Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9A0FL4)

• DOT Name: Troponin C, slow skeletal and cardiac muscles (TNNC1)
• Synonyms: TN-C
• Gene Name: TNNC1
• Related Disease:
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1Z
  Hypertrophic cardiomyopathy
  Hypertrophic cardiomyopathy 13
  Obsolete familial isolated dilated cardiomyopathy
  Arrhythmogenic right ventricular cardiomyopathy
• UniProt ID: TNNC1_HUMAN
• PDB ID: 1AP4 ; 1IH0 ; 1J1D ; 1J1E ; 1LXF ; 1MXL ; 1OZS ; 1SPY ; 1WRK ; 1WRL ; 2JT0 ; 2JT3 ; 2JT8 ; 2JTZ ; 2JXL ; 2KDH ; 2KFX ; 2KGB ; 2KRD ; 2L1R ; 2L98 ; 2MKP ; 2MLE ; 2MLF ; 2MZP ; 2N79 ; 2N7L ; 3RV5 ; 3SD6 ; 3SWB ; 4GJE ; 4GJF ; 4GJG ; 4Y99 ; 5VLN ; 5W88 ; 5WCL ; 6KN7 ; 6KN8 ; 6MV3 ; 7JGI ; 7SC2 ; 7SC3 ; 7SUP ; 7SVC ; 7SWG ; 7SWI ; 7SXC ; 7SXD ; 7UH9 ; 7UHA ; 7UTI ; 7UTL
• Pfam ID: PF13499 ; PF13833
• Sequence:
  MDDIYKAAVEQLTEEQKNEFKAAFDIFVLGAEDGCISTKELGKVMRMLGQNPTPEELQEM
  IDEVDEDGSGTVDFDEFLVMMVRCMKDDSKGKSEEELSDLFRMFDKNADGYIDLDELKIM
  LQATGETITEDDIEELMKDGDKNNDGRIDYDEFLEFMKGVE
• Function: Troponin is the central regulatory protein of striated muscle contraction. Tn consists of three components: Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin and Tn-C. The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Motor proteins (hsa04814)
  Cytoskeleton in muscle cells (hsa04820)
  Hypertrophic cardiomyopathy (hsa05410)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway: Striated Muscle Contraction (R-HSA-390522)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dilated cardiomyopathy	DISX608J	Definitive	Autosomal dominant	[1]
Dilated cardiomyopathy 1Z	DISI10RO	Definitive	Autosomal dominant	[2]
Hypertrophic cardiomyopathy	DISQG2AI	Definitive	Autosomal dominant	[1]
Hypertrophic cardiomyopathy 13	DISS47I8	Strong	Autosomal dominant	[3]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[4]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	No Known	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[16]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Troponin C, slow skeletal and cardiac muscles (TNNC1).	[13]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] A novel mutant cardiac troponin C disrupts molecular motions critical for calcium binding affinity and cardiomyocyte contractility. Biophys J. 2008 May 1;94(9):3577-89. doi: 10.1529/biophysj.107.112896. Epub 2008 Jan 22.
• [3] Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J Mol Cell Cardiol. 2008 Aug;45(2):281-8. doi: 10.1016/j.yjmcc.2008.05.003. Epub 2008 May 11.
• [4] Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2004 Nov 16;44(10):2033-40. doi: 10.1016/j.jacc.2004.08.027.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [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] Hypoxia-inducible factor-1 (HIF-1) pathway activation by quercetin in human lens epithelial cells. Exp Eye Res. 2009 Dec;89(6):995-1002. doi: 10.1016/j.exer.2009.08.011. Epub 2009 Sep 1.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] 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.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [15] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.