Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOIDCD2)

• DOT Name: Vacuolar protein sorting-associated protein 45
• Synonyms: h-VPS45; hlVps45
• Gene Name: VPS45
• Related Disease: Congenital neutropenia-myelofibrosis-nephromegaly syndrome
• UniProt ID: VPS45_HUMAN
• Pfam ID: PF00995
• Sequence:
  MNVVFAVKQYISKMIEDSGPGMKVLLMDKETTGIVSMVYTQSEILQKEVYLFERIDSQNR
  EIMKHLKAICFLRPTKENVDYIIQELRRPKYTIYFIYFSNVISKSDVKSLAEADEQEVVA
  EVQEFYGDYIAVNPHLFSLNILGCCQGRNWDPAQLSRTTQGLTALLLSLKKCPMIRYQLS
  SEAAKRLAECVKQVITKEYELFEFRRTEVPPLLLILDRCDDAITPLLNQWTYQAMVHELL
  GINNNRIDLSRVPGISKDLREVVLSAENDEFYANNMYLNFAEIGSNIKNLMEDFQKKKPK
  EQQKLESIADMKAFVENYPQFKKMSGTVSKHVTVVGELSRLVSERNLLEVSEVEQELACQ
  NDHSSALQNIKRLLQNPKVTEFDAARLVMLYALHYERHSSNSLPGLMMDLRNKGVSEKYR
  KLVSAVVEYGGKRVRGSDLFSPKDAVAITKQFLKGLKGVENVYTQHQPFLHETLDHLIKG
  RLKENLYPYLGPSTLRDRPQDIIVFVIGGATYEEALTVYNLNRTTPGVRIVLGGTTVHNT
  KSFLEEVLASGLHSRSKESSQVTSRSASRR
• Function: May play a role in vesicle-mediated protein trafficking from the Golgi stack through the trans-Golgi network.
• Tissue Specificity: Ubiquitous. Expression was highest in testis, heart and brain, intermediate in kidney, spleen, prostate, ovary, small intestine and thymus and low in lung, skeletal muscle, placenta, colon, pancreas, peripheral blood leukocytes and liver.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  SARS-CoV-2 modulates autophagy (R-HSA-9754560)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Intra-Golgi traffic (R-HSA-6811438)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital neutropenia-myelofibrosis-nephromegaly syndrome	DIS8VOO2	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Vacuolar protein sorting-associated protein 45.	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Vacuolar protein sorting-associated protein 45.	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Vacuolar protein sorting-associated protein 45.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Vacuolar protein sorting-associated protein 45.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Vacuolar protein sorting-associated protein 45.	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Vacuolar protein sorting-associated protein 45.	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Vacuolar protein sorting-associated protein 45.	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Vacuolar protein sorting-associated protein 45.	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Vacuolar protein sorting-associated protein 45.	[10]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Vacuolar protein sorting-associated protein 45.	[11]

References

• [1] The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy. Blood. 2013 Jun 20;121(25):5078-87. doi: 10.1182/blood-2012-12-475566. Epub 2013 Apr 18.
• [2] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] 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.
• [7] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [8] 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.
• [9] 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.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.