Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIM9XT8)

• DOT Name: CX3C chemokine receptor 1 (CX3CR1)
• Synonyms: C-X3-C CKR-1; CX3CR1; Beta chemokine receptor-like 1; CMK-BRL-1; CMK-BRL1; Fractalkine receptor; G-protein coupled receptor 13; V28
• Gene Name: CX3CR1
• UniProt ID: CX3C1_HUMAN
• PDB ID: 7XBW; 7XBX
• Pfam ID: PF00001
• Sequence:
  MDQFPESVTENFEYDDLAEACYIGDIVVFGTVFLSIFYSVIFAIGLVGNLLVVFALTNSK
  KPKSVTDIYLLNLALSDLLFVATLPFWTHYLINEKGLHNAMCKFTTAFFFIGFFGSIFFI
  TVISIDRYLAIVLAANSMNNRTVQHGVTISLGVWAAAILVAAPQFMFTKQKENECLGDYP
  EVLQEIWPVLRNVETNFLGFLLPLLIMSYCYFRIIQTLFSCKNHKKAKAIKLILLVVIVF
  FLFWTPYNVMIFLETLKLYDFFPSCDMRKDLRLALSVTETVAFSHCCLNPLIYAFAGEKF
  RRYLYHLYGKCLAVLCGRSVHVDFSSSESQRSRHGSVLSSNFTYHTSDGDALLLL
• Function: Receptor for the C-X3-C chemokine fractalkine (CX3CL1) present on many early leukocyte cells; CX3CR1-CX3CL1 signaling exerts distinct functions in different tissue compartments, such as immune response, inflammation, cell adhesion and chemotaxis. CX3CR1-CX3CL1 signaling mediates cell migratory functions. Responsible for the recruitment of natural killer (NK) cells to inflamed tissues. Acts as a regulator of inflammation process leading to atherogenesis by mediating macrophage and monocyte recruitment to inflamed atherosclerotic plaques, promoting cell survival. Involved in airway inflammation by promoting interleukin 2-producing T helper (Th2) cell survival in inflamed lung. Involved in the migration of circulating monocytes to non-inflamed tissues, where they differentiate into macrophages and dendritic cells. Acts as a negative regulator of angiogenesis, probably by promoting macrophage chemotaxis. Plays a key role in brain microglia by regulating inflammatory response in the central nervous system (CNS) and regulating synapse maturation. Required to restrain the microglial inflammatory response in the CNS and the resulting parenchymal damage in response to pathological stimuli. Involved in brain development by participating in synaptic pruning, a natural process during which brain microglia eliminates extra synapses during postnatal development. Synaptic pruning by microglia is required to promote the maturation of circuit connectivity during brain development. Acts as an important regulator of the gut microbiota by controlling immunity to intestinal bacteria and fungi. Expressed in lamina propria dendritic cells in the small intestine, which form transepithelial dendrites capable of taking up bacteria in order to provide defense against pathogenic bacteria. Required to initiate innate and adaptive immune responses against dissemination of commensal fungi (mycobiota) component of the gut: expressed in mononuclear phagocytes (MNPs) and acts by promoting induction of antifungal IgG antibodies response to confer protection against disseminated C.albicans or C.auris infection. Also acts as a receptor for C-C motif chemokine CCL26, inducing cell chemotaxis ; [Isoform 1]: (Microbial infection) Acts as a coreceptor with CD4 for HIV-1 virus envelope protein; [Isoform 2]: (Microbial infection) Acts as a coreceptor with CD4 for HIV-1 virus envelope protein. May have more potent HIV-1 coreceptothr activity than isoform 1 ; [Isoform 3]: (Microbial infection) Acts as a coreceptor with CD4 for HIV-1 virus envelope protein. May have more potent HIV-1 coreceptor activity than isoform 1.
• Tissue Specificity: Expressed in lymphoid and neural tissues . Expressed in lymphocyte subsets, such as natural killer (NK) cells, gamma-delta T-cells and terminally differentiated CD8(+) T-cells . Expressed in smooth muscle cells in atherosclerotic plaques .
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)
  Efferocytosis (hsa04148)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Chemokine receptors bind chemokines (R-HSA-380108)

Molecular Interaction Atlas (MIA) of This DOT

2 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 CX3C chemokine receptor 1 (CX3CR1).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of CX3C chemokine receptor 1 (CX3CR1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of CX3C chemokine receptor 1 (CX3CR1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of CX3C chemokine receptor 1 (CX3CR1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CX3C chemokine receptor 1 (CX3CR1).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of CX3C chemokine receptor 1 (CX3CR1).	[5]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of CX3C chemokine receptor 1 (CX3CR1).	[6]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of CX3C chemokine receptor 1 (CX3CR1).	[7]
Lindane	DMB8CNL	Approved	Lindane decreases the expression of CX3C chemokine receptor 1 (CX3CR1).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of CX3C chemokine receptor 1 (CX3CR1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of CX3C chemokine receptor 1 (CX3CR1).	[10]
GW-501516	DMPL2KM	Discontinued in Phase 4	GW-501516 decreases the expression of CX3C chemokine receptor 1 (CX3CR1).	[6]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of CX3C chemokine receptor 1 (CX3CR1).	[8]
Choline	DM5D9YK	Investigative	Choline affects the expression of CX3C chemokine receptor 1 (CX3CR1).	[12]
PAF	DMRZAQW	Investigative	PAF increases the expression of CX3C chemokine receptor 1 (CX3CR1).	[13]

References

• [1] 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.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] 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.
• [5] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [6] Rosiglitazone activation of PPARgamma suppresses fractalkine signaling. J Mol Endocrinol. 2010 Feb;44(2):135-42. doi: 10.1677/JME-09-0090. Epub 2009 Oct 22.
• [7] [Effect of simvastatin on monocyte CX3CR1 expression in patients with acute coronary syndrome]. Nan Fang Yi Ke Da Xue Xue Bao. 2008 Mar;28(3):475-7.
• [8] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [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] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] 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.
• [12] Lymphocyte gene expression in subjects fed a low-choline diet differs between those who develop organ dysfunction and those who do not. Am J Clin Nutr. 2007 Jul;86(1):230-9. doi: 10.1093/ajcn/86.1.230.
• [13] Oxidized phospholipid: POVPC binds to platelet-activating-factor receptor on human macrophagesImplications in atherosclerosis. Atherosclerosis. 2006 Oct;188(2):433-43.