Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKW75AE)

• DOT Name: Voltage-dependent anion-selective channel protein 1
• Synonyms: VDAC-1; hVDAC1; Outer mitochondrial membrane protein porin 1; Plasmalemmal porin; Porin 31HL; Porin 31HM
• Gene Name: VDAC1
• UniProt ID: VDAC1_HUMAN
• PDB ID: 2JK4; 2K4T; 5JDP; 5XDN; 5XDO; 6G6U; 6G73; 6TIQ; 6TIR; 7QI2
• Pfam ID: PF01459
• Sequence:
  MAVPPTYADLGKSARDVFTKGYGFGLIKLDLKTKSENGLEFTSSGSANTETTKVTGSLET
  KYRWTEYGLTFTEKWNTDNTLGTEITVEDQLARGLKLTFDSSFSPNTGKKNAKIKTGYKR
  EHINLGCDMDFDIAGPSIRGALVLGYEGWLAGYQMNFETAKSRVTQSNFAVGYKTDEFQL
  HTNVNDGTEFGGSIYQKVNKKLETAVNLAWTAGNSNTRFGIAAKYQIDPDACFSAKVNNS
  SLIGLGYTQTLKPGIKLTLSALLDGKNVNAGGHKLGLGLEFQA
• Function: Forms a channel through the mitochondrial outer membrane and also the plasma membrane. The channel at the outer mitochondrial membrane allows diffusion of small hydrophilic molecules; in the plasma membrane it is involved in cell volume regulation and apoptosis. It adopts an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV. The open state has a weak anion selectivity whereas the closed state is cation-selective. Binds various signaling molecules, including the sphingolipid ceramide, the phospholipid phosphatidylcholine, and the sterols cholesterol and oxysterol. In depolarized mitochondria, acts downstream of PRKN and PINK1 to promote mitophagy or prevent apoptosis; polyubiquitination by PRKN promotes mitophagy, while monoubiquitination by PRKN decreases mitochondrial calcium influx which ultimately inhibits apoptosis. May participate in the formation of the permeability transition pore complex (PTPC) responsible for the release of mitochondrial products that triggers apoptosis. May mediate ATP export from cells.
• Tissue Specificity: Expressed in erythrocytes (at protein level) . Expressed in heart, liver and skeletal muscle .
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Necroptosis (hsa04217)
  Cellular senescence (hsa04218)
  Neutrophil extracellular trap formation (hsa04613)
  NOD-like receptor sig.ling pathway (hsa04621)
  Cholesterol metabolism (hsa04979)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Shigellosis (hsa05131)
  Influenza A (hsa05164)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  PINK1-PRKN Mediated Mitophagy (R-HSA-5205685)
  Ub-specific processing proteases (R-HSA-5689880)
  Pyruvate metabolism (R-HSA-70268)
  Mitochondrial calcium ion transport (R-HSA-8949215)
  Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	Voltage-dependent anion-selective channel protein 1 affects the response to substance of Josamycin.	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Voltage-dependent anion-selective channel protein 1.	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Voltage-dependent anion-selective channel protein 1.	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Voltage-dependent anion-selective channel protein 1.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Voltage-dependent anion-selective channel protein 1.	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Voltage-dependent anion-selective channel protein 1.	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Voltage-dependent anion-selective channel protein 1.	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Voltage-dependent anion-selective channel protein 1.	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Voltage-dependent anion-selective channel protein 1.	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Voltage-dependent anion-selective channel protein 1.	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Voltage-dependent anion-selective channel protein 1.	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Voltage-dependent anion-selective channel protein 1.	[9]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Voltage-dependent anion-selective channel protein 1.	[10]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Voltage-dependent anion-selective channel protein 1.	[11]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Voltage-dependent anion-selective channel protein 1.	[12]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Voltage-dependent anion-selective channel protein 1.	[13]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of Voltage-dependent anion-selective channel protein 1.	[15]
BETULINIC ACID	DMBUI2A	Phase 1	BETULINIC ACID increases the expression of Voltage-dependent anion-selective channel protein 1.	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Voltage-dependent anion-selective channel protein 1.	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Voltage-dependent anion-selective channel protein 1.	[20]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of Voltage-dependent anion-selective channel protein 1.	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Voltage-dependent anion-selective channel protein 1.	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Voltage-dependent anion-selective channel protein 1.	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Voltage-dependent anion-selective channel protein 1.	[25]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Voltage-dependent anion-selective channel protein 1.	[26]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Voltage-dependent anion-selective channel protein 1.	[27]
Lead acetate	DML0GZ2	Investigative	Lead acetate decreases the expression of Voltage-dependent anion-selective channel protein 1.	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Sertraline	DM0FB1J	Approved	Sertraline affects the binding of Voltage-dependent anion-selective channel protein 1.	[14]
ME-344	DM6JN19	Phase 1/2	ME-344 affects the binding of Voltage-dependent anion-selective channel protein 1.	[16]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity. Toxicol Lett. 2017 Jun 5;275:28-38. doi: 10.1016/j.toxlet.2017.04.018. Epub 2017 Apr 27.
• [3] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [4] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [5] Differential protein expression of peroxiredoxin I and II by benzo(a)pyrene and quercetin treatment in 22Rv1 and PrEC prostate cell lines. Toxicol Appl Pharmacol. 2007 Apr 15;220(2):197-210. doi: 10.1016/j.taap.2006.12.030. Epub 2007 Jan 9.
• [6] Increased expression of VDAC1 sensitizes carcinoma cells to apoptosis induced by DNA cross-linking agents. Biochem Pharmacol. 2012 May 1;83(9):1172-82. doi: 10.1016/j.bcp.2012.01.017. Epub 2012 Jan 21.
• [7] Protective effects of asiatic acid on rotenone- or H2O2-induced injury in SH-SY5Y cells. Neurochem Res. 2009 Apr;34(4):746-54. doi: 10.1007/s11064-008-9844-0. Epub 2008 Sep 19.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [12] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [13] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [14] Antidepressant drug sertraline modulates AMPK-MTOR signaling-mediated autophagy via targeting mitochondrial VDAC1 protein. Autophagy. 2021 Oct;17(10):2783-2799. doi: 10.1080/15548627.2020.1841953. Epub 2020 Nov 9.
• [15] Mitochondrial proteomics investigation of a cellular model of impaired dopamine homeostasis, an early step in Parkinson's disease pathogenesis. Mol Biosyst. 2014 Jun;10(6):1332-44.
• [16] Voltage-Dependent Anion Channels Influence Cytotoxicity of ME-344, a Therapeutic Isoflavone. J Pharmacol Exp Ther. 2020 Aug;374(2):308-318. doi: 10.1124/jpet.120.000009. Epub 2020 Jun 16.
• [17] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [18] Effects and mechanisms of betulinic acid on improving EGFR TKI-resistance of lung cancer cells. Environ Toxicol. 2018 Nov;33(11):1153-1159.
• [19] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [20] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [21] Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Res. 2005 Jul;15(7):511-22.
• [22] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [23] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [26] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [27] Establishment of a 13 genes-based molecular prediction score model to discriminate the neurotoxic potential of food relevant-chemicals. Toxicol Lett. 2022 Feb 1;355:1-18. doi: 10.1016/j.toxlet.2021.10.013. Epub 2021 Nov 5.
• [28] Decreased expression of the voltage-dependent anion channel in differentiated PC-12 and SH-SY5Y cells following low-level Pb exposure. Toxicol Sci. 2010 Jan;113(1):169-76. doi: 10.1093/toxsci/kfp249. Epub 2009 Oct 12.
• [29] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.