Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO38I2R)

• DOT Name: Gamma-aminobutyric acid receptor subunit delta (GABRD)
• Synonyms: GABA(A) receptor subunit delta
• Gene Name: GABRD
• Related Disease:
  Complex neurodevelopmental disorder
  Epilepsy
  Epilepsy, idiopathic generalized, susceptibility to, 10
• UniProt ID: GBRD_HUMAN
• PDB ID: 7QN5; 7QN6; 7QN7; 7QN8; 7QN9; 7QNC; 7QND
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MDAPARLLAPLLLLCAQQLRGTRAMNDIGDYVGSNLEISWLPNLDGLIAGYARNFRPGIG
  GPPVNVALALEVASIDHISEANMEYTMTVFLHQSWRDSRLSYNHTNETLGLDSRFVDKLW
  LPDTFIVNAKSAWFHDVTVENKLIRLQPDGVILYSIRITSTVACDMDLAKYPMDEQECML
  DLESYGYSSEDIVYYWSESQEHIHGLDKLQLAQFTITSYRFTTELMNFKSAGQFPRLSLH
  FHLRRNRGVYIIQSYMPSVLLVAMSWVSFWISQAAVPARVSLGITTVLTMTTLMVSARSS
  LPRASAIKALDVYFWICYVFVFAALVEYAFAHFNADYRKKQKAKVKVSRPRAEMDVRNAI
  VLFSLSAAGVTQELAISRRQRRVPGNLMGSYRSVGVETGETKKEGAARSGGQGGIRARLR
  PIDADTIDIYARAVFPAAFAAVNVIYWAAYAM
• Function: GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Retrograde endocan.binoid sig.ling (hsa04723)
  GABAergic sy.pse (hsa04727)
  Morphine addiction (hsa05032)
  Nicotine addiction (hsa05033)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Moderate	Autosomal dominant	[1]
Epilepsy	DISBB28L	Limited	Autosomal dominant	[1]
Epilepsy, idiopathic generalized, susceptibility to, 10	DISD58Q7	Limited	Autosomal dominant	[2]

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 Gamma-aminobutyric acid receptor subunit delta (GABRD).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Gamma-aminobutyric acid receptor subunit delta (GABRD).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Gamma-aminobutyric acid receptor subunit delta (GABRD).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Gamma-aminobutyric acid receptor subunit delta (GABRD).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Gamma-aminobutyric acid receptor subunit delta (GABRD).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Gamma-aminobutyric acid receptor subunit delta (GABRD).	[7]

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] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] 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.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [7] 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.
• [8] 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.