Details of Drug Off-Target (DOT)

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

• DOT Name: Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1)
• Synonyms: Centromere protein 33; CENP-33; Origin recognition complex-associated protein; ORC-associated protein; ORCA
• Gene Name: LRWD1
• Related Disease:
  Azoospermia
  Dental caries
  Disease of orbital part of eye adnexa
  Ewing sarcoma
  Male infertility
  Mixed anxiety and depressive disorder
  Advanced cancer
  Neoplasm
  Ovarian neoplasm
  Periodontal disease
  Prostate cancer
  Prostate carcinoma
• UniProt ID: LRWD1_HUMAN
• Pfam ID: PF13855 ; PF00400
• Sequence:
  MGPLSARLLMQRGRPKSDRLGKIRSLDLSGLELLSEHLDPKLLCRLTQLQELDLSNNHLE
  TLPDNLGLSHLRVLRCANNQLGDVTALCQFPKLEELSLEGNPFLTVNDNLKVSFLLPTLR
  KVNGKDASSTYSQVENLNRELTSRVTAHWEKFMATLGPEEEAEKAQADFVKSAVRDVRYG
  PESLSEFTQWRVRMISEELVAASRTQVQKANSPEKPPEAGAAHKPRARLAALKRPDDVPL
  SLSPSKRACASPSAQVEGSPVAGSDGSQPAVKLEPLHFLQCHSKNNSPQDLETQLWACAF
  EPAWEEGATSQTVATCGGEAVCVIDCQTGIVLHKYKAPGEEFFSVAWTALMVVTQAGHKK
  RWSVLAAAGLRGLVRLLHVRAGFCCGVIRAHKKAIATLCFSPAHETHLFTASYDKRIILW
  DIGVPNQDYEFQASQLLTLDTTSIPLRLCPVASCPDARLLAGCEGGCCCWDVRLDQPQKR
  RVCEVEFVFSEGSEASGRRVDGLAFVNEDIVASKGSGLGTICLWSWRQTWGGRGSQSTVA
  VVVLARLQWSSTELAYFSLSACPDKGIVLCGDEEGNVWLYDVSNILKQPPLLPAALQAPT
  QILKWPQPWALGQVVTKTMVNTVVANASFTYLTALTDSNIVAIWGRM
• Function: Required for G1/S transition. Recruits and stabilizes the origin recognition complex (ORC) onto chromatin during G1 to establish pre-replication complex (preRC) and to heterochromatic sites in post-replicated cells. Binds a combination of DNA and histone methylation repressive marks on heterochromatin. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3 in a cooperative manner with DNA methylation. Required for silencing of major satellite repeats. May be important ORC2, ORC3 and ORC4 stability.
• Tissue Specificity: Testis-specific. Drastically down-regulated in testis from patients with Sertoli cell-only syndrome (SCOS).

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Azoospermia	DIS94181	Strong	Genetic Variation	[1]
Dental caries	DISRBCMD	Strong	Biomarker	[2]
Disease of orbital part of eye adnexa	DISGWPWX	Strong	Biomarker	[3]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[4]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[1]
Mixed anxiety and depressive disorder	DISV809X	Strong	Genetic Variation	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	moderate	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	moderate	Altered Expression	[6]
Periodontal disease	DISJQHVN	moderate	Biomarker	[7]
Prostate cancer	DISF190Y	moderate	Biomarker	[6]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[6]

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 Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Leucine-rich repeat and WD repeat-containing protein 1 (LRWD1).	[17]

References

• [1] Single-nucleotide polymorphisms in the LRWD1 gene may be a genetic risk factor for Japanese patients with Sertoli cell-only syndrome.Andrologia. 2014 Apr;46(3):273-6. doi: 10.1111/and.12077. Epub 2013 Feb 28.
• [2] Terminology of Dental Caries and Dental Caries Management: Consensus Report of a Workshop Organized by ORCA and Cariology Research Group of IADR.Caries Res. 2020;54(1):7-14. doi: 10.1159/000503309. Epub 2019 Oct 7.
• [3] BLANT-fast graphlet sampling tool.Bioinformatics. 2019 Dec 15;35(24):5363-5364. doi: 10.1093/bioinformatics/btz603.
• [4] High-throughput RNAi screen in Ewing sarcoma cells identifies leucine rich repeats and WD repeat domain containing 1 (LRWD1) as a regulator of EWS-FLI1 driven cell viability.Gene. 2017 Jan 5;596:137-146. doi: 10.1016/j.gene.2016.10.021. Epub 2016 Oct 17.
• [5] A unique database for gathering data from a mobile app and medical prescription software: a useful data source to collect and analyse patient-reported outcomes of depression and anxiety symptoms.Int J Psychiatry Clin Pract. 2017 Nov;21(4):318-321. doi: 10.1080/13651501.2017.1315139. Epub 2017 Apr 21.
• [6] ORCA-010, a novel potency-enhanced oncolytic adenovirus, exerts strong antitumor activity in preclinical models.Hum Gene Ther. 2014 Oct;25(10):897-904. doi: 10.1089/hum.2013.229. Epub 2014 Sep 17.
• [7] Role of microbial biofilms in the maintenance of oral health and in the development of dental caries and periodontal diseases. Consensus report of group 1 of the Joint EFP/ORCA workshop on the boundaries between caries and periodontal disease.J Clin Periodontol. 2017 Mar;44 Suppl 18:S5-S11. doi: 10.1111/jcpe.12682.
• [8] 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.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] 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.