Target Information
| Target General Information | Top | |||||
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| Target ID |
T73482
(Former ID: TTDC00153)
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| Target Name |
Orexin receptor type 1 (HCRTR1)
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| Synonyms |
Ox1r; Ox1-R; Ox-1-R; Orexin-1 receptor; Hypocretin receptor type 1; HFGAN72 receptor; 7-transmembrane G-protein coupledneuropeptide receptor
Click to Show/Hide
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| Gene Name |
HCRTR1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Depression [ICD-11: 6A70-6A7Z] | |||||
| 2 | Insomnia [ICD-11: 7A00-7A0Z] | |||||
| 3 | Opioid use disorder ICD-11: 6C43 | |||||
| Function |
Triggers an increase in cytoplasmic Ca(2+) levels in response to orexin-A binding. Moderately selective excitatory receptor for orexin-A and, with a lower affinity, for orexin-B neuropeptide.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MEPSATPGAQMGVPPGSREPSPVPPDYEDEFLRYLWRDYLYPKQYEWVLIAAYVAVFVVA
LVGNTLVCLAVWRNHHMRTVTNYFIVNLSLADVLVTAICLPASLLVDITESWLFGHALCK VIPYLQAVSVSVAVLTLSFIALDRWYAICHPLLFKSTARRARGSILGIWAVSLAIMVPQA AVMECSSVLPELANRTRLFSVCDERWADDLYPKIYHSCFFIVTYLAPLGLMAMAYFQIFR KLWGRQIPGTTSALVRNWKRPSDQLGDLEQGLSGEPQPRARAFLAEVKQMRARRKTAKML MVVLLVFALCYLPISVLNVLKRVFGMFRQASDREAVYACFTFSHWLVYANSAANPIIYNF LSGKFREQFKAAFSCCLPGLGPCGSLKAPSPRSSASHKSLSLQSRCSISKISEHVVLTSV TTVLP Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | JNJ-61393215 | Drug Info | Phase 2 | Major depressive disorder | [2] | |
| 2 | SB-649868 | Drug Info | Phase 2 | Insomnia | [3], [4] | |
| 3 | AZD4041 | Drug Info | Phase 1 | Opioid use disorder | [5] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | Almorexant | Drug Info | Terminated | Insomnia | [6], [7] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Antagonist | [+] 42 Antagonist drugs | + | ||||
| 1 | JNJ-61393215 | Drug Info | [8] | |||
| 2 | SB-649868 | Drug Info | [1] | |||
| 3 | AZD4041 | Drug Info | [9] | |||
| 4 | 1,2-diamino cyclopentane-based derivative 1 | Drug Info | [10] | |||
| 5 | 1,2-diamino cyclopentane-based derivative 10 | Drug Info | [10] | |||
| 6 | 1,2-diamino cyclopentane-based derivative 11 | Drug Info | [10] | |||
| 7 | 1,2-diamino cyclopentane-based derivative 12 | Drug Info | [10] | |||
| 8 | 1,2-diamino cyclopentane-based derivative 13 | Drug Info | [10] | |||
| 9 | 1,2-diamino cyclopentane-based derivative 14 | Drug Info | [10] | |||
| 10 | 1,2-diamino cyclopentane-based derivative 15 | Drug Info | [10] | |||
| 11 | 1,2-diamino cyclopentane-based derivative 16 | Drug Info | [10] | |||
| 12 | 1,2-diamino cyclopentane-based derivative 17 | Drug Info | [10] | |||
| 13 | 1,2-diamino cyclopentane-based derivative 18 | Drug Info | [10] | |||
| 14 | 1,2-diamino cyclopentane-based derivative 19 | Drug Info | [10] | |||
| 15 | 1,2-diamino cyclopentane-based derivative 2 | Drug Info | [10] | |||
| 16 | 1,2-diamino cyclopentane-based derivative 20 | Drug Info | [10] | |||
| 17 | 1,2-diamino cyclopentane-based derivative 21 | Drug Info | [10] | |||
| 18 | 1,2-diamino cyclopentane-based derivative 22 | Drug Info | [10] | |||
| 19 | 1,2-diamino cyclopentane-based derivative 23 | Drug Info | [10] | |||
| 20 | 1,2-diamino cyclopentane-based derivative 24 | Drug Info | [10] | |||
| 21 | 1,2-diamino cyclopentane-based derivative 25 | Drug Info | [10] | |||
| 22 | 1,2-diamino cyclopentane-based derivative 26 | Drug Info | [10] | |||
| 23 | 1,2-diamino cyclopentane-based derivative 27 | Drug Info | [10] | |||
| 24 | 1,2-diamino cyclopentane-based derivative 29 | Drug Info | [10] | |||
| 25 | 1,2-diamino cyclopentane-based derivative 3 | Drug Info | [10] | |||
| 26 | 1,2-diamino cyclopentane-based derivative 30 | Drug Info | [10] | |||
| 27 | 1,2-diamino cyclopentane-based derivative 31 | Drug Info | [10] | |||
| 28 | 1,2-diamino cyclopentane-based derivative 32 | Drug Info | [10] | |||
| 29 | 1,2-diamino cyclopentane-based derivative 33 | Drug Info | [10] | |||
| 30 | 1,2-diamino cyclopentane-based derivative 34 | Drug Info | [10] | |||
| 31 | 1,2-diamino cyclopentane-based derivative 4 | Drug Info | [10] | |||
| 32 | 1,2-diamino cyclopentane-based derivative 5 | Drug Info | [10] | |||
| 33 | 1,2-diamino cyclopentane-based derivative 6 | Drug Info | [10] | |||
| 34 | 1,2-diamino cyclopentane-based derivative 7 | Drug Info | [10] | |||
| 35 | 1,2-diamino cyclopentane-based derivative 8 | Drug Info | [10] | |||
| 36 | 1,2-diamino cyclopentane-based derivative 9 | Drug Info | [10] | |||
| 37 | Almorexant | Drug Info | [11], [12] | |||
| 38 | PMID15261275C1 | Drug Info | [14] | |||
| 39 | SB-334867 | Drug Info | [11] | |||
| 40 | SB-408124 | Drug Info | [11] | |||
| 41 | SB-410220 | Drug Info | [15] | |||
| 42 | [3H]SB-674042 | Drug Info | [16] | |||
| Agonist | [+] 1 Agonist drugs | + | ||||
| 1 | orexin-B | Drug Info | [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: Lemborexant | Ligand Info | |||||
| Structure Description | Crystal structure of the Orexin-1 receptor in complex with lemborexant | PDB:6TOT | ||||
| Method | X-ray diffraction | Resolution | 2.22 Å | Mutation | Yes | [17] |
| PDB Sequence |
SEDEFLRYLW
36 RDYLYPKQYA46 WVLIAAYVAV56 FVVALVGNTL66 VCLAVWRNHH76 MRTVTNYFLV 86 NLSLADVLAT96 AICLPASLLV106 DITESWLFGH116 ALCKVIPYLQ126 AVSVSVAVLT 136 LSFIALDRWY146 AICHPLLFKS156 TARRALGSIL166 GIWAVSLAIM176 VPQAAVMECS 186 SVRAFSVCDE204 RWADDLAPKI214 YHSCFFIVTY224 LAPLGLMAMA234 YFQIFRKLWE 286 VKQMRARRKT296 AKMLMVVVLV306 FALCYLPISV316 LNVLKRVFGM326 FRQASDREAV 336 YAAFTFSHWL346 VYANSAANPI356 IYNFLSGKFR366 EQFKAAFSWW376 |
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CYS99
3.701
ALA102
3.563
SER103
2.776
VAL106
3.124
ASP107
3.557
TRP112
3.622
ILE122
3.731
PRO123
3.227
GLN126
2.516
ALA127
3.661
VAL130
3.306
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| Ligand Name: Suvorexant | Ligand Info | |||||
| Structure Description | Crystal structure of the Orexin-1 receptor in complex with suvorexant at 2.29 A resolution | PDB:6TO7 | ||||
| Method | X-ray diffraction | Resolution | 2.26 Å | Mutation | Yes | [17] |
| PDB Sequence |
YAWVLIAAYV
54 AVFVVALVGN64 TLVCLAVWRN74 HHMRTVTNYF84 LVNLSLADVL94 ATAICLPASL 104 LVDITESWLF114 GHALCKVIPY124 LQAVSVSVAV134 LTLSFIALDR144 WYAICHPLLF 154 KSTARRALGS164 ILGIWAVSLA174 IMVPQAAVME184 CSSVLPELAA194 RTRAFSVCDE 204 RWADDLAPKI214 YHSCFFIVTY224 LAPLGLMAMA234 YFQIFRKLWG244 RIPGTTSAEV 287 KQMRARRKTA297 KMLMVVVLVF307 ALCYLPISVL317 NVLKRVFGMF327 RQASDREAVY 337 AAFTFSHWLV347 YANSAANPII357 YNFLSGKFRE367 QFKAAFSWWL377 |
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CYS99
4.098
ALA102
3.562
SER103
3.530
VAL106
3.635
TRP112
3.506
ILE122
3.723
PRO123
3.516
GLN126
3.236
ALA127
4.298
VAL130
3.567
GLN179
3.448
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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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| 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 | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.43E-04 | Radiality | 5.80E-03 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 2.00E+00 | Topological coefficient | 1.00E+00 | Eccentricity | 2 |
| 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 Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | G alpha (q) signalling events | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | GPCRs, Class A Rhodopsin-like | |||||
| 2 | Gastrin-CREB signalling pathway via PKC and MAPK | |||||
| 3 | GPCR ligand binding | |||||
| 4 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of GlaxoSmithKline (2009). | |||||
| REF 2 | ClinicalTrials.gov (NCT04080752) A Study of JNJ-61393215 in the Treatment of Depression. U.S. National Institutes of Health. | |||||
| REF 3 | 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: 4461). | |||||
| REF 4 | ClinicalTrials.gov (NCT00426816) To Evaluate The Effects Of SB-649868 (10, 30 Mg And 60 Mg) On Subjects With Primary Insomnia. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT05587998) A Randomized, Double-blind, Placebo-controlled, Fixed Sequence Study to Assess the Effect on Respiratory Drive of Multiple Doses of AZD4041 When Co-administered With a Single Dose of Morphine in Healthy Recreational Opioid Users. U.S.National Institutes of Health. | |||||
| REF 6 | 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: 2886). | |||||
| REF 7 | Emerging drugs for eating disorder treatment. Expert Opin Emerg Drugs. 2006 May;11(2):315-36. | |||||
| REF 8 | Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans. Transl Psychiatry. 2020 Sep 7;10(1):308. | |||||
| REF 9 | Clinical pipeline report, company report or official report of AstraZeneca | |||||
| REF 10 | Substituted cyclopentanes, tetrahydrofurans and pyrrolidines as orexin-1-receptor antagonists for treatment of various CNS disorders (WO2015/055994; WO2015/124932; WO2015/124934).Expert Opin Ther Pat. 2016;26(3):409-15. | |||||
| REF 11 | Biochemical and electrophysiological characterization of almorexant, a dual orexin 1 receptor (OX1)/orexin 2 receptor (OX2) antagonist: comparison ... Mol Pharmacol. 2009 Sep;76(3):618-31. | |||||
| REF 12 | Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat. J Pharmacol Exp Ther. 2009 Jul;330(1):142-51. | |||||
| REF 13 | Agonist ligand discrimination by the two orexin receptors depends on the expression system. Neurosci Lett. 2011 Apr 20;494(1):57-60. | |||||
| REF 14 | Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4225-9. | |||||
| REF 15 | Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br J Pharmacol. 2004 Jan;141(2):340-6. | |||||
| REF 16 | Mapping the binding pocket of dual antagonist almorexant to human orexin 1 and orexin 2 receptors: comparison with the selective OX1 antagonist SB-674042 and the selective OX2 antagonist N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). Mol Pharmacol. 2010 Jul;78(1):81-93. | |||||
| REF 17 | Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis. J Med Chem. 2020 Feb 27;63(4):1528-1543. | |||||
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