Details of Drug Off-Target (DOT)

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

• DOT Name: Period circadian protein homolog 3 (PER3)
• Synonyms: hPER3; Cell growth-inhibiting gene 13 protein; Circadian clock protein PERIOD 3
• Gene Name: PER3
• Related Disease:
  Lung cancer
  Lung carcinoma
  Seasonal affective disorder
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Adenoma
  Alcohol dependence
  Anxiety
  Anxiety disorder
  B-cell lymphoma
  Bipolar disorder
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Carcinoma
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Crohn disease
  Glioblastoma multiforme
  Glioma
  Head-neck squamous cell carcinoma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Inflammatory bowel disease
  Insomnia
  Major depressive disorder
  Mental disorder
  Mood disorder
  Multiple sclerosis
  Myocardial infarction
  Neoplasm
  Non-hodgkin lymphoma
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Obesity
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Sleep disorder
  Substance withdrawal syndrome
  Ulcerative colitis
  Breast neoplasm
  Advanced sleep phase syndrome
  Advanced cancer
  Depression
  Neuroblastoma
  Rheumatoid arthritis
  Type-1/2 diabetes
• UniProt ID: PER3_HUMAN
• Pfam ID: PF08447 ; PF21353 ; PF12114
• Sequence:
  MPRGEAPGPGRRGAKDEALGEESGERWSPEFHLQRKLADSSHSEQQDRNRVSEELIMVVQ
  EMKKYFPSERRNKPSTLDALNYALRCVHSVQANSEFFQILSQNGAPQADVSMYSLEELAT
  IASEHTSKNTDTFVAVFSFLSGRLVHISEQAALILNRKKDVLASSHFVDLLAPQDMRVFY
  AHTARAQLPFWNNWTQRAARYECAPVKPFFCRIRGGEDRKQEKCHSPFRIIPYLIHVHHP
  AQPELESEPCCLTVVEKIHSGYEAPRIPVNKRIFTTTHTPGCVFLEVDEKAVPLLGYLPQ
  DLIGTSILSYLHPEDRSLMVAIHQKVLKYAGHPPFEHSPIRFCTQNGDYIILDSSWSSFV
  NPWSRKISFIIGRHKVRTSPLNEDVFATKIKKMNDNDKDITELQEQIYKLLLQPVHVSVS
  SGYGSLGSSGSQEQLVSIASSSEASGHRVEETKAEQMTLQQVYASVNKIKNLGQQLYIES
  MTKSSFKPVTGTRTEPNGGGECKTFTSFHQTLKNNSVYTEPCEDLRNDEHSPSYQQINCI
  DSVIRYLKSYNIPALKRKCISCTNTTSSSSEEDKQNHKADDVQALQAGLQIPAIPKSEMP
  TNGRSIDTGGGAPQILSTAMLSLGSGISQCGYSSTIVHVPPPETARDATLFCEPWTLNMQ
  PAPLTSEEFKHVGLTAAVLSAHTQKEEQNYVDKFREKILSSPYSSYLQQESRSKAKYSYF
  QGDSTSKQTRSAGCRKGKHKRKKLPEPPDSSSSNTGSGPRRGAHQNAQPCCPSAASSPHT
  SSPTFPPAAMVPSQAPYLVPAFPLPAATSPGREYAAPGTAPEGLHGLPLSEGLQPYPAFP
  FPYLDTFMTVFLPDPPVCPLLSPSFLPCPFLGATASSAISPSMSSAMSPTLDPPPSVTSQ
  RREEEKWEAQSEGHPFITSRSSSPLQLNLLQEEMPRPSESPDQMRRNTCPQTEYCVTGNN
  GSESSPATTGALSTGSPPRENPSHPTASALSTGSPPMKNPSHPTASALSTGSPPMKNPSH
  PTASTLSMGLPPSRTPSHPTATVLSTGSPPSESPSRTGSAASGSSDSSIYLTSSVYSSKI
  SQNGQQSQDVQKKETFPNVAEEPIWRMIRQTPERILMTYQVPERVKEVVLKEDLEKLESM
  RQQQPQFSHGQKEELAKVYNWIQSQTVTQEIDIQACVTCENEDSADGAATSCGQVLVEDS
  C
• Function: Originally described as a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1, NR1D2, RORA, RORB and RORG, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. Has a redundant role with the other PER proteins PER1 and PER2 and is not essential for the circadian rhythms maintenance. In contrast, plays an important role in sleep-wake timing and sleep homeostasis probably through the transcriptional regulation of sleep homeostasis-related genes, without influencing circadian parameters. Can bind heme.
• KEGG Pathway:
  Circadian rhythm (hsa04710)
  Circadian entrainment (hsa04713)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]
Seasonal affective disorder	DIS908VO	Definitive	Genetic Variation	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Adenoma	DIS78ZEV	Strong	Genetic Variation	[4]
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[5]
Anxiety	DISIJDBA	Strong	Genetic Variation	[6]
Anxiety disorder	DISBI2BT	Strong	Genetic Variation	[6]
B-cell lymphoma	DISIH1YQ	Strong	Genetic Variation	[7]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[8]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[9]
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[10]
Colon cancer	DISVC52G	Strong	Biomarker	[11]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[11]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[11]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[12]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[13]
Glioma	DIS5RPEH	Strong	Genetic Variation	[14]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[15]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[16]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[17]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[18]
Insomnia	DIS0AFR7	Strong	Genetic Variation	[19]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[20]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[21]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[8]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[22]
Myocardial infarction	DIS655KI	Strong	Biomarker	[23]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[14]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[14]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[14]
Obesity	DIS47Y1K	Strong	Biomarker	[24]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[14]
Prostate cancer	DISF190Y	Strong	Altered Expression	[25]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[25]
Sleep disorder	DIS3JP1U	Strong	Genetic Variation	[19]
Substance withdrawal syndrome	DISTT24U	Strong	Biomarker	[26]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[27]
Breast neoplasm	DISNGJLM	moderate	Biomarker	[28]
Advanced sleep phase syndrome	DIS28KRD	Supportive	Autosomal dominant	[29]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[30]
Depression	DIS3XJ69	Limited	Genetic Variation	[6]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[31]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[32]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Period circadian protein homolog 3 (PER3).	[34]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Period circadian protein homolog 3 (PER3).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Period circadian protein homolog 3 (PER3).	[36]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Period circadian protein homolog 3 (PER3).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Period circadian protein homolog 3 (PER3).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Period circadian protein homolog 3 (PER3).	[39]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Period circadian protein homolog 3 (PER3).	[40]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Period circadian protein homolog 3 (PER3).	[41]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Period circadian protein homolog 3 (PER3).	[42]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Period circadian protein homolog 3 (PER3).	[43]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Period circadian protein homolog 3 (PER3).	[44]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Period circadian protein homolog 3 (PER3).	[45]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Period circadian protein homolog 3 (PER3).	[46]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Period circadian protein homolog 3 (PER3).	[47]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Period circadian protein homolog 3 (PER3).	[48]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Period circadian protein homolog 3 (PER3).	[43]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Period circadian protein homolog 3 (PER3).	[49]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Period circadian protein homolog 3 (PER3).	[50]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Period circadian protein homolog 3 (PER3).	[52]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Period circadian protein homolog 3 (PER3).	[53]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Period circadian protein homolog 3 (PER3).	[51]

References

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