas, lung, fat, skeletal muscle, heart, placenta and blood leukocytes.; [Isoform Alpha-2]: Widely expressed.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  Nuclear Receptor transcription pathway (R-HSA-383280)
  Circadian Clock (R-HSA-400253)
  SUMOylation of intracellular receptors (R-HSA-4090294)
  PTK6 Expression (R-HSA-8849473)
  Regulation of RUNX2 expression and activity (R-HSA-8939902)
  FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017)
  Potential therapeutics for SARS (R-HSA-9679191)
  Regulation of NPAS4 gene transcription (R-HSA-9768777)
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glucocorticoid resistance	DIS3HNXT	Strong	Autosomal dominant	[1]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dexamethasone	DMMWZET	Approved	Glucocorticoid receptor (NR3C1) decreases the response to substance of Dexamethasone.	[71]
Irinotecan	DMP6SC2	Approved	Glucocorticoid receptor (NR3C1) decreases the response to substance of Irinotecan.	[72]
Methylprednisolone	DM4BDON	Approved	Glucocorticoid receptor (NR3C1) increases the Hepatotoxicity ADR of Methylprednisolone.	[73]
Lamotrigine	DM8SXYG	Approved	Glucocorticoid receptor (NR3C1) increases the response to substance of Lamotrigine.	[74]
Aminophenol	DMEMCQ9	Investigative	Glucocorticoid receptor (NR3C1) affects the response to substance of Aminophenol.	[76]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Corticotropin	DMP9TWZ	Approved	Glucocorticoid receptor (NR3C1) affects the abundance of Corticotropin.	[75]

7 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 Glucocorticoid receptor (NR3C1).	[2]
Promegestone	DMK4S8I	Approved	Promegestone increases the phosphorylation of Glucocorticoid receptor (NR3C1).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Glucocorticoid receptor (NR3C1).	[53]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Glucocorticoid receptor (NR3C1).	[55]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Glucocorticoid receptor (NR3C1).	[57]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Glucocorticoid receptor (NR3C1).	[65]
Deoxycorticosterone	DMW6YLS	Investigative	Deoxycorticosterone increases the phosphorylation of Glucocorticoid receptor (NR3C1).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Glucocorticoid receptor (NR3C1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glucocorticoid receptor (NR3C1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glucocorticoid receptor (NR3C1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glucocorticoid receptor (NR3C1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Glucocorticoid receptor (NR3C1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Glucocorticoid receptor (NR3C1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glucocorticoid receptor (NR3C1).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Glucocorticoid receptor (NR3C1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Glucocorticoid receptor (NR3C1).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Glucocorticoid receptor (NR3C1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Glucocorticoid receptor (NR3C1).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Glucocorticoid receptor (NR3C1).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Glucocorticoid receptor (NR3C1).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Glucocorticoid receptor (NR3C1).	[16]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Glucocorticoid receptor (NR3C1).	[17]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Glucocorticoid receptor (NR3C1).	[18]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Glucocorticoid receptor (NR3C1).	[19]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Glucocorticoid receptor (NR3C1).	[20]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Glucocorticoid receptor (NR3C1).	[21]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Glucocorticoid receptor (NR3C1).	[22]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Glucocorticoid receptor (NR3C1).	[23]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Glucocorticoid receptor (NR3C1).	[8]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Glucocorticoid receptor (NR3C1).	[24]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Glucocorticoid receptor (NR3C1).	[3]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the activity of Glucocorticoid receptor (NR3C1).	[25]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Glucocorticoid receptor (NR3C1).	[26]
Zidovudine	DM4KI7O	Approved	Zidovudine affects the expression of Glucocorticoid receptor (NR3C1).	[27]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Glucocorticoid receptor (NR3C1).	[8]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Glucocorticoid receptor (NR3C1).	[8]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the activity of Glucocorticoid receptor (NR3C1).	[25]
Colchicine	DM2POTE	Approved	Colchicine increases the activity of Glucocorticoid receptor (NR3C1).	[28]
Prednisolone	DMQ8FR2	Approved	Prednisolone increases the activity of Glucocorticoid receptor (NR3C1).	[29]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of Glucocorticoid receptor (NR3C1).	[31]
Prasterone	DM67VKL	Approved	Prasterone increases the expression of Glucocorticoid receptor (NR3C1).	[32]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine increases the expression of Glucocorticoid receptor (NR3C1).	[33]
Teriflunomide	DMQ2FKJ	Approved	Teriflunomide increases the activity of Glucocorticoid receptor (NR3C1).	[34]
Budesonide	DMJIBAW	Approved	Budesonide decreases the expression of Glucocorticoid receptor (NR3C1).	[35]
Aldosterone	DM9S2JW	Approved	Aldosterone increases the activity of Glucocorticoid receptor (NR3C1).	[36]
Terbutaline	DMD4381	Approved	Terbutaline increases the expression of Glucocorticoid receptor (NR3C1).	[35]
Betamethasone	DMAHJEF	Approved	Betamethasone increases the activity of Glucocorticoid receptor (NR3C1).	[29]
Triamcinolone	DM98IXF	Approved	Triamcinolone increases the activity of Glucocorticoid receptor (NR3C1).	[29]
Cortisone	DMU5QZX	Approved	Cortisone increases the activity of Glucocorticoid receptor (NR3C1).	[40]
Ciclopirox	DMN5T2A	Approved	Ciclopirox decreases the activity of Glucocorticoid receptor (NR3C1).	[25]
Flumethasone	DMUNG4A	Approved	Flumethasone increases the activity of Glucocorticoid receptor (NR3C1).	[29]
Deflazacort	DMV0RNS	Approved	Deflazacort increases the activity of Glucocorticoid receptor (NR3C1).	[29]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glucocorticoid receptor (NR3C1).	[41]
Beclomethasone dipropionate	DM5NW1E	Phase 4	Beclomethasone dipropionate increases the expression of Glucocorticoid receptor (NR3C1).	[42]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Glucocorticoid receptor (NR3C1).	[43]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Glucocorticoid receptor (NR3C1).	[44]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Glucocorticoid receptor (NR3C1).	[45]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of Glucocorticoid receptor (NR3C1).	[46]
Triptolide	DMCMDVR	Phase 3	Triptolide increases the expression of Glucocorticoid receptor (NR3C1).	[47]
Dalcetrapib	DMKNCVM	Phase 3	Dalcetrapib increases the expression of Glucocorticoid receptor (NR3C1).	[48]
Anacetrapib	DMP2BFG	Phase 3	Anacetrapib increases the expression of Glucocorticoid receptor (NR3C1).	[48]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Glucocorticoid receptor (NR3C1).	[50]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Glucocorticoid receptor (NR3C1).	[54]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Glucocorticoid receptor (NR3C1).	[56]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Glucocorticoid receptor (NR3C1).	[48]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Glucocorticoid receptor (NR3C1).	[58]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Glucocorticoid receptor (NR3C1).	[59]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Glucocorticoid receptor (NR3C1).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Glucocorticoid receptor (NR3C1).	[60]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Glucocorticoid receptor (NR3C1).	[61]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Glucocorticoid receptor (NR3C1).	[62]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the activity of Glucocorticoid receptor (NR3C1).	[63]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Glucocorticoid receptor (NR3C1).	[64]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Glucocorticoid receptor (NR3C1).	[66]
Forskolin	DM6ITNG	Investigative	Forskolin increases the activity of Glucocorticoid receptor (NR3C1).	[25]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Glucocorticoid receptor (NR3C1).	[67]
15-deoxy-Delta(12, 14)-prostaglandin J(2)	DM8VUX3	Investigative	15-deoxy-Delta(12, 14)-prostaglandin J(2) affects the activity of Glucocorticoid receptor (NR3C1).	[68]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX decreases the expression of Glucocorticoid receptor (NR3C1).	[69]
Ginsenoside Re	DM46FVD	Investigative	Ginsenoside Re increases the activity of Glucocorticoid receptor (NR3C1).	[70]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid increases the localization of Glucocorticoid receptor (NR3C1).	[30]
Fluticasone propionate	DMRWLB2	Approved	Fluticasone propionate affects the localization of Glucocorticoid receptor (NR3C1).	[38]
Isoflurophate	DMBSK7X	Approved	Isoflurophate decreases the degradation of Glucocorticoid receptor (NR3C1).	[39]
Salmeterol	DMIEU69	Approved	Salmeterol affects the localization of Glucocorticoid receptor (NR3C1).	[38]
Mapracorat	DMR23M1	Phase 3	Mapracorat affects the binding of Glucocorticoid receptor (NR3C1).	[49]
APX3330	DMU6NBO	Phase 2	APX3330 increases the localization of Glucocorticoid receptor (NR3C1).	[51]
Onapristone	DMT6E5N	Phase 2	Onapristone affects the binding of Glucocorticoid receptor (NR3C1).	[52]

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