Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM0GDTP)

• DOT Name: Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)
• Synonyms: Eukaryotic translation initiation factor 2 subunit alpha; eIF-2-alpha; eIF-2A; eIF-2alpha; eIF2-alpha
• Gene Name: EIF2S1
• Related Disease:
  Alcoholic liver diseases
  Acute myelogenous leukaemia
  Adenoma
  Adenovirus infection
  Alzheimer disease
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Carcinoma
  Chagas disease
  Classic Hodgkin lymphoma
  Colorectal carcinoma
  Epithelial neoplasm
  Familial adenomatous polyposis
  Familial Alzheimer disease
  Fatty liver disease
  Herpes simplex infection
  Intellectual disability
  Leukoencephalopathy with vanishing white matter
  Liposarcoma
  Liver cirrhosis
  MEHMO syndrome
  Melanocytic nevus
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Polycythemia vera
  Schizophrenia
  Status epilepticus seizure
  Thyroid tumor
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Myotonic dystrophy type 2
  Neurodegenerative disease
  Osteosarcoma
  Type-1/2 diabetes
  Wolcott-Rallison syndrome
  Cognitive impairment
  Nasopharyngeal carcinoma
  Prostate cancer
  Prostate carcinoma
  Temporal lobe epilepsy
• UniProt ID: IF2A_HUMAN
• PDB ID: 1KL9; 1Q8K; 6K71; 6K72; 6O81; 6O85; 6O9Z; 6YBV; 6ZMW; 6ZP4; 7A09; 7D43; 7D44; 7D45; 7F66; 7F67; 7NZM; 7QP6; 7QP7; 7SYR; 7SYS; 8PPL
• Pfam ID: PF07541 ; PF00575
• Sequence:
  MPGLSCRFYQHKFPEVEDVVMVNVRSIAEMGAYVSLLEYNNIEGMILLSELSRRRIRSIN
  KLIRIGRNECVVVIRVDKEKGYIDLSKRRVSPEEAIKCEDKFTKSKTVYSILRHVAEVLE
  YTKDEQLESLFQRTAWVFDDKYKRPGYGAYDAFKHAVSDPSILDSLDLNEDEREVLINNI
  NRRLTPQAVKIRADIEVACYGYEGIDAVKEALRAGLNCSTENMPIKINLIAPPRYVMTTT
  TLERTEGLSVLSQAMAVIKEKIEEKRGVFNVQMEPKVVTDTDETELARQMERLERENAEV
  DGDDDAEEMEAKAED
• Function: Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. This complex binds to a 40S ribosomal subunit, followed by mRNA binding to form a 43S pre-initiation complex (43S PIC). Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF2 and release of an eIF2-GDP binary complex. In order for eIF2 to recycle and catalyze another round of initiation, the GDP bound to eIF2 must exchange with GTP by way of a reaction catalyzed by eIF2B. EIF2S1/ component of the integrated stress response (ISR), required for adaptation to various stress: phosphorylation by metabolic-stress sensing protein kinases (EIF2AK1/HRI, EIF2AK2/PKR, EIF2AK3/PERK and EIF2AK4/GCN2) in response to stress converts EIF2S1/eIF2-alpha in a global protein synthesis inhibitor, leading to an attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activators ATF4 and QRICH1, and hence allowing ATF4- and QRICH1-mediated reprogramming.
• KEGG Pathway:
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
  Protein processing in endoplasmic reticulum (hsa04141)
  Apoptosis (hsa04210)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Hepatitis C (hsa05160)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Herpes simplex virus 1 infection (hsa05168)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  PERK regulates gene expression (R-HSA-381042)
  ABC-family proteins mediated transport (R-HSA-382556)
  Translation initiation complex formation (R-HSA-72649)
  Formation of the ternary complex, and subsequently, the 43S complex (R-HSA-72695)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  Recycling of eIF2 (R-HSA-72731)
  Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012)
  Response of EIF2AK1 (HRI) to heme deficiency (R-HSA-9648895)
  PKR-mediated signaling (R-HSA-9833482)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alcoholic liver diseases	DISXEPHQ	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Adenoma	DIS78ZEV	Strong	Altered Expression	[3]
Adenovirus infection	DISUYSBZ	Strong	Posttranslational Modification	[4]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[5]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[7]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[7]
Carcinoma	DISH9F1N	Strong	Altered Expression	[3]
Chagas disease	DIS8KNVF	Strong	Posttranslational Modification	[8]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Epithelial neoplasm	DIS0T594	Strong	Altered Expression	[3]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[11]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[12]
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[13]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[14]
Intellectual disability	DISMBNXP	Strong	Biomarker	[15]
Leukoencephalopathy with vanishing white matter	DIS3J8NN	Strong	Posttranslational Modification	[16]
Liposarcoma	DIS8IZVM	Strong	Biomarker	[17]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[13]
MEHMO syndrome	DISPH301	Strong	Genetic Variation	[18]
Melanocytic nevus	DISYS32D	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[19]
Obesity	DIS47Y1K	Strong	Biomarker	[20]
Polycythemia vera	DISB5FPO	Strong	Genetic Variation	[21]
Schizophrenia	DISSRV2N	Strong	Biomarker	[22]
Status epilepticus seizure	DISY3BIC	Strong	Biomarker	[23]
Thyroid tumor	DISLVKMD	Strong	Altered Expression	[24]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Biomarker	[25]
Liver cancer	DISDE4BI	moderate	Biomarker	[25]
Myotonic dystrophy type 2	DIS5ZWF1	moderate	Altered Expression	[26]
Neurodegenerative disease	DISM20FF	moderate	Biomarker	[27]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[6]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[28]
Wolcott-Rallison syndrome	DISKVKXN	moderate	Genetic Variation	[28]
Cognitive impairment	DISH2ERD	Limited	Posttranslational Modification	[29]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[30]
Prostate cancer	DISF190Y	Limited	Altered Expression	[31]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[31]
Temporal lobe epilepsy	DISNOPXX	Limited	Posttranslational Modification	[32]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1) affects the response to substance of Mitoxantrone.	[89]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[33]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[34]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[36]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[37]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[38]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[39]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[41]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[42]
Marinol	DM70IK5	Approved	Marinol increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[43]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[36]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[49]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[50]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[42]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[52]
Cantharidin	DMBP5N3	Approved	Cantharidin increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[59]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[36]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[49]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[74]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[75]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[76]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[39]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[78]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[84]
HONOKIOL	DMJWT3X	Investigative	HONOKIOL increases the expression of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[87]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[35]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[40]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[44]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[45]
Bortezomib	DMNO38U	Approved	Bortezomib increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[46]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[47]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[48]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[51]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[53]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[54]
Sertraline	DM0FB1J	Approved	Sertraline increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[55]
Glucosamine	DM4ZLFD	Approved	Glucosamine increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[56]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[57]
Penicillamine	DM40EF6	Approved	Penicillamine increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[58]
Bupropion	DM5PCS7	Approved	Bupropion increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[60]
Pyrazinamide	DM4IF32	Approved	Pyrazinamide increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[61]
Oxycodone	DMXLKHV	Approved	Oxycodone increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[62]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[63]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[64]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[65]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[66]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[67]
PEITC	DMOMN31	Phase 2	PEITC increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[68]
URSOLIC ACID	DM4SOAW	Phase 2	URSOLIC ACID increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[69]
Rocilinostat	DMSTH01	Phase 2	Rocilinostat increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[70]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[71]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[72]
Hydroxyqunoline analog 4	DMGQMCZ	Patented	Hydroxyqunoline analog 4 increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[73]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[77]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[79]
D-glucose	DMMG2TO	Investigative	D-glucose increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[80]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[81]
acrolein	DMAMCSR	Investigative	acrolein increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[82]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[83]
Dorsomorphin	DMKYXJW	Investigative	Dorsomorphin increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[79]
NORCANTHARIDIN	DM9B6Y1	Investigative	NORCANTHARIDIN increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[51]
P-Coumaric Acid	DMGJSVD	Investigative	P-Coumaric Acid increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[44]
1,4-Dithiothreitol	DMIFOXE	Investigative	1,4-Dithiothreitol increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[85]
Aloe-emodin	DMPTY8S	Investigative	Aloe-emodin increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[86]
2-arachidonoylglycerol	DMM0KOJ	Investigative	2-arachidonoylglycerol increases the phosphorylation of Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1).	[88]

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