Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMGGM47)

• DOT Name: Calcitonin gene-related peptide type 1 receptor (CALCRL)
• Synonyms: CGRP type 1 receptor; Calcitonin receptor-like receptor
• Gene Name: CALCRL
• Related Disease: Lymphatic malformation 8
• UniProt ID: CALRL_HUMAN
• PDB ID: 3AQF; 3N7P; 3N7R; 3N7S; 4RWF; 4RWG; 5V6Y; 6D1U; 6E3Y; 6UMG; 6UUN; 6UUS; 6UVA; 6V2E; 6ZHO; 6ZIS; 7KNT; 7KNU; 7P0F; 7P0I; 8AX5; 8AX6; 8AX7
• Pfam ID: PF00002 ; PF02793
• Sequence:
  MEKKCTLYFLVLLPFFMILVTAELEESPEDSIQLGVTRNKIMTAQYECYQKIMQDPIQQA
  EGVYCNRTWDGWLCWNDVAAGTESMQLCPDYFQDFDPSEKVTKICDQDGNWFRHPASNRT
  WTNYTQCNVNTHEKVKTALNLFYLTIIGHGLSIASLLISLGIFFYFKSLSCQRITLHKNL
  FFSFVCNSVVTIIHLTAVANNQALVATNPVSCKVSQFIHLYLMGCNYFWMLCEGIYLHTL
  IVVAVFAEKQHLMWYYFLGWGFPLIPACIHAIARSLYYNDNCWISSDTHLLYIIHGPICA
  ALLVNLFFLLNIVRVLITKLKVTHQAESNLYMKAVRATLILVPLLGIEFVLIPWRPEGKI
  AEEVYDYIMHILMHFQGLLVSTIFCFFNGEVQAILRRNWNQYKIQFGNSFSNSEALRSAS
  YTVSTISDGPGYSHDCPSEHLNGKSIHDIENVLLKPENLYN
• Function: Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3. Receptor for adrenomedullin together with RAMP2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
• Tissue Specificity: Predominantly expressed in the lung and heart.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Vascular smooth muscle contraction (hsa04270)
• Reactome Pathway:
  Calcitonin-like ligand receptors (R-HSA-419812)
  G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lymphatic malformation 8	DISBHSXC	Limited	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[6]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[6]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[10]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[8]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Calcitonin gene-related peptide type 1 receptor (CALCRL).	[12]

References

• [1] hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia. J Exp Med. 2018 Sep 3;215(9):2339-2353. doi: 10.1084/jem.20180528. Epub 2018 Aug 16.
• [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] 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.
• [7] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [8] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [9] 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.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Global gene expression analysis reveals novel transcription factors associated with long-term low-level exposure of EA.hy926 human endothelial cells to bisphenol A. Chem Biol Interact. 2023 Aug 25;381:110571. doi: 10.1016/j.cbi.2023.110571. Epub 2023 May 25.
• [12] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.