Target Information
| Target General Information | Top | |||||
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| Target ID |
T27376
(Former ID: TTDI01909)
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| Target Name |
GABA(A) receptor delta (GABRD)
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| Synonyms |
Gammaaminobutyric acid receptor subunit delta; GABRD; GABA(A) receptor subunit delta
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| Gene Name |
GABRD
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Depression [ICD-11: 6A70-6A7Z] | |||||
| 2 | Insomnia [ICD-11: 7A00-7A0Z] | |||||
| 3 | Mental/behavioural/neurodevelopmental disorder [ICD-11: 6E20-6E8Z] | |||||
| 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.
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| BioChemical Class |
Ligand-gated ion channel
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| UniProt ID | ||||||
| Sequence |
MDAPARLLAPLLLLCAQQLRGTRAMNDIGDYVGSNLEISWLPNLDGLIAGYARNFRPGIG
GPPVNVALALEVASIDHISEANMEYTMTVFLHQSWRDSRLSYNHTNETLGLDSRFVDKLW LPDTFIVNAKSAWFHDVTVENKLIRLQPDGVILYSIRITSTVACDMDLAKYPMDEQECML DLESYGYSSEDIVYYWSESQEHIHGLDKLQLAQFTITSYRFTTELMNFKSAGQFPRLSLH FHLRRNRGVYIIQSYMPSVLLVAMSWVSFWISQAAVPARVSLGITTVLTMTTLMVSARSS LPRASAIKALDVYFWICYVFVFAALVEYAFAHFNADYRKKQKAKVKVSRPRAEMDVRNAI VLFSLSAAGVTQELAISRRQRRVPGNLMGSYRSVGVETGETKKEGAARSGGQGGIRARLR PIDADTIDIYARAVFPAAFAAVNVIYWAAYAM Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Allopregnanolone | Drug Info | Approved | Postpartum depression | [2], [3] | |
| 2 | Gaboxadol | Drug Info | Approved | Insomnia | [4], [5] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | SAGE-217b | Drug Info | Phase 2 | Major depressive disorder | [2] | |
| Discontinued Drug(s) | [+] 4 Discontinued Drugs | + | ||||
| 1 | PF-4480682 | Drug Info | Discontinued in Phase 2 | Neuropathic pain | [6] | |
| 2 | PF-2393296 | Drug Info | Discontinued in Phase 1 | Neuropathic pain | [7] | |
| 3 | Co-60549 | Drug Info | Terminated | Anxiety disorder | [8] | |
| 4 | Org-20599 | Drug Info | Terminated | Anaesthesia | [9] | |
| Mode of Action | [+] 5 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | Allopregnanolone | Drug Info | [2] | |||
| Modulator | [+] 5 Modulator drugs | + | ||||
| 1 | Gaboxadol | Drug Info | [1] | |||
| 2 | PF-4480682 | Drug Info | [10] | |||
| 3 | Co-60549 | Drug Info | [12] | |||
| 4 | Org-20599 | Drug Info | [13] | |||
| 5 | RU-5135 | Drug Info | [14] | |||
| Immunostimulant | [+] 1 Immunostimulant drugs | + | ||||
| 1 | SAGE-217b | Drug Info | [2] | |||
| Agonist | [+] 1 Agonist drugs | + | ||||
| 1 | PF-2393296 | Drug Info | [11] | |||
| Blocker (channel blocker) | [+] 1 Blocker (channel blocker) drugs | + | ||||
| 1 | TBPS | Drug Info | [11] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Gaboxadol | Ligand Info | |||||
| Structure Description | Cryo-EM structure of human full-length extrasynaptic alpha4beta3delta GABA(A)R in complex with THIP (gaboxadol), histamine and nanobody Nb25 | PDB:7QNC | ||||
| Method | Electron microscopy | Resolution | 2.90 Å | Mutation | No | [15] |
| PDB Sequence |
PNLDGLIAGY
51 ARNFRPGIGG61 PPVNVALALE71 VASIDHISEA81 NMEYTMTVFL91 HQSWRDSRLS 101 YNHTNETLGL111 DSRFVDKLWL121 PDTFIVNAKS131 AWFHDVTVEN141 KLIRLQPDGV 151 ILYSIRITST161 VACDMDLAKY171 PMDEQECMLD181 LESYGYSSED191 IVYYWSESQE 201 HIHGLDKLQL211 AQFTITSYRF221 TTELMNFKSA231 GQFPRLSLHF241 HLRRNRGVYI 251 IQSYMPSVLL261 VAMSWVSFWI271 SQAAVPARVS281 LGITTVLTMT291 TLMVSARSSL 301 PRASAIKALD311 VYFWICYVFV321 FAALVEYAFA331 HFNADADTID428 IYARAVFPAA 438 FAAVNVIYWA448 AYA
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Decane | Ligand Info | |||||
| Structure Description | Cryo-EM structure of human full-length extrasynaptic alpha4beta3delta GABA(A)R in complex with nanobody Nb25 | PDB:7QN5 | ||||
| Method | Electron microscopy | Resolution | 2.50 Å | Mutation | No | [15] |
| PDB Sequence |
PNLDGLIAGY
51 ARNFRPGIGG61 PPVNVALALE71 VASIDHISEA81 NMEYTMTVFL91 HQSWRDSRLS 101 YNHTNETLGL111 DSRFVDKLWL121 PDTFIVNAKS131 AWFHDVTVEN141 KLIRLQPDGV 151 ILYSIRITST161 VACDMDLAKY171 PMDEQECMLD181 LESYGYSSED191 IVYYWSESQE 201 HIHGLDKLQL211 AQFTITSYRF221 TTELMNFKSA231 GQFPRLSLHF241 HLRRNRGVYI 251 IQSYMPSVLL261 VAMSWVSFWI271 SQAAVPARVS281 LGITTVLTMT291 TLMVSARSSL 301 PRASAIKALD311 VYFWICYVFV321 FAALVEYAFA331 HFNADADTID428 IYARAVFPAA 438 FAAVNVIYWA448 AYA
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Retrograde endocannabinoid signaling | hsa04723 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| GABAergic synapse | hsa04727 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 5 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| 2 | Retrograde endocannabinoid signaling | |||||
| 3 | GABAergic synapse | |||||
| 4 | Morphine addiction | |||||
| 5 | Nicotine addiction | |||||
| References | Top | |||||
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| REF 1 | Gaboxadol--a new awakening in sleep.Curr Opin Pharmacol.2006 Feb;6(1):30-6. | |||||
| REF 2 | Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357. | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4322). | |||||
| REF 5 | Highway driving performance and cognitive functioning the morning after bedtime and middle-of-the-night use of gaboxadol, zopiclone and zolpidem. J Sleep Res. 2009 Dec;18(4):387-96. | |||||
| REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025530) | |||||
| REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027949) | |||||
| REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007012) | |||||
| REF 9 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003651) | |||||
| REF 10 | WO patent application no. 2014,1515,17, Methods of improving microvascular integrity. | |||||
| REF 11 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 416). | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007012) | |||||
| REF 13 | The anaesthetic action and modulation of GABAA receptor activity by the novel water-soluble aminosteroid Org 20599. Neuropharmacology. 1996;35(9-10):1209-22. | |||||
| REF 14 | Complex interactions between the steroid derivative RU 5135 and the GABAA-receptor complex. Eur J Pharmacol. 1992 Oct 1;227(2):147-51. | |||||
| REF 15 | Differential assembly diversifies GABA(A) receptor structures and signalling. Nature. 2022 Apr;604(7904):190-194. | |||||
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