Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB4D6FL)

• DOT Name: Myeloid differentiation primary response protein MyD88 (MYD88)
• Gene Name: MYD88
• Related Disease: Pyogenic bacterial infections due to MyD88 deficiency
• UniProt ID: MYD88_HUMAN
• PDB ID: 2JS7; 2Z5V; 3MOP; 4DOM; 4EO7; 6I3N; 7BEQ; 7BER; 7L6W
• Pfam ID: PF00531 ; PF13676
• Sequence:
  MAAGGPGAGSAAPVSSTSSLPLAALNMRVRRRLSLFLNVRTQVAADWTALAEEMDFEYLE
  IRQLETQADPTGRLLDAWQGRPGASVGRLLELLTKLGRDDVLLELGPSIEEDCQKYILKQ
  QQEEAEKPLQVAAVDSSVPRTAELAGITTLDDPLGHMPERFDAFICYCPSDIQFVQEMIR
  QLEQTNYRLKLCVSDRDVLPGTCVWSIASELIEKRCRRMVVVVSDDYLQSKECDFQTKFA
  LSLSPGAHQKRLIPIKYKAMKKEFPSILRFITVCDYTNPCTKSWFWTRLAKALSLP
• Function: Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response. Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Increases IL-8 transcription. Involved in IL-18-mediated signaling pathway. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. Upon TLR8 activation by GU-rich single-stranded RNA (GU-rich RNA) derived from viruses such as SARS-CoV-2, SARS-CoV and HIV-1, induces IL1B release through NLRP3 inflammasome activation. MyD88-mediated signaling in intestinal epithelial cells is crucial for maintenance of gut homeostasis and controls the expression of the antimicrobial lectin REG3G in the small intestine.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  NF-kappa B sig.ling pathway (hsa04064)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  Alcoholic liver disease (hsa04936)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Yersinia infection (hsa05135)
  Leishmaniasis (hsa05140)
  Chagas disease (hsa05142)
  African trypanosomiasis (hsa05143)
  Malaria (hsa05144)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coro.virus disease - COVID-19 (hsa05171)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  MyD88 (R-HSA-166058)
  RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476)
  p75NTR recruits signalling complexes (R-HSA-209543)
  DEx/H-box helicases activate type I IFN and inflammatory cytokines production (R-HSA-3134963)
  MyD88 deficiency (TLR2/4) (R-HSA-5602498)
  MyD88 deficiency (TLR5) (R-HSA-5602680)
  IRAK4 deficiency (TLR5) (R-HSA-5603037)
  IRAK4 deficiency (TLR2/4) (R-HSA-5603041)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Interleukin-1 signaling (R-HSA-9020702)
  TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling (R-HSA-975110)
  TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (R-HSA-975138)
  MyD88 dependent cascade initiated on endosome (R-HSA-975155)
  MyD88 cascade initiated on plasma membrane (R-HSA-975871)
  ER-Phagosome pathway (R-HSA-1236974)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pyogenic bacterial infections due to MyD88 deficiency	DIS9697Z	Strong	Autosomal recessive	[1]

29 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 Myeloid differentiation primary response protein MyD88 (MYD88).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[14]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[15]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[16]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[17]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the activity of Myeloid differentiation primary response protein MyD88 (MYD88).	[19]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[22]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[23]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[24]
acrolein	DMAMCSR	Investigative	acrolein increases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[25]
I-BET151	DMYRUH2	Investigative	I-BET151 decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[26]
PFI-1	DMVFK3J	Investigative	PFI-1 decreases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[26]
PAF	DMRZAQW	Investigative	PAF increases the expression of Myeloid differentiation primary response protein MyD88 (MYD88).	[27]

References

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• [11] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [12] 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.
• [13] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [14] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [15] Synergistic antiproliferative effect of arsenic trioxide combined with bortezomib in HL60 cell line and primary blasts from patients affected by myeloproliferative disorders. Cancer Genet Cytogenet. 2010 Jun;199(2):110-20. doi: 10.1016/j.cancergencyto.2010.02.010.
• [16] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [17] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Resveratrol inhibits Staphylococcus aureus-induced TLR2/MyD88/NF-B-dependent VCAM-1 expression in human lung epithelial cells. Clin Sci (Lond). 2014 Sep;127(6):375-90. doi: 10.1042/CS20130816.
• [20] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [22] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [23] Epigallocatechin-3-gallate alleviates paraquat-induced acute lung injury and inhibits upregulation of toll-like receptors. Life Sci. 2017 Feb 1;170:25-32. doi: 10.1016/j.lfs.2016.11.021. Epub 2016 Nov 24.
• [24] Quercetin and chrysin inhibit nickel-induced invasion and migration by downregulation of TLR4/NF-B signaling in A549?cells. Chem Biol Interact. 2018 Aug 25;292:101-109. doi: 10.1016/j.cbi.2018.07.010. Epub 2018 Jul 19.
• [25] Apigenin and apigenin-7, 4'-O-dioctanoate protect against acrolein-aggravated inflammation via inhibiting the activation of NLRP3 inflammasome and HMGB1/MYD88/NF-B signaling pathway in Human umbilical vein endothelial cells (HUVEC). Food Chem Toxicol. 2022 Oct;168:113400. doi: 10.1016/j.fct.2022.113400. Epub 2022 Aug 31.
• [26] BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):15713-8. doi: 10.1073/pnas.1522163112. Epub 2015 Dec 7.
• [27] LncRNA PVT1 exacerbates the inflammation and cell-barrier injury during asthma by regulating miR-149. J Biochem Mol Toxicol. 2020 Nov;34(11):e22563. doi: 10.1002/jbt.22563. Epub 2020 Aug 24.