Target Information
| Target General Information | Top | |||||
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| Target ID |
T73495
(Former ID: TTDS00122)
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| Target Name |
Glutamate receptor ionotropic kainate 1 (GRIK1)
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| Synonyms |
Glutamate receptor 5; GluR5 kainate receptor; GluR5; GluR-5; GRIK1; Excitatory amino acid receptor 3; EAA3
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| Gene Name |
GRIK1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Epilepsy/seizure [ICD-11: 8A61-8A6Z] | |||||
| 2 | Substance abuse [ICD-11: 6C40] | |||||
| Function |
Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading tothe opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus.
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| BioChemical Class |
Glutamate-gated ion channel
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| UniProt ID | ||||||
| Sequence |
MEHGTLLAQPGLWTRDTSWALLYFLCYILPQTAPQVLRIGGIFETVENEPVNVEELAFKF
AVTSINRNRTLMPNTTLTYDIQRINLFDSFEASRRACDQLALGVAALFGPSHSSSVSAVQ SICNALEVPHIQTRWKHPSVDNKDLFYINLYPDYAAISRAILDLVLYYNWKTVTVVYEDS TGLIRLQELIKAPSRYNIKIKIRQLPSGNKDAKPLLKEMKKGKEFYVIFDCSHETAAEIL KQILFMGMMTEYYHYFFTTLDLFALDLELYRYSGVNMTGFRLLNIDNPHVSSIIEKWSME RLQAPPRPETGLLDGMMTTEAALMYDAVYMVAIASHRASQLTVSSLQCHRHKPWRLGPRF MNLIKEARWDGLTGHITFNKTNGLRKDFDLDIISLKEEGTEKAAGEVSKHLYKVWKKIGI WNSNSGLNMTDSNKDKSSNITDSLANRTLIVTTILEEPYVMYRKSDKPLYGNDRFEGYCL DLLKELSNILGFIYDVKLVPDGKYGAQNDKGEWNGMVKELIDHRADLAVAPLTITYVREK VIDFSKPFMTLGISILYRKPNGTNPGVFSFLNPLSPDIWMYVLLACLGVSCVLFVIARFT PYEWYNPHPCNPDSDVVENNFTLLNSFWFGVGALMQQGSELMPKALSTRIVGGIWWFFTL IIISSYTANLAAFLTVERMESPIDSADDLAKQTKIEYGAVRDGSTMTFFKKSKISTYEKM WAFMSSRQQTALVRNSDEGIQRVLTTDYALLMESTSIEYVTQRNCNLTQIGGLIDSKGYG VGTPIGSPYRDKITIAILQLQEEGKLHMMKEKWWRGNGCPEEDNKEASALGVENIGGIFI VLAAGLVLSVFVAIGEFIYKSRKNNDIEQAFCFFYGLQCKQTHPTNSTSGTTLSTDLECG KLIREERGIRKQSSVHTV Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T39KQU | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Topiramate | Drug Info | Approved | Alcohol dependence | [2], [3], [4] | |
| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | LY293558 | Drug Info | Phase 2 | Pain | [5], [6] | |
| 2 | NS 1209 | Drug Info | Phase 2 | Neuropathic pain | [7], [8] | |
| 3 | NBQX | Drug Info | Phase 1 | Neurological disorder | [9] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | YM-90K | Drug Info | Discontinued in Phase 2 | Convulsion | [10] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Antagonist | [+] 8 Antagonist drugs | + | ||||
| 1 | Topiramate | Drug Info | [1] | |||
| 2 | 2,4-epi-neodysiherbaine | Drug Info | [13] | |||
| 3 | ACET | Drug Info | [13] | |||
| 4 | LY382884 | Drug Info | [13] | |||
| 5 | LY466195 | Drug Info | [13] | |||
| 6 | MSVIII-19 | Drug Info | [13] | |||
| 7 | NS3763 | Drug Info | [13] | |||
| 8 | UBP310 | Drug Info | [13], [21] | |||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | LY293558 | Drug Info | [6] | |||
| 2 | NS 1209 | Drug Info | [7] | |||
| Inhibitor | [+] 14 Inhibitor drugs | + | ||||
| 1 | NBQX | Drug Info | [11] | |||
| 2 | YM-90K | Drug Info | [11] | |||
| 3 | (2S,4R)-4-(3-Methoxy-3-oxopropyl)glutamic Acid | Drug Info | [12] | |||
| 4 | 2-(3-(3-bromophenyl)ureido)-4-chlorobenzoic acid | Drug Info | [14] | |||
| 5 | 2-(3-bromobenzoylamino)-4-chlorobenzoic acid | Drug Info | [14] | |||
| 6 | 2-AMINO-3-(4-HYDROXY-1,2,5-OXADIAZOL-3-YL)PROPIONIC ACID (STRUCTURAL MIX) | Drug Info | [15] | |||
| 7 | 2S,4R-4-METHYLGLUTAMATE | Drug Info | [12] | |||
| 8 | DIHYDROKAINATE | Drug Info | [16] | |||
| 9 | DNQX | Drug Info | [17] | |||
| 10 | Domoric acid | Drug Info | [12] | |||
| 11 | S-ATPO | Drug Info | [18] | |||
| 12 | TQX-173 | Drug Info | [19] | |||
| 13 | UBP-302 | Drug Info | [20] | |||
| 14 | [3H]quisqualate | Drug Info | [12] | |||
| Agonist | [+] 9 Agonist drugs | + | ||||
| 1 | (S)-4-AHCP | Drug Info | [13] | |||
| 2 | (S)-5-iodowillardiine | Drug Info | [13] | |||
| 3 | 8-deoxy-neodysiherbaine | Drug Info | [13] | |||
| 4 | ATPA | Drug Info | [13] | |||
| 5 | domoic acid | Drug Info | [13] | |||
| 6 | dysiherbaine | Drug Info | [13] | |||
| 7 | LY339434 | Drug Info | [13] | |||
| 8 | SYM2081 | Drug Info | [13] | |||
| 9 | [3H]kainate | Drug Info | [12], [13] | |||
| 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: Dysiherbaine | Ligand Info | |||||
| Structure Description | Crystal Structure of the human glutamate receptor, GluR5, ligand-binding core in complex with dysiherbaine in space group P1 | PDB:3FV1 | ||||
| Method | X-ray diffraction | Resolution | 1.50 Å | Mutation | No | [22] |
| PDB Sequence |
ANRTLIVTTI
424 LEEPYVMYRK434 SDKPLYGNDR444 FEGYCLDLLK454 ELSNILGFIY464 DVKLVPDGKY 474 GAQNDKGEWN484 GMVKELIDHR494 ADLAVAPLTI504 TYVREKVIDF514 SKPFMTLGIS 524 ILYRKGTPID654 SADDLAKQTK664 IEYGAVRDGS674 TMTFFKKSKI684 STYEKMWAFM 694 SSRQQTALVR704 NSDEGIQRVL714 TTDYALLMES724 TSIEYVTQRN734 CNLTQIGGLI 744 DSKGYGVGTP754 IGSPYRDKIT764 IAILQLQEEG774 KLHMMKEKWW784 RGNGCP |
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GLU426
3.455
TYR429
4.291
TYR474
3.273
PRO501
2.828
LEU502
3.428
THR503
2.834
ARG508
2.750
VAL670
3.363
GLY673
3.323
SER674
2.777
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Dasolampanel | Ligand Info | |||||
| Structure Description | Crystal Structure of Human GRIK1 complexed with a 6-(tetrazolyl)aryl decahydroisoquinoline antagonist | PDB:4MF3 | ||||
| Method | X-ray diffraction | Resolution | 3.00 Å | Mutation | No | [23] |
| PDB Sequence |
SLANRTLIVT
10 TILEEPYVMY20 RKSDKPLYGN30 DRFEGYCLDL40 LKELSNILGF50 IYDVKLVPDG 60 KYGAQNDKGE70 WNGMVKELID80 HRADLAVAPL90 TITYVREKVI100 DFSKPFMTLG 110 ISILYRKGTP120 IDSADDLAKQ130 TKIEYGAVRD140 GSTMTFFKKS150 KISTYEKMWA 160 FMSSRQQTAL170 VRNSDEGIQR180 VLTTDYALLM190 ESTSIEYVTQ200 RNCNLTQIGG 210 LIDSKGYGVG220 TPIGSPYRDK230 ITIAILQLQE240 EGKLHMMKEK250 WWRGNGCP |
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| 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 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 | ||
| Glutamatergic synapse | hsa04724 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 1.23E-04 |
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| Closeness centrality | 2.02E-01 | Radiality | 1.35E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 4.40E+01 | Topological coefficient | 5.00E-01 | 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 Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| 2 | Glutamatergic synapse | |||||
| Panther Pathway | [+] 4 Panther Pathways | + | ||||
| 1 | Huntington disease | |||||
| 2 | Ionotropic glutamate receptor pathway | |||||
| 3 | Metabotropic glutamate receptor group III pathway | |||||
| 4 | Metabotropic glutamate receptor group I pathway | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Development of medications for alcohol use disorders: recent advances and ongoing challenges. Expert Opin Emerg Drugs. 2005 May;10(2):323-43. | |||||
| 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: 6849). | |||||
| REF 3 | Use of second-generation antiepileptic drugs in the pediatric population. Paediatr Drugs. 2008;10(4):217-54. | |||||
| REF 4 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 5 | 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: 4245). | |||||
| REF 6 | Pharmacogenetics of new analgesics. Br J Pharmacol. 2011 Jun;163(3):447-60. | |||||
| REF 7 | The efficacy of the AMPA receptor antagonist NS1209 and lidocaine in nerve injury pain: a randomized, double-blind, placebo-controlled, three-way crossover study. Anesth Analg. 2009 Apr;108(4):1311-9. | |||||
| REF 8 | Emerging drugs for epilepsy. Expert Opin Emerg Drugs. 2007 Sep;12(3):407-22. | |||||
| REF 9 | 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: 4264). | |||||
| REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002155) | |||||
| REF 11 | 4,10-Dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives: highly potent and selective AMPA receptors antagonists with... Bioorg Med Chem Lett. 2000 May 15;10(10):1133-7. | |||||
| REF 12 | Chemo-enzymatic synthesis of a series of 2,4-syn-functionalized (S)-glutamate analogues: new insight into the structure-activity relation of ionotr... J Med Chem. 2008 Jul 24;51(14):4093-103. | |||||
| REF 13 | 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: 450). | |||||
| REF 14 | Bioisosteric modifications of 2-arylureidobenzoic acids: selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5. J Med Chem. 2004 Dec 30;47(27):6948-57. | |||||
| REF 15 | 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological charact... J Med Chem. 2010 May 27;53(10):4110-8. | |||||
| REF 16 | Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human exci... J Med Chem. 2008 Jul 24;51(14):4085-92. | |||||
| REF 17 | Synthesis of chiral 1-(2'-amino-2'-carboxyethyl)-1,4-dihydro-6,7-quinoxaline-2,3-diones: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate recep... J Med Chem. 1996 Oct 25;39(22):4430-8. | |||||
| REF 18 | 3-Substituted phenylalanines as selective AMPA- and kainate receptor ligands. Bioorg Med Chem. 2009 Sep 1;17(17):6390-401. | |||||
| REF 19 | Synthesis, ionotropic glutamate receptor binding affinity, and structure-activity relationships of a new set of 4,5-dihydro-8-heteroaryl-4-oxo-1,2,... J Med Chem. 2001 Sep 13;44(19):3157-65. | |||||
| REF 20 | Structural investigation of the 7-chloro-3-hydroxy-1H-quinazoline-2,4-dione scaffold to obtain AMPA and kainate receptor selective antagonists. Syn... J Med Chem. 2006 Oct 5;49(20):6015-26. | |||||
| REF 21 | Mapping the ligand binding sites of kainate receptors: molecular determinants of subunit-selective binding of the antagonist [3H]UBP310. Mol Pharmacol. 2010 Dec;78(6):1036-45. | |||||
| REF 22 | Binding and selectivity of the marine toxin neodysiherbaine A and its synthetic analogues to GluK1 and GluK2 kainate receptors. J Mol Biol. 2011 Oct 28;413(3):667-83. | |||||
| REF 23 | GluK1 antagonists from 6-(tetrazolyl)phenyl decahydroisoquinoline derivatives: in vitro profile and in vivo analgesic efficacy. Bioorg Med Chem Lett. 2013 Dec 1;23(23):6463-6. | |||||
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