Target Information
| Target General Information | Top | |||||
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| Target ID |
T26368
(Former ID: TTDR01042)
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| Target Name |
GABA(A) receptor alpha-5 (GABRA5)
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| Synonyms |
GABRA5; GABAA alpha 5; GABA-A alpha-5
Click to Show/Hide
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| Gene Name |
GABRA5
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Intentional self-harm [ICD-11: PC91] | |||||
| 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 |
MDNGMFSGFIMIKNLLLFCISMNLSSHFGFSQMPTSSVKDETNDNITIFTRILDGLLDGY
DNRLRPGLGERITQVRTDIYVTSFGPVSDTEMEYTIDVFFRQSWKDERLRFKGPMQRLPL NNLLASKIWTPDTFFHNGKKSIAHNMTTPNKLLRLEDDGTLLYTMRLTISAECPMQLEDF PMDAHACPLKFGSYAYPNSEVVYVWTNGSTKSVVVAEDGSRLNQYHLMGQTVGTENISTS TGEYTIMTAHFHLKRKIGYFVIQTYLPCIMTVILSQVSFWLNRESVPARTVFGVTTVLTM TTLSISARNSLPKVAYATAMDWFIAVCYAFVFSALIEFATVNYFTKRGWAWDGKKALEAA KIKKKREVILNKSTNAFTTGKMSHPPNIPKEQTPAGTSNTTSVSVKPSEEKTSESKKTYN SISKIDKMSRIVFPVLFGTFNLVYWATYLNREPVIKGAASPK 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) | [+] 1 Approved Drugs | + | ||||
| 1 | Flumazenil | Drug Info | Approved | Benzodiazepine overdose | [2], [3] | |
| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | Basmisanil | Drug Info | Phase 2 | Alzheimer disease | [4] | |
| 2 | GSK683699 | Drug Info | Phase 2 | Inflammatory bowel disease | [5] | |
| 3 | RG-7816 | Drug Info | Phase 1 | Autism spectrum disorder | [6] | |
| Mode of Action | [+] 5 Modes of Action | + | ||||
| Modulator (allosteric modulator) | [+] 10 Modulator (allosteric modulator) drugs | + | ||||
| 1 | Flumazenil | Drug Info | [1] | |||
| 2 | alpha3IA | Drug Info | [1] | |||
| 3 | alpha5IA | Drug Info | [1] | |||
| 4 | DMCM | Drug Info | [1] | |||
| 5 | RY024 | Drug Info | [1] | |||
| 6 | tetrahydrodeoxycorticosterone | Drug Info | [1] | |||
| 7 | TP003 | Drug Info | [1] | |||
| 8 | [18F]fluoroethylflumazenil | Drug Info | [1] | |||
| 9 | [3H]CGS8216 | Drug Info | [1] | |||
| 10 | [3H]L655708 | Drug Info | [1] | |||
| Modulator | [+] 3 Modulator drugs | + | ||||
| 1 | Basmisanil | Drug Info | [7] | |||
| 2 | RG-7816 | Drug Info | [6] | |||
| 3 | [3H]RY80 | Drug Info | [17] | |||
| Inhibitor | [+] 24 Inhibitor drugs | + | ||||
| 1 | GSK683699 | Drug Info | [8] | |||
| 2 | (2E,4S)-4-ammoniopent-2-enoate | Drug Info | [9] | |||
| 3 | (4R)-4-ammoniopentanoate | Drug Info | [9] | |||
| 4 | (4S)-4-ammoniopentanoate | Drug Info | [9] | |||
| 5 | 3-(3-Methyl-butoxy)-9H-beta-carboline | Drug Info | [10] | |||
| 6 | 3-(benzyloxy)-9H-pyrido[3,4-b]indole | Drug Info | [10] | |||
| 7 | 3-(hexa-1,3-dienyloxy)-9H-pyrido[3,4-b]indole | Drug Info | [10] | |||
| 8 | 3-Butoxy-9H-beta-carboline | Drug Info | [10] | |||
| 9 | 3-Ethoxy-9H-beta-carboline | Drug Info | [10] | |||
| 10 | 3-Isobutoxy-9H-beta-carboline | Drug Info | [10] | |||
| 11 | 3-Propoxy-9H-beta-carboline | Drug Info | [10] | |||
| 12 | 5-[(1R)-1-ammonioethyl]isoxazol-3-olate | Drug Info | [9] | |||
| 13 | 5-[(1S)-1-ammonioethyl]isoxazol-3-olate | Drug Info | [9] | |||
| 14 | 9H-beta-Carboline-3-carboxylic acid ethyl ester | Drug Info | [10] | |||
| 15 | AMENTOFLAVONE | Drug Info | [11] | |||
| 16 | Barbituric acid derivative | Drug Info | [12] | |||
| 17 | Beta-Carboline-3-carboxylic acid t-butyl ester | Drug Info | [10] | |||
| 18 | CI-218872 | Drug Info | [10] | |||
| 19 | Ethyl 6-iodo-9H-pyrido[3,4-b]indole-3-carboxylate | Drug Info | [10] | |||
| 20 | L-655708 | Drug Info | [13] | |||
| 21 | Ro-15-3505 | Drug Info | [14] | |||
| 22 | Ro-4938581 | Drug Info | [15] | |||
| 23 | Sec-butyl 9H-pyrido[3,4-b]indole-3-carboxylate | Drug Info | [10] | |||
| 24 | [3H]Ro154513 | Drug Info | [16] | |||
| Agonist | [+] 3 Agonist drugs | + | ||||
| 1 | HT-2678 | Drug Info | [1] | |||
| 2 | isonipecotic acid | Drug Info | [1] | |||
| 3 | piperidine-4-sulphonic acid | Drug Info | [1] | |||
| Blocker (channel blocker) | [+] 2 Blocker (channel blocker) drugs | + | ||||
| 1 | TBPS | Drug Info | [1] | |||
| 2 | [35S]TBPS | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| 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 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).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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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 | ||
| Taste transduction | hsa04742 | Affiliated Target |
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| Class: Organismal Systems => Sensory system | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.72E-01 | Radiality | 1.27E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.00E+01 | Topological coefficient | 1.00E+00 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| 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) |
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| 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 | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Ligand-gated ion channel transport | |||||
| 2 | GABA A receptor activation | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell | |||||
| 2 | Iron uptake and transport | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | 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: 408). | |||||
| REF 2 | 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: 4192). | |||||
| REF 3 | ClinicalTrials.gov (NCT00997087) A Randomized, Double-Blind, Placebo-Controlled Trial of Flumazenil for the Treatment of Obsessive Compulsive Disorder. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT02484703) A Study of RG1662 in Down Syndrome Among Children 6 to 11 Years of Age. | |||||
| REF 5 | Emerging drugs to treat Crohn's disease. Expert Opin Emerg Drugs. 2007 Mar;12(1):49-59. | |||||
| REF 6 | Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357. | |||||
| REF 7 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 8 | New anticonvulsants: Schiff bases of gamma-aminobutyric acid and gamma-aminobutyramide. J Med Chem. 1980 Jun;23(6):702-4. | |||||
| REF 9 | gamma-Aminobutyric acid agonists, antagonists, and uptake inhibitors. Design and therapeutic aspects. J Med Chem. 1981 Dec;24(12):1377-83. | |||||
| REF 10 | Design, synthesis, and subtype selectivity of 3,6-disubstituted -carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents f... Bioorg Med Chem. 2010 Nov 1;18(21):7548-64. | |||||
| REF 11 | Semisynthetic preparation of amentoflavone: A negative modulator at GABA(A) receptors. Bioorg Med Chem Lett. 2003 Jul 21;13(14):2281-4. | |||||
| REF 12 | Whiting PJ: The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57. | |||||
| REF 13 | 3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and analogues: high-affinity gamma-aminobutyric acid-A benzodiazepine receptor li... J Med Chem. 2004 Mar 25;47(7):1807-22. | |||||
| REF 14 | The GABA(A) receptor as a target for photochromic molecules. Bioorg Med Chem. 2010 Nov 15;18(22):7731-8. | |||||
| REF 15 | The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABAA alpha5 inverse agonists for the treatment... Bioorg Med Chem Lett. 2009 Oct 15;19(20):5940-4. | |||||
| REF 16 | Synthesis and pharmacological properties of novel 8-substituted imidazobenzodiazepines: high-affinity, selective probes for alpha 5-containing GABA... J Med Chem. 1996 Apr 26;39(9):1928-34. | |||||
| REF 17 | [3H]RY 80: A high-affinity, selective ligand for gamma-aminobutyric acidA receptors containing alpha-5 subunits. J Pharmacol Exp Ther. 1997 Nov;283(2):488-93. | |||||
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