Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT40Y9CN)

• DOT Name: Heparin cofactor 2 (SERPIND1)
• Synonyms: Heparin cofactor II; HC-II; Protease inhibitor leuserpin-2; HLS2; Serpin D1
• Gene Name: SERPIND1
• Related Disease: Heparin cofactor 2 deficiency
• UniProt ID: HEP2_HUMAN
• PDB ID: 1JMJ; 1JMO; 2NAT; 2NCU; 2NCV; 2NCW; 6J12; 6KBO; 6KBV
• Pfam ID: PF00079
• Sequence:
  MKHSLNALLIFLIITSAWGGSKGPLDQLEKGGETAQSADPQWEQLNNKNLSMPLLPADFH
  KENTVTNDWIPEGEEDDDYLDLEKIFSEDDDYIDIVDSLSVSPTDSDVSAGNILQLFHGK
  SRIQRLNILNAKFAFNLYRVLKDQVNTFDNIFIAPVGISTAMGMISLGLKGETHEQVHSI
  LHFKDFVNASSKYEITTIHNLFRKLTHRLFRRNFGYTLRSVNDLYIQKQFPILLDFKTKV
  REYYFAEAQIADFSDPAFISKTNNHIMKLTKGLIKDALENIDPATQMMILNCIYFKGSWV
  NKFPVEMTHNHNFRLNEREVVKVSMMQTKGNFLAANDQELDCDILQLEYVGGISMLIVVP
  HKMSGMKTLEAQLTPRVVERWQKSMTNRTREVLLPKFKLEKNYNLVESLKLMGIRMLFDK
  NGNMAGISDQRIAIDLFKHQGTITVNEEGTQATTVTTVGFMPLSTQVRFTVDRPFLFLIY
  EHRTSCLLFMGRVANPSRS
• Function: Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate. In the presence of the latter, HC-II becomes the predominant thrombin inhibitor in place of antithrombin III (AT-III). Also inhibits chymotrypsin, but in a glycosaminoglycan-independent manner; Peptides at the N-terminal of HC-II have chemotactic activity for both monocytes and neutrophils.
• Tissue Specificity: Expressed predominantly in liver. Also present in plasma.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Common Pathway of Fibrin Clot Formation (R-HSA-140875)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Heparin cofactor 2 deficiency	DISP3Z8W	Definitive	Autosomal dominant	[1]

9 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 Heparin cofactor 2 (SERPIND1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Heparin cofactor 2 (SERPIND1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Heparin cofactor 2 (SERPIND1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Heparin cofactor 2 (SERPIND1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Heparin cofactor 2 (SERPIND1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Heparin cofactor 2 (SERPIND1).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Heparin cofactor 2 (SERPIND1).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Heparin cofactor 2 (SERPIND1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Heparin cofactor 2 (SERPIND1).	[10]

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 increases the methylation of Heparin cofactor 2 (SERPIND1).	[8]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [10] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.