Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNIYCH9)

• DOT Name: Voltage-dependent anion-selective channel protein 2
• Synonyms: VDAC-2; hVDAC2; Outer mitochondrial membrane protein porin 2
• Gene Name: VDAC2
• UniProt ID: VDAC2_HUMAN
• Pfam ID: PF01459
• Sequence:
  MATHGQTCARPMCIPPSYADLGKAARDIFNKGFGFGLVKLDVKTKSCSGVEFSTSGSSNT
  DTGKVTGTLETKYKWCEYGLTFTEKWNTDNTLGTEIAIEDQICQGLKLTFDTTFSPNTGK
  KSGKIKSSYKRECINLGCDVDFDFAGPAIHGSAVFGYEGWLAGYQMTFDSAKSKLTRNNF
  AVGYRTGDFQLHTNVNDGTEFGGSIYQKVCEDLDTSVNLAWTSGTNCTRFGIAAKYQLDP
  TASISAKVNNSSLIGVGYTQTLRPGVKLTLSALVDGKSINAGGHKVGLALELEA
• Function: Forms a channel through the mitochondrial outer membrane that allows diffusion of small hydrophilic molecules. The channel 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 lipids, including the sphingolipid ceramide, the phospholipid phosphatidylcholine, and the sterols cholesterol and oxysterol. Binding of ceramide promotes the mitochondrial outer membrane permeabilization (MOMP) apoptotic pathway.
• Tissue Specificity: Expressed in erythrocytes (at protein level) . Expressed in all tissues examined .
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Ferroptosis (hsa04216)
  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)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Mitochondrial calcium ion transport (R-HSA-8949215)
  Ub-specific processing proteases (R-HSA-5689880)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	Voltage-dependent anion-selective channel protein 2 affects the response to substance of Josamycin.	[14]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	Voltage-dependent anion-selective channel protein 2 affects the binding of 4-hydroxy-2-nonenal.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Voltage-dependent anion-selective channel protein 2.	[1]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Voltage-dependent anion-selective channel protein 2.	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Voltage-dependent anion-selective channel protein 2.	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Voltage-dependent anion-selective channel protein 2.	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Voltage-dependent anion-selective channel protein 2.	[5]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Voltage-dependent anion-selective channel protein 2.	[6]
Dopamine	DMPGUCF	Approved	Dopamine affects the expression of Voltage-dependent anion-selective channel protein 2.	[7]
Piperazinyl methyl quinazolinone derivative 2	DM913KS	Patented	Piperazinyl methyl quinazolinone derivative 2 decreases the expression of Voltage-dependent anion-selective channel protein 2.	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Voltage-dependent anion-selective channel protein 2.	[11]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Voltage-dependent anion-selective channel protein 2.	[12]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Voltage-dependent anion-selective channel protein 2.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
ME-344	DM6JN19	Phase 1/2	ME-344 affects the binding of Voltage-dependent anion-selective channel protein 2.	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Voltage-dependent anion-selective channel protein 2.	[9]

References

• [1] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [2] 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.
• [3] Identification of biomarkers for the initiation of apoptosis in human preneoplastic colonocytes by proteome analysis. Int J Cancer. 2004 Mar 20;109(2):220-9. doi: 10.1002/ijc.11692.
• [4] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [5] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [10] RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007 Jun 14;447(7146):864-8. doi: 10.1038/nature05859.
• [11] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [12] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [13] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [14] 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.
• [15] Site-specific protein adducts of 4-hydroxy-2(E)-nonenal in human THP-1 monocytic cells: protein carbonylation is diminished by ascorbic acid. Chem Res Toxicol. 2010 Jan;23(1):37-47. doi: 10.1021/tx9002462.