Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJUR82A)

• DOT Name: Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1)
• Synonyms: LIC1; Dynein light chain A; DLC-A; Dynein light intermediate chain 1, cytosolic; DLIC-1
• Gene Name: DYNC1LI1
• Related Disease:
  Influenza
  Osteoarthritis
• UniProt ID: DC1L1_HUMAN
• PDB ID: 6B9H; 6PSD; 6PSE
• Pfam ID: PF05783
• Sequence:
  MAAVGRVGSFGSSPPGLSSTYTGGPLGNEIASGNGGAAAGDDEDGQNLWSCILSEVSTRS
  RSKLPAGKNVLLLGEDGAGKTSLIRKIQGIEEYKKGRGLEYLYLNVHDEDRDDQTRCNVW
  ILDGDLYHKGLLKFSLDAVSLKDTLVMLVVDMSKPWTALDSLQKWASVVREHVDKLKIPP
  EEMKQMEQKLIRDFQEYVEPGEDFPASPQRRNTASQEDKDDSVVLPLGADTLTHNLGIPV
  LVVCTKCDAISVLEKEHDYRDEHFDFIQSHIRKFCLQYGAALIYTSVKENKNIDLVYKYI
  VQKLYGFPYKIPAVVVEKDAVFIPAGWDNDKKIGILHENFQTLKAEDNFEDIITKPPVRK
  FVHEKEIMAEDDQVFLMKLQSLLAKQPPTAAGRPVDASPRVPGGSPRTPNRSVSSNVASV
  SPIPAGSKKIDPNMKAGATSEGVLANFFNSLLSKKTGSPGGPGVSGGSPAGGAGGGSSGL
  PPSTKKSGQKPVLDVHAELDRITRKPVTVSPTTPTSPTEGEAS
• Function: Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. May play a role in binding dynein to membranous organelles or chromosomes. Probably involved in the microtubule-dependent transport of pericentrin. Is required for progress through the spindle assembly checkpoint. The phosphorylated form appears to be involved in the selective removal of MAD1L1 and MAD1L2 but not BUB1B from kinetochores. Forms a functional Rab11/RAB11FIP3/dynein complex onto endosomal membrane that regulates the movement of peripheral sorting endosomes (SE) along microtubule tracks toward the microtubule organizing center/centrosome, generating the endosomal recycling compartment (ERC).
• KEGG Pathway:
  Phagosome (hsa04145)
  Motor proteins (hsa04814)
  Vasopressin-regulated water reabsorption (hsa04962)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  MHC class II antigen presentation (R-HSA-2132295)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Neutrophil degranulation (R-HSA-6798695)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  Mitotic Prometaphase (R-HSA-68877)
  HCMV Early Events (R-HSA-9609690)
  Aggrephagy (R-HSA-9646399)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Influenza	DIS3PNU3	Strong	Biomarker	[1]
Osteoarthritis	DIS05URM	Limited	Genetic Variation	[2]

11 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 Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[7]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[8]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[10]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Cytoplasmic dynein 1 light intermediate chain 1 (DYNC1LI1).	[14]

References

• [1] Prevalence of genetic differences in phosphorylcholine expression between nontypeable Haemophilus influenzae and Haemophilus haemolyticus.BMC Microbiol. 2010 Nov 12;10:286. doi: 10.1186/1471-2180-10-286.
• [2] Protective Actions of Oral Administration of Bifidobacterium longum CBi0703 in Spontaneous Osteoarthritis in Dunkin Hartley Guinea Pig Model.Cartilage. 2021 Dec;13(2_suppl):1204S-1213S. doi: 10.1177/1947603519841674. Epub 2019 Apr 13.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [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] 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.
• [8] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] 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.
• [11] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [14] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.