Target Information
| Target General Information | Top | |||||
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| Target ID |
T69485
(Former ID: TTDR01056)
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| Target Name |
Orexin receptor type 2 (HCRTR2)
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| Synonyms |
Ox2r; Ox2-R; Ox-2-R; Orexin-2 receptor; Hypocretin receptor type 2; HFGANP
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| Gene Name |
HCRTR2
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Insomnia [ICD-11: 7A00-7A0Z] | |||||
| Function |
Triggers an increase in cytoplasmic Ca(2+) levels in response to orexin-A binding. Nonselective, high-affinity receptor for both orexin-A and orexin-B neuropeptides.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MSGTKLEDSPPCRNWSSASELNETQEPFLNPTDYDDEEFLRYLWREYLHPKEYEWVLIAG
YIIVFVVALIGNVLVCVAVWKNHHMRTVTNYFIVNLSLADVLVTITCLPATLVVDITETW FFGQSLCKVIPYLQTVSVSVSVLTLSCIALDRWYAICHPLMFKSTAKRARNSIVIIWIVS CIIMIPQAIVMECSTVFPGLANKTTLFTVCDERWGGEIYPKMYHICFFLVTYMAPLCLMV LAYLQIFRKLWCRQIPGTSSVVQRKWKPLQPVSQPRGPGQPTKSRMSAVAAEIKQIRARR KTARMLMIVLLVFAICYLPISILNVLKRVFGMFAHTEDRETVYAWFTFSHWLVYANSAAN PIIYNFLSGKFREEFKAAFSCCCLGVHHRQEDRLTRGRTSTESRKSLTTQISNFDNISKL SEQVVLTSISTLPAANGAGPLQNW 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 | Suvorexant | Drug Info | Approved | Insomnia | [1], [2], [3] | |
| Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
| 1 | MIN-202 | Drug Info | Phase 2 | Major depressive disorder | [4] | |
| 2 | MK-3697 | Drug Info | Phase 2 | Insomnia | [5] | |
| 3 | TAK-861 | Drug Info | Phase 2 | Narcolepsy type 1 | [6] | |
| 4 | TAK-925 | Drug Info | Phase 1 | Narcolepsy | [7] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 3 Modulator drugs | + | ||||
| 1 | Suvorexant | Drug Info | [1] | |||
| 2 | MK-3697 | Drug Info | [9] | |||
| 3 | JNJ-10397049 | Drug Info | [14] | |||
| Antagonist | [+] 40 Antagonist drugs | + | ||||
| 1 | MIN-202 | Drug Info | [8] | |||
| 2 | 1,2-diamino cyclopentane-based derivative 1 | Drug Info | [12] | |||
| 3 | 1,2-diamino cyclopentane-based derivative 10 | Drug Info | [12] | |||
| 4 | 1,2-diamino cyclopentane-based derivative 11 | Drug Info | [12] | |||
| 5 | 1,2-diamino cyclopentane-based derivative 12 | Drug Info | [12] | |||
| 6 | 1,2-diamino cyclopentane-based derivative 13 | Drug Info | [12] | |||
| 7 | 1,2-diamino cyclopentane-based derivative 14 | Drug Info | [12] | |||
| 8 | 1,2-diamino cyclopentane-based derivative 15 | Drug Info | [12] | |||
| 9 | 1,2-diamino cyclopentane-based derivative 16 | Drug Info | [12] | |||
| 10 | 1,2-diamino cyclopentane-based derivative 17 | Drug Info | [12] | |||
| 11 | 1,2-diamino cyclopentane-based derivative 18 | Drug Info | [12] | |||
| 12 | 1,2-diamino cyclopentane-based derivative 19 | Drug Info | [12] | |||
| 13 | 1,2-diamino cyclopentane-based derivative 2 | Drug Info | [12] | |||
| 14 | 1,2-diamino cyclopentane-based derivative 20 | Drug Info | [12] | |||
| 15 | 1,2-diamino cyclopentane-based derivative 21 | Drug Info | [12] | |||
| 16 | 1,2-diamino cyclopentane-based derivative 22 | Drug Info | [12] | |||
| 17 | 1,2-diamino cyclopentane-based derivative 23 | Drug Info | [12] | |||
| 18 | 1,2-diamino cyclopentane-based derivative 24 | Drug Info | [12] | |||
| 19 | 1,2-diamino cyclopentane-based derivative 25 | Drug Info | [12] | |||
| 20 | 1,2-diamino cyclopentane-based derivative 26 | Drug Info | [12] | |||
| 21 | 1,2-diamino cyclopentane-based derivative 27 | Drug Info | [12] | |||
| 22 | 1,2-diamino cyclopentane-based derivative 29 | Drug Info | [12] | |||
| 23 | 1,2-diamino cyclopentane-based derivative 3 | Drug Info | [12] | |||
| 24 | 1,2-diamino cyclopentane-based derivative 30 | Drug Info | [12] | |||
| 25 | 1,2-diamino cyclopentane-based derivative 31 | Drug Info | [12] | |||
| 26 | 1,2-diamino cyclopentane-based derivative 32 | Drug Info | [12] | |||
| 27 | 1,2-diamino cyclopentane-based derivative 33 | Drug Info | [12] | |||
| 28 | 1,2-diamino cyclopentane-based derivative 34 | Drug Info | [12] | |||
| 29 | 1,2-diamino cyclopentane-based derivative 4 | Drug Info | [12] | |||
| 30 | 1,2-diamino cyclopentane-based derivative 5 | Drug Info | [12] | |||
| 31 | 1,2-diamino cyclopentane-based derivative 6 | Drug Info | [12] | |||
| 32 | 1,2-diamino cyclopentane-based derivative 7 | Drug Info | [12] | |||
| 33 | 1,2-diamino cyclopentane-based derivative 8 | Drug Info | [12] | |||
| 34 | 1,2-diamino cyclopentane-based derivative 9 | Drug Info | [12] | |||
| 35 | EMPA | Drug Info | [13] | |||
| 36 | PMID15261275C1 | Drug Info | [16] | |||
| 37 | SB-334867 | Drug Info | [17] | |||
| 38 | SB-408124 | Drug Info | [17] | |||
| 39 | TCS-OX2-29 | Drug Info | [18] | |||
| 40 | [3H]SB-674042 | Drug Info | [17] | |||
| Agonist | [+] 3 Agonist drugs | + | ||||
| 1 | TAK-861 | Drug Info | [10] | |||
| 2 | TAK-925 | Drug Info | [11] | |||
| 3 | orexin-B | Drug Info | [15] | |||
| 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: Oleic acid | Ligand Info | |||||
| Structure Description | Structure of the orexin-2 receptor(OX2R) bound to TAK-925, Gi and scFv16 | PDB:7SQO | ||||
| Method | Electron microscopy | Resolution | 3.17 Å | Mutation | No | [11] |
| PDB Sequence |
WVLIAGYIIV
64 FVVALIGNVL74 VCVAVWKNHH84 MRTVTNYFIV94 NLSLADVLVT104 ITCLPATLVV 114 DITETWFFGQ124 SLCKVIPYLQ134 TVSVSVSVLT144 LSCIALDRWY154 AICHPLMFKS 164 TAKRARNSIV174 IIWIVSCIIM184 IPQAIVMECS194 TVCDERWGGE217 IYPKMYHICF 227 FLVTYMAPLC237 LMVLAYLQIF247 RKLWCRQIIK294 QIRARRKTAR304 MLMVVLLVFA 314 ICYLPISILN324 VLKRVFGMFR339 ETVYAWFTFS349 HWLVYANSAA359 NPIIYNFLSG 369 KFREEFKAAF379
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PHE92
4.984
LEU143
2.331
SER146
3.351
CYS147
2.911
LEU150
2.595
TRP153
2.437
TYR154
3.240
HIS158
3.770
MET161
4.128
LYS163
4.473
ARG168
3.787
ASN171
4.258
SER172
2.520
ILE175
2.534
ILE176
2.913
VAL179
3.870
ILE183
4.628
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| Ligand Name: Danavorexton | Ligand Info | |||||
| Structure Description | Structure of the orexin-2 receptor(OX2R) bound to TAK-925, Gi and scFv16 | PDB:7SQO | ||||
| Method | Electron microscopy | Resolution | 3.17 Å | Mutation | No | [11] |
| PDB Sequence |
WVLIAGYIIV
64 FVVALIGNVL74 VCVAVWKNHH84 MRTVTNYFIV94 NLSLADVLVT104 ITCLPATLVV 114 DITETWFFGQ124 SLCKVIPYLQ134 TVSVSVSVLT144 LSCIALDRWY154 AICHPLMFKS 164 TAKRARNSIV174 IIWIVSCIIM184 IPQAIVMECS194 TVCDERWGGE217 IYPKMYHICF 227 FLVTYMAPLC237 LMVLAYLQIF247 RKLWCRQIIK294 QIRARRKTAR304 MLMVVLLVFA 314 ICYLPISILN324 VLKRVFGMFR339 ETVYAWFTFS349 HWLVYANSAA359 NPIIYNFLSG 369 KFREEFKAAF379
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VAL103
4.977
CYS107
3.611
ALA110
3.455
THR111
3.136
VAL114
2.317
TRP120
3.696
PRO131
2.877
GLN134
2.490
THR135
2.681
VAL138
2.489
GLN187
3.027
CYS210
4.961
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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 | 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81. | |||||
| 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: 2890). | |||||
| REF 3 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 4 | ClinicalTrials.gov (NCT02464046) Study to Evaluate Efficacy, Safety and Tolerability of JNJ-42847922 in Participants With Insomnia Disorder Without Psychiatric Comorbidity. | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800033199) | |||||
| REF 6 | ClinicalTrials.gov (NCT05687903) A Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-861 for the Treatment of Narcolepsy With Cataplexy (Narcolepsy Type 1). U.S.National Institutes of Health. | |||||
| REF 7 | ClinicalTrials.gov (NCT03748979) A 3-Part, Randomized, Double-Blind, Placebo-Controlled, Multiple Rising Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TAK-925 in Healthy Volunteers and Patients With Narcolepsy. U.S.National Institutes of Health. | |||||
| REF 8 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 9 | Discovery of MK-3697: a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia. Bioorg Med Chem Lett. 2014 Oct 15;24(20):4884-90. | |||||
| REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2023. Adis Insight | |||||
| REF 11 | Molecular mechanism of the wake-promoting agent TAK-925. Nat Commun. 2022 May 25;13(1):2902. | |||||
| REF 12 | 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 13 | Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX(2) receptor. Br J Pharmacol. 2009 Apr;156(8):1326-41. | |||||
| REF 14 | 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: 322). | |||||
| REF 15 | The signalling profile of recombinant human orexin-2 receptor. Cell Signal. 2008 Sep;20(9):1651-61. | |||||
| REF 16 | 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 17 | 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 18 | N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: the first orexin-2 receptor selective non-peptidic antagonist. Bioorg Med Chem Lett. 2003 Dec 15;13(24):4497-9. | |||||
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