Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT56N6SA)

• DOT Name: Claudin-18 (CLDN18)
• Gene Name: CLDN18
• UniProt ID: CLD18_HUMAN
• Pfam ID: PF00822
• Sequence:
  MSTTTCQVVAFLLSILGLAGCIAATGMDMWSTQDLYDNPVTSVFQYEGLWRSCVRQSSGF
  TECRPYFTILGLPAMLQAVRALMIVGIVLGAIGLLVSIFALKCIRIGSMEDSAKANMTLT
  SGIMFIVSGLCAIAGVSVFANMLVTNFWMSTANMYTGMGGMVQTVQTRYTFGAALFVGWV
  AGGLTLIGGVMMCIACRGLAPEETNYKAVSYHASGHSVAYKPGGFKASTGFGSNTKNKKI
  YDGGARTEDEVQSYPSKHDYV
• Function: Involved in alveolar fluid homeostasis via regulation of alveolar epithelial tight junction composition and therefore ion transport and solute permeability, potentially via downstream regulation of the actin cytoskeleton organization and beta-2-adrenergic signaling. Required for lung alveolarization and maintenance of the paracellular alveolar epithelial barrier. Acts to maintain epithelial progenitor cell proliferation and organ size, via regulation of YAP1 localization away from the nucleus and thereby restriction of YAP1 target gene transcription. Acts as a negative regulator of RANKL-induced osteoclast differentiation, potentially via relocation of TJP2/ZO-2 away from the nucleus, subsequently involved in bone resorption in response to calcium deficiency. Mediates the osteoprotective effects of estrogen, potentially via acting downstream of estrogen signaling independently of RANKL signaling pathways; [Isoform A1]: Involved in the maintenance of homeostasis of the alveolar microenvironment via regulation of pH and subsequent T-cell activation in the alveolar space, is therefore indirectly involved in limiting C. neoformans infection; [Isoform A2]: Required for the formation of the gastric paracellular barrier via its role in tight junction formation, thereby involved in the response to gastric acidification.
• Tissue Specificity: .Expression is restricted to the lung.; [Isoform A2]: Expression is restricted to the stomach mucosa where it is predominantly observed in the epithelial cells of the pit region and the base of the gastric glands including exocrine and endocrine cells (at protein level).
• KEGG Pathway:
  Cell adhesion molecules (hsa04514)
  Tight junction (hsa04530)
  Leukocyte transendothelial migration (hsa04670)
  Pathogenic Escherichia coli infection (hsa05130)
  Hepatitis C (hsa05160)
• Reactome Pathway: Tight junction interactions (R-HSA-420029)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Claudin-18 (CLDN18).	[1]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Claudin-18 (CLDN18).	[3]
Coprexa	DMA0WEK	Phase 3	Coprexa decreases the expression of Claudin-18 (CLDN18).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Claudin-18 (CLDN18).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Claudin-18 (CLDN18).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Claudin-18 (CLDN18).	[6]

References

• [1] 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.
• [2] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [3] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [4] Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition. Chem Biol Interact. 2023 Sep 1;382:110546. doi: 10.1016/j.cbi.2023.110546. Epub 2023 Jun 7.
• [5] 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.
• [6] 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.